Department of Oncology, St. Olavs Hospital, Trondheim University Hospital, Norway; Norwegian University of Science and Technology (NTNU), Department of Cancer Research and Molecular Medicine, Trondheim, Norway.

Soluble mesothelin-related protein (SMRP) in serum is potentially a sensitive marker of malignant mesothelioma (MM) diagnosis and progression, and may be useful as screening marker. Mesothelin expression in tumors is regarded as a sensitive marker for diagnosis and disease progression, and is a candidate prognostic marker. Levels of SMRP, CA125 and CYFRA 21-1 in pre-diagnostic (1-30 years) serum samples from 47 mesothelioma cases and 141 matched controls were analysed. Mesothelin expression in tumors was assessed. The association between biomarker level and mesothelioma risk and survival was analysed, adjusting for asbestos exposure. Survival related to tumor mesothelin expression, age, sex, histological type, location, asbestos exposure and pre-clinical SMRP was analysed. There was no significant association between biomarker levels and mesothelioma risk when analysed as continuous variables or as tertiles. Biomarker levels <10, 10-19 and >/=20 years before diagnosis were not significantly associated to mesothelioma risk. Mesothelin expressed in >50% of tumor cells was seen in 36 of 47 (77%) tumors. Mesothelin expression in <50% of tumor cells was a significant negative prognostic marker in all cases of malignant mesothelioma (median survival=6 months vs. 12 months, hazard ratio (HR)=2.49, 95%CI 1.17-5.27), and also when only epithelial mesothelioma was analysed (median=6 months vs. 14 months, HR=2.36, 95%CI 1.07-5.22). When adjusted for age and gender, the prognosis was still dismal, but non-significant (HR=1.85, 95%CI 0.85-4.05). High age (>65 years) was an independent negative prognostic factor that was related to both mesothelin expression and asbestos exposure. Mesothelioma of the epithelial type of the peritoneum had a significantly longer survival than epithelial type in pleura and was also related to mesothelin expression.

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Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Kamiyoga, Tokyo, Japan.

Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/ carcinogenic properties, especially of their long-term biodurability, are fully assessed.

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ChemRisk, Inc., San Francisco, California 94105, USA.

Numerous investigators have suggested that there is likely to be a cumulative chrysotile exposure below which there is negligible risk of asbestos-related diseases. However, to date, little research has been conducted to identify an actual “no-effect” exposure level for chrysotile-related lung cancer and mesothelioma. The purpose of this analysis is to summarize and present all of the cumulative exposure-response data reported for predominantly chrysotile-exposed cohorts in the published literature. Criteria for consideration in this analysis included stratification of relative risk or mortality ratio estimates by cumulative chrysotile exposure. Over 350 studies were initially evaluated and subsequently excluded from the analysis due primarily to lack of cumulative exposure information, lack of information on fiber type, and/or evidence of significant exposures to amphiboles. Fourteen studies meeting the inclusion criteria were found where lung cancer risk was stratified by cumulative chrysotile exposure; four such studies were found for mesothelioma. All of the studies involved cohorts exposed to high levels of chrysotile in mining or manufacturing settings. The preponderance of the cumulative “no-effects” exposure levels for lung cancer and mesothelioma fall in a range of approximately 25-1,000 fibers per cubic centimeter per year (f/cc-yr) and 15-500 f/cc-yr, respectively, and a majority of the studies did not report an increased risk at the highest estimated exposure. Sources of uncertainty in these values include errors in the cumulative exposure estimates, conversion of dust counts to fiber data, and use of national age-adjusted mortality rates. Numerous potential biases also exist. For example, smoking was rarely controlled for and amphibole exposure did in fact occur in a majority of the studies, which would bias many of the reported “no-effect” exposure levels towards lower values. However, many of the studies likely lack sufficient power (e.g., due to small cohort size) to assess whether there could have been a significant increase in risk at the reported no-observed-adverse-effects level (NOAEL); additional statistical analyses are required to address this source of bias and the attendant influence on these values. The chrysotile NOAELs appear to be consistent with exposure-response information for certain cohorts with well-established industrial hygiene and epidemiology data. Specifically, the range of chrysotile NOAELs were found to be consistently higher than upper-bound cumulative chrysotile exposure estimates that have been published for pre-1980s automobile mechanics (e.g., 95th percentile of 2.0 f/ cc-yr), an occupation that historically worked with chrysotile-containing friction products yet has been shown to have no increased risk of asbestos-related diseases. While the debate regarding chrysotile as a risk factor for mesothelioma will likely continue for some time, future research into nonlinear, threshold cancer risk models for chrysotile-related respiratory diseases appears to be warranted.

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Biological Mechanisms and Prevention of Work-related Diseases, Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland.

