The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

Oxidative stress biomarkers and otoacoustic emissions in humans exposed to styrene and noise.

OBJECTIVE: Evaluating the correlation between otoacoustic emission levels, styrene exposure, and oxidative stress biomarkers concentration in styrene-exposed subjects, to investigate the role of oxidative stress in outer hair cell damage. DESIGN: Distortion product otoacoustic emissions were measured in the exposed workers and in a control group. Separation between the distortion and reflection otoacoustic components was performed by time-frequency-domain filtering. The urinary concentration of the DNA and RNA oxidation products, namely 8-oxo-7,8-dihydroguanine (oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxodGuo), and 8-oxo-7,8-dihydroguanosine (oxoGuo), were evaluated. STUDY SAMPLE: Nine subjects exposed to styrene in a fiberglass factory, eight control subjects. The two groups were statistically equivalent in mean age. RESULTS: Statistically significant differences were found in the distortion component levels between the exposed and the control group. High levels of the oxidative damage biomarkers were found in the workers exposed to high levels of styrene. Significant negative correlation was found between the otoacoustic emission distortion component levels and the concentration of the oxoGuo biomarker. CONCLUSIONS: Exposure-induced damage of the cochlear amplifier is shown in the mid-frequency range, confirming animal experiments, in which hair cells in the cochlear middle turn were damaged. Hearing damage is consistent with the outer hair cell apoptosis pathway associated with oxidative stress.

Trends in colorectal incidence by anatomic subsite from 1985 to 2005: a population-based study.

BACKGROUND: Conflicting results on the shift of right-left ratio in colon cancer incidence have been reported. We examine incidence trends by subsite in a population-based study. MATERIALS AND METHODS: Colorectal cancer cases diagnosed in the 1985-2005 period were identified through the Tuscany Cancer Registry. Colon subsite was defined as proximal and distal; gender, age at diagnosis, histology, and stage were analyzed. Average annual incidence and age-specific rates according to subsite were calculated. RESULTS: A total of 21,160 colorectal cancer cases were extracted; in 18,311 cases, the subsite was identified: 6,916 rectal, 5,239 proximal, and 6,156 distal. A larger proportion of distal colon cancers presented as early stage when compared with proximal. Incidence of rectal and distal colon cancer remained stable, while proximal colon cancer incidence increased. CONCLUSIONS: Proximal colon cancer incidence rate increased through the period. Temporal variations in the incidence rate by subsite could suggest different carcinogenic pathways of right- and left-sided colon cancer.

Otoacoustic emission sensitivity to exposure to styrene and noise.

The ototoxic effect of the exposure to styrene is evaluated, also in the presence of simultaneous exposure to noise, using otoacoustic emissions as biomarkers of mild cochlear damage. Transient-evoked and distortion product otoacoustic emissions were recorded and analyzed in a sample of workers (15 subjects) exposed to styrene and noise in a fiberglass manufacturing facility and in a control group of 13 non-exposed subjects. Individual exposure monitoring of the airborne styrene concentrations was performed, as well as biological monitoring, based on the urinary concentration of two styrene metabolites, the Mandelic and Phenylglyoxylic acids. Noise exposure was evaluated using wearable phonometers, and hearing loss with pure tone audiometry. Due to their different job tasks, one group of workers was exposed to high noise and low styrene levels, another group to higher styrene levels, close to the limit of 20 ppm, and to low noise levels. A significant negative correlation was found between the otoacoustic emission levels and the concentration of the styrene urinary metabolites. Otoacoustic emissions, and particularly distortion products, were able to discriminate the exposed workers from the controls, providing also a rough estimate of the slope of the dose-response relation between otoacoustic levels and styrene exposure.

Does an organised screening programme reduce the inequalities in breast cancer survival?

BACKGROUND: The aim of the present study was to examine whether the implementation of an organised mammographic screening programme in Florence has been successful in reducing socioeconomic inequalities in breast cancer survival. PATIENTS AND METHODS: All invasive breast cancer cases diagnosed in women resident in the city of Florence in a prescreening period and in the first 10 years of the screening programme were selected. Their socioeconomic status (SES) was determined by using the national census 2001 data. All breast cancers were followed up to 10 years after the diagnosis. RESULTS: In the prescreening period, the survival of deprived women was 12 percentage points lower than the reference class, both in the younger age class (<50 years old) and in the age class target of the screening programme (50-69 years old). This difference progressively decreases until disappearing completely during the first 10 years of the screening programme for the age class invited to screening, whereas it remains stable in the younger age class. Participation in breast cancer screening and diagnostic accuracy were similar by SES. CONCLUSION: The organised breast cancer screening implemented in the Florentine area achieved the goal of reducing inequalities in breast cancer survival.

