Ian Pagano

Malignant mesothelioma: facts, myths, and hypotheses.

Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5–10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50–80% of pleural MM in men and 20–30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro‐inflammatory molecules, especially HMGB‐1, the master switch that starts the inflammatory process, and TNF‐alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co‐factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. 227: 44–58, 2012.

Risk Factors for Exclusive E-Cigarette Use and Dual E-Cigarette Use and Tobacco Use in Adolescents

OBJECTIVE: To describe electronic cigarette (e-cigarette) use and cigarette use among adolescents and determine whether established risk factors for smoking discriminate user categories. METHODS: School-based survey of 1941 high school students (mean age 14.6 years) in Hawaii; data collected in 2013. The survey assessed e-cigarette use and cigarette use, alcohol and marijuana use, and psychosocial risk and protective variables (eg, parental support, academic involvement, smoking expectancies, peer smoking, sensation seeking). Analysis of variance and multinomial regression examined variation in risk and protective variables across the following categories of ever-use: e-cigarette only, cigarette only, dual use (use of both products), and nonuser (never used either product). RESULTS: Prevalence for the categories was 17% (e-cigarettes only), 12% (dual use), 3% (cigarettes only), and 68% (nonusers). Dual users and cigarette-only users were highest on risk status (elevated on risk factors and lower on protective factors) compared with other groups. E-cigarette only users were higher on risk status than nonusers but lower than dual users. E-cigarette only users and dual users more often perceived e-cigarettes as healthier than cigarettes compared with nonusers. CONCLUSIONS: This study reports a US adolescent sample with one of the largest prevalence rates of e-cigarette only use in the existing literature. Dual use also had a substantial prevalence. The fact that e-cigarette only users were intermediate in risk status between nonusers and dual users raises the possibility that e-cigarettes are recruiting medium-risk adolescents, who otherwise would be less susceptible to tobacco product use.

Cancer Cell Secretion of the DAMP Protein HMGB1 Supports Progression in Malignant Mesothelioma

Human malignant mesothelioma is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor because of late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in malignant mesothelioma cells that influences their proliferation and survival. Malignant mesothelioma cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in malignant mesothelioma patient sera were higher than that found in healthy individuals. The motility, survival, and anchorage-independent growth of HMGB1-secreting malignant mesothelioma cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products, a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of malignant mesothelioma xenografts in severe-combined immunodeficient mice and extended host survival. Taken together, our findings indicate that malignant mesothelioma cells rely on HMGB1, and they offer a preclinical proof-of-principle that antibody-mediated ablation of HMBG1 is sufficient to elicit therapeutic activity, suggesting a novel therapeutic approach for malignant mesothelioma treatment.

Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta-analysis

BACKGROUND Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

A longitudinal investigation of mammographic density : The multiethnic cohort

Mammographic densities are hypothesized to reflect the cumulative exposure to risk factors that influence breast cancer incidence. This report analyzed percent densities over time and explored predictors of density change in relation to age. The study population consisted of 607 breast cancer cases and 667 frequency matched controls with 1,956 and 1,619 mammographic readings, respectively. Mammograms done over >20 years and before a diagnosis of breast cancer were assessed for densities using a computer-assisted method. Using multilevel modeling to allow for repeated measurements, we estimated the effect of ethnicity, case status, reproductive characteristics, hormonal therapy, body mass index, and soy intake on initial status and longitudinal change. After integrating the area under the percent density curve, cumulative percent density was compared with age-specific breast cancer rates in Hawaii. Percent densities decreased ∼5.6% per 10 years but a nonlinear effect indicated a faster decline earlier in life. Cumulative percent densities and age-specific breast cancer rates increased at very similar rates; both standardized regression coefficients were >0.9. Japanese ancestry, overweight, estrogen/progestin treatment, and, to a lesser degree, estrogen-only therapy predicted a slower decline in densities with age. Case status and adult soy intake were related to higher densities whereas overweight and having any child were associated with lower densities at initial status. Risk factors that influence the decline in mammographic densities over time may be important for breast cancer prevention because cumulative percent densities may reflect the age-related increase in breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(4):732–9)

Longitudinal study of e-cigarette use and onset of cigarette smoking among high school students in Hawaii

Objective Use of electronic cigarettes (e-cigarettes) is prevalent among adolescents, but there is little knowledge about the consequences of their use. We examined, longitudinally, how e-cigarette use among adolescents is related to subsequent smoking behaviour. Methods Longitudinal school-based survey with a baseline sample of 2338 students (9th and 10th graders, mean age 14.7 years) in Hawaii surveyed in 2013 (time 1, T1) and followed up 1 year later (time 2, T2). We assessed e-cigarette use, tobacco cigarette use, and psychosocial covariates (demographics, parental support and monitoring, and sensation seeking and rebelliousness). Regression analyses including the covariates tested whether e-cigarette use was related to the onset of smoking among youth who had never smoked cigarettes, and to change in smoking frequency among youth who had previously smoked cigarettes. Results Among T1 never-smokers, those who had used e-cigarettes at T1 were more likely to have smoked cigarettes at T2; for a complete-case analysis, adjusted OR=2.87, 95% CI 2.03 to 4.05, p<0.0001. Among ever-smokers at T1, using e-cigarettes was not related to significant change in their frequency of smoking at T2. Uptake of e-cigarette use among T1 never-users of either product was predicted by age, Caucasian or Native Hawaiian (vs Asian-American) ethnicity, lower parental education and parental support, higher rebelliousness, and perception of e-cigarettes as healthier. Conclusions Adolescents who use e-cigarettes are more likely to start smoking cigarettes. This result together with other findings suggests that policies restricting adolescents’ access to e-cigarettes may have a rationale from a public health standpoint.