Exposure to asbestos is known to induce lung cancer, and our previous studies have suggested that specific chromosomal regions, such as 19p13, are preferentially aberrant in lung tumours of asbestos-exposed patients. Here, we further examined the association between the 19p region and exposure to asbestos, using array comparative genomic hybridization and fluorescence in situ hybridization (FISH) in lung tumours and FISH characterization of asbestos-induced micronuclei in human bronchial epithelial BEAS 2B cells in vitro. We detected an increased number of 19p losses in the tumours of asbestos-exposed patients in comparison with tumours from non-exposed subjects with similar distribution of tumour histology in both groups (13/33; 39% vs. 3/25; 12%, P=0.04). In BEAS 2B cells, a 48-h exposure to crocidolite asbestos (2.0 mug/cm(2)) was found to induce centromere-negative micronuclei harbouring chromosomal fragments. Furthermore, an increased frequency of rare micronuclei containing a 19p fragment was observed after the crocidolite treatment in comparison with untreated controls (6/6000 vs. 1/10000, P=0.01). The results suggest that 19p has significance in asbestos-associated carcinogenesis and that asbestos may be capable of inducing specific chromosome aberrations.

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Università Politecnica delle Marche, Dipartimento di Patologia Molecolare e Terapie Innovative, Clinica di Medicina del Lavoro, Tronto 10/a, 0020 Torrette, AN. m.amati@univpm.it

Improved detection methods for diagnosis of asymptomatic malignant pleural mesothelioma (MPM) are essential for an early and reliable detection and treatment of this disease. Thus, focus has been on finding tumour markers in the blood. 94 asbestos-exposed subjects, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the significance of 8-hydroxy-2′-deoxy-guanosine (80HdG) in white blood cells and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors (PDGFbeta, HGF, bFGF, VEGFbeta), and matrix proteases (MMP2, MMP9, TIMP1, TIMP2) for potential early detection of MM. The area under ROC curves (AUC) indicates that 80HdG levels can discriminate asbestos-exposed subjects from controls but not from MPM patients. Significant AUC values were found for SMRP discriminating asbestos-exposed subjects from MPM patients but not from controls. VEGFbeta can significantly differentiate asbestos-exposed subjects from control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, TIMP2. The sensitivity and specificity results of markers were calculated at defined cut-offs. The combination of 80HdG, VEGFbeta and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MPM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

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Unit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy.

Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.

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Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.

The expression of mucin (MUC2) in prostate cancer has not been well studied previously and may be of prognostic and pathobiologic significance. It is, however, well known that MUC2 expression in mucinous pancreatic and breast cancer represents an indolent pathway since these tumors have a significantly better outcome than their conventional counterparts. Twenty-five cases each of Gleason pattern 3 and 4 mucinous adenocarcinoma of the prostate defined by greater than 25% mucinous component and nonmucinous adenocarcinoma of the prostate were obtained from the surgical pathology files of the Johns Hopkins Hospital and Emory University Hospital. Immunohistochemical stains were performed for MUC2 on all 50 cases. Mean patient age was 60 years (range 44-72 years). MUC2 was expressed in all 25 cases (100%) of mucinous adenocarcinoma of the prostate, irrespective of the Gleason pattern. The nonmucinous component of these cases was negative for MUC2. In contrast, MUC2 expression was significantly lower in nonmucinous adenocarcinoma of the prostate, detected in only 6/25 cases as a focal finding, while 19/25 (76%) of nonmucinous adenocarcinoma of the prostate were completely negative for MUC2 (P<0.01). In six cases that showed focal positivity, MUC2 was expressed in areas with Gleason pattern 3 cancer with extensive mucinous fibroplasia (one case) and prominent intraluminal mucin (five cases). Other areas of these tumors were negative for MUC2. Mucinous adenocarcinoma of the prostate shows diffuse expression of MUC2, a known tumor suppressor, which is not present in either normal prostate or the majority of conventional adenocarcinomas of this organ. This indicates that mucinous adenocarcinoma of the prostate is indeed of the ‘colloid type’ akin to those in other exocrine organs. It is highly conceivable that this de novo expression of MUC2 has a role, not only in the mucinous differentiation of these tumors and their colloid pattern, but also in their relatively indolent behavior that has been recently elucidated.Modern Pathology advance online publicaton, 16 May 2008; doi:10.1038/modpathol.2008.47.

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Department of Respiratory Cancer Medicine, Peking University Third Hospital, Haidian District, Beijing 100083, China.