Occupational exposure to styrene in the fibreglass reinforced plastic industry: comparison between two different manufacturing processes.

BACKGROUND: Styrene is used in manufacturing fiberglass reinforced plastics: and occupational exposure was related to neurotoxicology and genotoxicity. The sum of the metabolites mandelic and phenylglyoxylic acids is the ACGIH biomarker for occupational exposure with a BEI of 400 mg/g of creatinine in end shift urine corresponding to a airborne styrene concentration of 85 mg/m3. There are two main molding processes, open and closed, the last more effective at controlling worker's styrene exposure. OBJECTIVES: To compare the open molding process to the compression of fiber reinforced resin foils, a kind of closed molding, monitoring the styrene exposure of workers in two production sites (A and B). METHODS: Environmental Monitoring was carried out by Radiello samplers and Biological Monitoring by means of the determination of MA and PGA with HPLC/MS/MS in 10 workers at Site A and 14 at Site B. RESULTS: The median values for styrene exposure resulted 31.1 mg/m3 for Site A and 24.4 mg/m for Site B, while the medians for the sum of the two metabolites in the end shift urine were 86.7 e 33.8 mg/g creatinine respectively. There is a significant linear correlation between personal styrene exposure and the excretion of styrene metabolites (R = 0.74). CONCLUSIONS: As expected the exposure markers of the workers of the two production sites resulted higher in the open process. The analytical results of both environmental and biological monitoring were all below the occupational exposure limits, confirming the efficacy of the protective devices.

Breast cancer screening case-control study design: impact on breast cancer mortality.

BACKGROUND: Recent case-control studies on the effectiveness of population-based breast cancer screening show differences in the magnitude of breast cancer mortality reduction. We investigated the role played by aspects of the case-control study design on these differences, e.g. the definition of cases and exposure to screening. MATERIAL AND METHODS: We investigated six case-control studies conducted in East Anglia (UK), Wales, Iceland, central and northern Italy, South Australia and The Netherlands. RESULTS: The breast cancer mortality reduction in the different case-control studies ranged from 38% to 70% in the screened versus the nonscreened women. We identified differences in design, e.g. the inclusion or exclusion of the first years of screening, and the correction factor for self-selection bias. CONCLUSIONS: Overall, the design of the case-control studies was similar. The differences in the magnitude of breast cancer mortality reductions are therefore unlikely to be caused by variations in the design of the case-control studies. These differences must be due to other factors, like the organisation of the service screening programme and the attendance rate. The reduction in breast cancer mortality estimated in these case-control studies indicates that the impact of current mammographic screening is at least consistent with the effect reported by the former randomised screening trials.

[Biological monitoring of the PAH exposure in the hardening of metals]. / Monitoraggio biologico dell'esposizione ad IPA nella tempra dei metalli.

The hardening of metals involves the immersion of hot components in mineral oil with production of aerosols containing PAHs, to wich workers can be exposed. The determination of airborne PAHs and urinary 1-hydroxypyrene (1-OHPy) was performed for a group of workers and the latter resulted within the reference values. However, the average 1-OHPy concentration on metal workers (0.07 microg/g creatinine) was statistically different from the average value obtained for a group of employees (0.03 microg/g creatinine), highlighting the risk of exposure to PAHs. Therefore, being these potentially carcinogenic compounds, interventions were prescribed in order to reduce the risk of occupational exposure.

[Synergistic exposure to noise and styrene and cochlear functionality in a sample of exposed workers: preliminary results]. / Esposizione sinergica a rumore e stirene e funzionalità cocleare in un campione di lavoratori esposti: risultati preliminari.

This study is aimed at testing the cochlear functionality using otoacoustic emissions, analyzing the synergistic effects of simultaneous exposure to noise and organic solvents EBTx on workers of a glass-reinforced plastic products factory. Exposure to organic solvents was assessed using ambiental measurements and evaluation of the salivary concentration. Biological monitoring was performed evaluating the urinary concentration of the styrene metabolites. Statistical analysis shows that otoacoustic tests can discriminate between different exposure groups. Significant differences were found between controls and subjects exposed to high styrene and low noise levels, showing the ototoxic effect (at sub-clinical level) of the styrene exposure.

CHARMM: the biomolecular simulation program.

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

Effectiveness of service screening: a case-control study to assess breast cancer mortality reduction.