Trends and Dietary Determinants of Overweight and Obesity in a Multiethnic Population

Objectives: To describe trends in BMI among different ethnic groups in Hawaii and to explore the relation of nutrient and food intake with excess weight.

Assessment of Survivor Concerns (ASC): A newly proposed brief questionnaire

BackgroundThe purpose of this study was to design a brief questionnaire to measure fears about recurrence and health in cancer survivors. Research involving fear of recurrence has been increasing, indicating that it is an important concern among cancer survivors.MethodsWe developed and tested a six-item instrument, the Assessment of Survivor Concerns (ASC). Construct validity was examined in a multiple group confirmatory factor analysis (CFA) with 592 short-term and 161 long-term cancer survivors. Convergent and discriminant validity was examined through comparisons with the PANAS (Positive and Negative Affect Schedule) and the CES-D (Center for Epidemiologic Studies Depression) measures.ResultsCFA models for the ASC with short- and long-term survivors showed good fit, with equivalent structure across both groups of cancer survivors. Convergent and discriminant validity was also supported through analyses of the PANAS and CES-D. One item (childrens health worry) did not perform as well as the others, so the models were re-run with the item excluded, and the overall fit was improved.ConclusionThe ASC showed excellent internal consistency and validity. We recommend the revised five-item instrument as an appropriate measure for assessment of cancer survivor worries.

The association of mammographic density with ductal carcinoma in situ of the breast: the Multiethnic Cohort.

IntroductionIt is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density. However, little research has been done on mammographic density and ductal carcinoma in situ (DCIS) of the breast, which is thought to be a precursor lesion to some invasive breast cancers.MethodWe conducted a nested case-control study within the Multiethnic Cohort, and compared the mammographic densities of 482 patients with invasive breast cancer and 119 with breast DCIS cases versus those of 667 cancer-free control subjects. A reader blinded to disease status performed computer-assisted density assessment. For women with more than one mammogram, mean density values were computed. Polytomous logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for two measurements of mammographic density: percentage density and dense area.ResultsMammographic density was associated with invasive breast cancer and breast DCIS. For the highest category of percentage breast density (≥50%) as compared with the lowest (<10%), the OR was 3.58 (95% CI 2.26–5.66) for invasive breast cancer and 2.86 (1.38–5.94) for breast DCIS. Similarly, for the highest category of dense area (≥45 cm2) as compared with the lowest (<15 cm2), the OR was 2.92 (95% CI 2.01–4.25) for invasive breast cancer and 2.59 (1.39–4.82) for breast DCIS. Trend tests were significant for invasive breast cancer (P for trend < 0.0001) and breast DCIS (P for trend < 0.001) for both percentage density and dense area.ConclusionThe similar strength of association for mammographic density with breast DCIS and invasive breast cancer supports the hypothesis that both diseases may have a common etiology.

E-cigarette use and willingness to smoke: a sample of adolescent non-smokers

Objective There is little evidence on the consequences of using electronic cigarettes (e-cigarette) in adolescence. With a multiethnic sample of non-smokers, we assessed the relation between e-cigarette use and social-cognitive factors that predict smoking of combustible cigarettes. Methods School-based cross-sectional survey of 2309 high school students (mean age 14.7 years). Participants reported on e-cigarette use and cigarette use; on smoking-related cognitions (smoking expectancies, prototypes of smokers) and peer smoker affiliations; and on willingness to smoke cigarettes. Regression analyses conducted for non-cigarette smokers tested the association between e-cigarette use and willingness to smoke cigarettes, controlling for demographics, parenting, academic and social competence, and personality variables. Structural equation modelling (SEM) analysis tested whether the relation between e-cigarette use and willingness to smoke was mediated through any of the three smoking-related variables. Results Non-smokers who had used e-cigarettes (18% of the total sample) showed more willingness to smoke cigarettes compared with those who had never used any tobacco product; the adjusted OR was 2.35 (95% CI 1.73 to 3.19). SEM showed that the relation between e-cigarette use and willingness to smoke was partly mediated through more positive expectancies about smoking, but there was also a direct path from e-cigarette use to willingness. Conclusions Among adolescent non-smokers, e-cigarette use is associated with willingness to smoke, a predictor of future cigarette smoking. The results suggest that use of e-cigarettes by adolescents is not without attitudinal risk for cigarette smoking. These findings have implications for formulation of policy about access to e-cigarettes by adolescents.