OBJECTIVE: Previous studies have cancer demonstrated that exercise-induced asthma and bronchial hyperresponsiveness commonly occur in athletes. The present study investigates pulmonary function and cytokine levels in professional athletes to explore the impact of various sports on respiratory system cancer function and to evaluate the possible role of systemic anaphylaxis. METHODS: Lung function was measured at rest in professional athletes without a history of smoking. Athletes were recruited from 10 different sports including swimming, water ballet, shooting, volleyball, softball, football, kickboxing, fencing, judo, and track and field. Measurements included forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), vital capacity (VC), peak expiratory flow (PEF), maximal mid-expiratory flow curve (MMEF), and forced expiratory flow rate (FEF(25-75)%). In addition, the medical history of all athletes was recorded. Correlations between lung function measurements and the different sports, age, gender, height and weight were analyzed. In some athletes, serum was sampled to detect IL-4 and IL-10 concentrations. In these subjects, the correlation between pulmonary function and cytokine levels was analyzed. RESULTS: A total of 147 professional athletes and 30 healthy volunteers were enrolled in the study. Allergic rhinitis and asthma were detected only in swimmers with an incidence of 56.52% (13/23) and 8.70% (2/23), respectively. Lung function measures were significantly correlated with sport, age, gender, height, and weight. Ventilation functions (including FVC, FEV(1), FEV(1)/FVC, and MMV) in male athletes were superior to those in females, and the ventilation functions in swimmers were superior to those in others. However, the small airway functions (MMEF, FEF(50), FEF(75)) in swimmers and in track and field athletes were lower than predicted (swimmers: 72%, 70%, and 78%, respectively; track and field athletes: 79%, 75%, and 99%, respectively). Serum analyses for IL-4 and IL-10 revealed that IL-4 concentrations were higher in swimmers 69.34 +/- 22.4 pg/mL relative to non-swimmers (p = 0.000). By contrast IL-10 concentrations were lower in swimmers 34.94 +/- 9.71 pg/mL than that in the static group (44.69 +/- 16.32 pg/mL; p = 0.027). IL-4 levels were negatively correlated with FEV(1)%, FEF(25)%, FEF(50)%, and MMEF%. By contrast, IL-10 levels were not correlated with any of these measures. CONCLUSIONS: The lung function measurements were correlated with sport, age, gender, height, and weight in the various athletes. The lung capacity of swimmers was greater than that of other athletes. Small airway dysfunction was observed in some swimmers and endurance athletes. We observed an association between systemic anaphylaxis and small airway dysfunction after prolonged regular training, particularly following swimming and endurance training.

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Authors’ Affiliations: Laboratory of Molecular Neuro-oncology, Departments of Research and Surgery, University Hospitals, Basel, Switzerland.

PURPOSE: High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. EXPERIMENTAL DESIGN: Because tumorigenesis is considered a multistep process of accumulating mutations affecting distinct signaling pathways, combinations of compounds, which inhibit nonoverlapping pathways, are being explored to improve treatment of gliomas. Histone deacetylase inhibitors (HDI) have proven antitumor activity by blocking cell proliferation, promoting differentiation, and inducing tumor cell apoptosis. RESULTS: In this report, we show that the HDIs trichostatin A, sodium butyrate, and low nanomolar doses of LAQ824 combined with the glycolysis inhibitor 2-deoxy-d-glucose induce strong apoptosis in cancer cell lines of brain, breast, and cervix in a p53-independent manner. HDIs up-regulate p21, which is blocked by concomitant administration of 2-deoxy-d-glucose. CONCLUSIONS: We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.

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Affiliations of authors: Department of Surgery, University of cancer Michigan, Ann Arbor, MI (AMM, AJH, JDB); Michigan Surgical Collaborative for Outcomes Research and Evaluation, University of Michigan, Ann Arbor, MI (AMM, JDB); Department of Family Medicine, University of Washington, Seattle, WA (BM, LMB); Department of cancer Surgery, Oregon Health and Science University, Portland, OR (KGB).

Background Black patients with rectal cancer are considerably less likely than white patients to receive adjuvant therapy. We examined the hypothesis that the lower treatment rate for blacks is due to cancer underreferral to cancer medical and radiation cancer oncologists. Methods We used 1992-1999 Surveillance, Epidemiology, and End Results-Medicare data to identify elderly (>/=66 years of age) patients who had been hospitalized for resection of stage II or III rectal cancer (n = 2716). We used chi(2) tests to examine associations between race and 1) consultation with an cancer oncologist and 2) receipt of adjuvant therapy. We then used logistic regression to analyze the influence of sociodemographic and clinical characteristics (age at diagnosis, sex, marital status, median income and education in area of residence, comorbidity, and cancer stage) on black-white differences in the receipt of adjuvant therapy. All statistical tests were two-sided. Results There was no statistically significant difference between the 134 black patients and the 2582 white cancer patients in the frequency of consultation with a medical oncologist (73.1% for blacks vs 74.9% for whites, difference = 1.8%, 95% confidence interval [CI] = >5.9% to 9.5%, P = .64) or radiation oncologist (56.7% vs 64.8%, difference = 8.1%, 95% CI = >0.5% to 16.7%, P = .06), but blacks were less likely than whites to consult with both a medical oncologist and a radiation oncologist (49.2% vs 58.8%, difference = 9.6%, 95% CI = 0.9% to 18.2%, P = .03). Among patients who saw an cancer oncologist, black patients were less likely than white patients to receive cancer chemotherapy (54.1% vs 70.2%, difference = 16.1%, 95% CI = 6.0% to 26.2%, P = .006), radiation therapy (73.7% vs 83.4%, difference = 9.7%, 95% CI = 0.4% to 19.8%, P = .06), or both (60.6% vs 76.9%, difference = 16.3%, 95% CI = 4.3% to 28.3%, P = .008). Patient and provider characteristics had minimal influence on the racial disparity in the use of adjuvant therapy. Conclusion Racial differences in oncologist consultation rates do not explain disparities in the use of adjuvant cancer treatment for rectal cancer. A better understanding of patient preferences, patient-provider interactions, and potential influences on provider decision making is necessary to develop strategies to increase the use of adjuvant treatment for rectal cancer among black patients.

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