The aim of this study was the evaluation of the impact of service screening programmes on breast cancer mortality in five regions of Italy. We conducted a matched case-control study with four controls for each case. Cases were defined as breast cancer deaths occurred not later than 31 December 2002. Controls were sampled from the local municipality list and matched by date of birth. Screening histories were assessed by the local, computerised, screening database and subjects were classified as either invited or not-yet-invited and as either screened or unscreened. There were a total of 1750 breast cancer deaths within the 50 to 74-year-old breast cancer cases and a total of 7000 controls. The logistic conditional estimate of the cumulative odds ratios comparing invited with not-yet-invited women was 0.75 (95% CI: 0.62-0.92). Restricting the analyses to invited women, the odds ratio of screened to never-respondent women corrected for self-selection bias was 0.55 (95% CI: 0.36-0.85). The introduction of breast cancer screening programmes in Italy is associated with a reduction in breast cancer mortality attributable to the additional impact of service screening over and above the background access to mammography.

Gender differences in non-small cell lung cancer: a population-based study.

BACKGROUND: A retrospective study including all patients with non-small cell lung cancer carcinoma in a population-based registry was performed to characterize gender differences in lung cancer and to analyze the factors influencing prognosis in women. METHODS: We retrieved through the Tuscan Cancer Registry (RTT) archive 2,523 lung tumor cases diagnosed during the period 1996-1998 in the provinces of Florence and Prato, central Italy. We compared the prognosis within 464 non-small lung cancer women and 1,798 men in a population-based case series. The influence of the following variables on postoperative survival were analyzed: age, cell type, pathologic T and N status, site of tumor and type of surgical resection. RESULTS: The age at diagnosis was similar in women and in men. Women were significantly more likely to have adenocarcinoma but less likely to have squamous cell carcinoma compared with men. Fewer pneumonectomies were performed in women than in men. Nevertheless, prognosis was similar in both sexes and type of surgical resection was significant prognostic factor. CONCLUSIONS: Lung cancer was more frequent in men than in women, but overall survival is similar. Differences in lung cancer histology and rate of pneumonectomies were found between men and women.

Gastric cancer after positive screening faecal occult blood testing and negative assessment.

BACKGROUND: Gastric cancer may be suspected with otherwise unexplained positive faecal occult blood testing. AIMS: To assess the frequency of gastric cancer following positive faecal occult blood testing and negative colonoscopy. SUBJECTS: Age 40-74 cohort at first screening (1985-2001) with (a) faecal occult blood testing- (83,489), (b) faecal occult blood testing +/colonoscopy+ (2025), or faecal occult blood testing+/colonoscopy- (3555). METHODS: Gastric cancer incidence in faecal occult blood testing subsets, compared with expected standardized incidence rates. RESULTS: Gastric cancer risk was increased (standardized incidence rate=146.7; 95% confidence interval: 105.8-203.4) in faecal occult blood testing+/colonoscopy- subjects. A four-fold excess incidence occurred during first year (observed cases=10, standardized incidence rate=408.3; 95% confidence interval: 219.7-758.8), irrespective of faecal occult blood testing type (guaiac, immunological). No excess risk occurred in faecal occult blood testing- (observed cases=53, standardized incidence rate=91.2; 95% confidence interval: 84.1-98.8) or in faecal occult blood testing+/colonoscopy+ subjects (observed cases=2, standardized incidence rate=101.9; 95% confidence interval: 25.5-407.4). Assuming a 100% 3-year study sensitivity for gastric cancer, faecal occult blood testing positive predictive value would be 0.4% (40-74 years) or 0.7% (> or =60 years) in faecal occult blood testing+/colonoscopy- subjects. CONCLUSIONS: Data suggest an association of faecal occult blood testing+/colonoscopy- and excess gastric cancer incidence in the following year. Due to low faecal occult blood testing+ positive predictive value, routine upper digestive tract endoscopy in these subjects is questionable.

[Isotopic dilution HPLC/MS/MS urinary trans, trans-muconic quantitative analysis among refinery workers]. / Determinazione quantitativa di acido trans, trans-muconico nelle urine dei lavoratori di una raffineria mediante HPLC/MS/MS con diluizione isotopica.

The determination of trans, trans muconic acid (t,t-MA) in human urine, a biomarker suggested by the American Conference of Governmental Industrial Hygienists for occupational benzene exposure, with a limit value of 500 microg/g creatinine, is usually performed by means of gas or liquid chromatographic methods. Almost all the HPLC methods make use of strong ionic exchange cartridges for sample cleaning, reverse phase separation and detection either by UV at lambda = 259 nm or; more recently, by electrospray tandem mass spectrometry: yet, not all of these methods have been validated for quantitative analysis considering also the matrix effect. This paper presents the quantitative analysis of t,t-MA in 94 end-shift urine samples from workers of an oil refinery performed by means of an HPLC/MS/MS analytical method that uses a commercially available deuterium labeled isotope as internal standard, that during the validation has highlited the problem of interferences due to urine ion suppression effect and to the interference from isobaric ions both for the analyte and the internal standared. The following mean values have been obtained: 47.37 microg/g creatinine for non smokers non occupationally exposed to benzene, 97.40 microg/g creatinine for non smokers exposed to benzene, 142.38 microg/g creatinine for smokers non occupationally exposed and 149.08 microg/g creatinine for smokers occupationally exposed to benzene. The results obtained demonstrate that using this analytical method for urinary t,t,MA it is possible to discriminate among groups with different levels of benzene exposure, due to all the possible benzenene sources: environmetal, occupational, due to smoking, and their possible combinations.

[Occupational exposure to hexavalent chromium during aircraft painting]. / Esposizione occupazionale a cromo esavalente nelle operazioni di verniciatura degli aeromobili.

Hygienists are interested in hexavalent chromium due to its genotoxic and carcinogenic effect on humans. The use of products containing hexavalent chromium is decreasing in many industrial fields because of the substitution with less-toxic compounds. In the aeronautical industry, however, the chromate are added to primer paint as a corrosion inhibitor of aircrafts surfaces: so hexavalent chromium compounds are available in many primers with a composition ranging from 10% to 13%. The application of these primers by using electrostatic guns potentially exposes painting and coating workers at high concentrations of aerosols containing Cr(VI). The aim of the present study is the evaluation of professional exposure to hexavalent chromium during aircraft painting, by adopting both environmental personal sampling and biological monitoring. To valuate workers exposure levels the personal measurements results have been compared with the exposure limit values (TLV-TWA) and the urinary chromium contents with the biological exposure indices (IBE). Moreover the strategy of coupling environmental sampling with biological monitoring seems to be a useful instrument to measure the validity of the individual protection devices.

Association of exposure to benzene and smoking with oxidative damage to nucleic acids by means of biological monitoring of general population volunteers.

In this study, the validation of liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) isotopic dilution method for the determination of benzene and nicotine metabolites in urine was carried out. Limit of detection are 0.026 µg/L for S-phenylmercapturic acid (SPMA), 0.55 µg/L for t,t-muconic acid (t,t-MA), and 12.41 µg/L for the cotinine, and the relative combined uncertainty was also calculated. The study involves 446 healthy volunteer residents since at least 10 years in an area of central Italy. SPMA resulted to be strongly correlated with cotinine (p = 0.75), its concentration in smokers (93) being about ten times than in non/ex-smokers (197/156), while the t,t-MA of smokers is about twice the non/ex-smokers value. A cutoff value for the definition of smoker is set at 100 µg/g creat. Oxidative stress was studied in smokers and non- and ex-smokers by means of the determination of the biomarkers 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-Oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-Oxo-7,8-dihydroguanine (8-oxoGua): no significant differences were found between smokers and non/ex-smokers, but when subjects are classified according to the cotinine cutoff value, a correlation in smokers' urinary 8-oxodGuo is found with SPMA and cotinine (p = 0.60 and p = 0.57). Results were confirmed by chemometric analysis that also identified the experimental variables most contributing the discrimination as cotinine and t,t-MA.

[Determination of free and total S-phenylmercapturic acid in the biologic monitoring of exposure to benzene]. / Determinazione dell'acido S-fenilmercapturico libero e totale nel monitoraggio biologico dell'esposizione a benzene.

One of the biomarkers suggested by the ACGIH to assess the professional exposure to benzene is the S-phenylmercapturic acid in the end-shift urine. The existence in the urine of N-acetyl-S(1,2-dihydro-2hydroxypHenyl)-L-Cysteine, a precursor of SPMA that can be turned into it by acid hydrolysis, is a possible cause of miscorrelation between environmental and biological monitoring. The amount of measured SPMA depends on the degree of hydrolysis and therefore it is a function both of the urine PH and of the storage conditions of the sample. 40 urine samples have been collected from workers exposed to benzene, both smokers and not smokers, and for each sample the percentage of SPMA measurable at pH 2 and without pH correction (free SPMA) has been calculated with respect to the SPMA measured after quantitative hydrolysis, with the objectives to determine if a correct assessment of the exposure requires the determination of total SPMA and which concentration value could correspond to the BEI of 25 microg/g of creatinine established by the ACGIH. An aliquot of the urine samples has been treated with 9M H2SO4, a second one is brought to pH 2 and a third one is analyzed as it is. All samples are analyzed by HPLC/MS/MS in negative ions/MRM mode, and quantitative analysis is performed using the internal standard method. The percentage found in samples treated at pH 2 is on average 45% of the total SPMA for smokers and 60% for non smokers, while the free SPMA varies from 1% to 66% due to the urine pH variability and to the lower concentrations detected. The determination of total SPMA allows the standardization of the preanalyticalfactors and the dosage with analytical methods less sensitive than HPLC/MS/MS.

Sex differences in the outcome of juvenile social isolation on HPA axis function in rats.

Women are more likely than men to suffer from anxiety disorders and major depression. These disorders share hyperresponsiveness to stress as an etiological factor. Thus, sex differences in brain arousal systems and their regulation by chronic stress may account for the increased vulnerability to these disorders in women. Social isolation is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like and depressive-like behaviors. Here we investigated the sex difference in the effects of post-weaning social isolation on acute stress sensitivity and behavior in rats. In both sexes, social isolation at weaning reduced basal levels of the neuroactive steroid allopregnanolone in the brain and of corticosterone in plasma. Moreover, acute stress increased plasma corticosterone levels in both group-housed and socially isolated male and female rats; however this effect was greater in male than female rats subjected to social isolation. Intriguingly, group-housed female rats showed no change in plasma and brain levels of allopregnanolone after acute foot-shock stress. The absence of stress-induced effects on allopregnanolone synthesis might be due to the physiologically higher levels of this hormone in females vs. males. Accordingly, increasing allopregnanolone levels in male rats blunted the response to foot-shock stress in these animals. Socially isolated male, but not female, rats also display depressive-like behavior and increased hippocampal brain-derived neurotrophic factor (BDNF). The ovarian steroids could "buffer" the effect of this adverse experience in females on these parameters. Finally, the dexamethasone (DEX) suppression test indicated that the chronic stress associated with social isolation impairs feedback inhibition in both sexes in which an increase in the abundance of glucocorticoid receptors (GRs) in the hippocampus was found. Altogether, these results demonstrate that social isolation affects neuroendocrine reactivity to stress, plasticity and emotionality in a sexually dimorphic manner.

Effectiveness of HPV vaccination in women reaching screening age in Italy.

BACKGROUND AND OBJECTIVES: A randomized trial was conducted in Tuscany, Italy, to evaluate the effectiveness of HPV vaccination for 25year old (yo) women who attend at the first time cervical cancer screening. The trial also evaluated immune response after vaccination, reductions of cytological abnormalities and the impact of vaccination on screening activity. STUDY DESIGN: During 2010-2011, all 25 yo women who were invited to the Florence cervical cancer screening programme were also asked to participate in the trial. Enrolled women were randomized into study and control groups. Those in the study group were offered HPV vaccination after the usual Pap test. The cytology distribution and prevalence for any high risk (hr) HPV type were compared at the subsequent screening round in an intention-to-treat analysis. The impact of HPV vaccination was evaluated per protocol comparing vaccinated women with the control group. RESULTS: Our results showed a reduction in HPV prevalence at recall for any hr-HPV type but it was not statistically significant, being 17.1% vs 21.4%, p=0.20 in the study and control groups, respectively. If we restricted the analysis to vaccinated women, strong reductions of the HPV 16,18,31,33,45 and HPV 31,33,45 infections were observed, being 5.3% vs 12.8%, p<0.01 and 2.1% vs 6.5%, p=0.02, respectively. Significant reductions for any hr-HPV infection and for HPV 16 infection were also observed in women HPV 16/18 negative at enrolment, being 12% vs 21.4%, p<0.01 and 0.6% vs 6.7%, p-value<0.01, respectively. In women hr-HPV negative at enrolment no infections due to HPV 16 or HPV 18 were observed and there was a big reduction for any hr-HPV infection (7.1% vs 21.4% p<0.01). A strong antibody response was observed not only for HPV 16 & 18 but also for their related types. CONCLUSIONS: Our findings suggest that HPV vaccination at the age 25 is beneficial if it is offered to hr-HPV negative women. Our data will assist in developing a cost effectiveness model for choosing the best strategy to integrate screening and vaccination for the coming years. Clinical trial registration number is NCT02296255.