OxLDL-targeted iron oxide nanoparticles for in vivo MRI detection of perivascular carotid collar induced atherosclerotic lesions in ApoE-deficient mice.

Atherosclerotic disease is a leading cause of morbidity and mortality in developed countries, and oxidized LDL (OxLDL) plays a key role in the formation, rupture, and subsequent thrombus formation in atherosclerotic plaques. In the current study, anti-mouse OxLDL polyclonal antibody and nonspecific IgG antibody were conjugated to polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, and a carotid perivascular collar model in apolipoprotein E-deficient mice was imaged at 7.0 Tesla MRI before contrast administration and at 8 h and 24 h after injection of 30 mg Fe/kg. The results showed MRI signal loss in the carotid atherosclerotic lesions after administration of targeted anti-OxLDL-USPIO at 8 h and 24 h, which is consistent with the presence of the nanoparticles in the lesions. Immunohistochemistry confirmed the colocalization of the OxLDL/macrophages and iron oxide nanoparticles. The nonspecific IgG-USPIO, unconjugated USPIO nanoparticles, and competitive inhibition groups had limited signal changes (p < 0.05). This report shows that anti-OxLDL-USPIO nanoparticles can be used to directly detect OxLDL and image atherosclerotic lesions within 24 h of nanoparticle administration and suggests a strategy for the therapeutic evaluation of atherosclerotic plaques in vivo.

Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy.

BACKGROUND: Treatment options remain limited for patients with castration-resistant prostate cancer (CRPC). We evaluated eribulin mesylate (E7389), a nontaxane halichondrin B analog microtubule inhibitor, in patients with metastatic CRPC with or without previous taxane exposure. PATIENTS AND METHODS: Men with histologically proven CRPC, with or without prior taxane exposure, were enrolled in an open-label, single-arm phase II trial. Patients received eribulin mesylate 1.4 mg/m(2) as a 2- to 5-min i.v. bolus infusion on days 1 and 8 of a 21-day cycle. The primary efficacy end point was prostate-specific antigen (PSA) response rate. RESULTS: In total, 108 patients were assessable for safety (50 were taxane-pretreated) and 105 for efficacy in the per-protocol population. The median age of patients was 71 years and median number of cycles was 4. PSA decreases of ≥ 50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients, respectively. The most common grade 3/4 adverse event was neutropenia, seen in 22.4% of chemo-naive and 40% of taxane-pretreated men. Grade 3 peripheral neuropathy occurred in none of the taxane-naive patients and 6.0% of taxane-pretreated patients. CONCLUSION: Eribulin mesylate demonstrated activity and a relatively favorable toxicity profile in metastatic CRPC.

Reevaluation of the confounding effect of cigarette smoking on the relationship between alcohol use and lung cancer risk, with larynx cancer used as a positive control.

BACKGROUND: The effect of smoking on lung cancer risk has been well documented, while the effect of alcohol remains controversial. We examined the hypothesis that the apparent association between alcohol intake and lung cancer risk is fully due to the confounding effect of cigarette smoke. METHODS: Our sample of hospitalized patients included 2,953 male and 1,622 female lung cancer cases; 521 male and 159 female larynx cancers cases; and 8,169 male and 4,154 female controls, admitted to participating hospitals between 1981 and 1994. All controls had been diagnosed with non-smoking-related diseases. Larynx cancer was used as a positive control for lung cancer. Relative risks were estimated through odds ratios, adjusted through multiple logistic regression. RESULTS: Although the odds ratios for alcohol had been significantly elevated prior to adjustment for smoking (OR = 2.4, 95% CI = 2.0-2.8), alcohol had no effect on lung cancer following this adjustment (OR = 1.2, 95% CI = 1.0-1.4). By contrast, the effect of alcohol on larynx cancer remained high even after adjustment for smoking (OR = 5.6, 95% CI = 3.7-8.6). CONCLUSION: The often-reported association between alcohol and lung cancer risk can be fully explained by the confounding effect of cigarette use.

Smoking trends in the United States between 1969 and 1995 based on patients hospitalized with non-smoking-related diseases.

BACKGROUND: This study examines smoking trends in the United States by race, gender, education, and occupation. METHODS: The data were collected between 1969 and 1995 through a hospital-based case-control study on tobacco-related cancers, including 21,057 male and 14,448 female control subjects who had been diagnosed of non-smoking-related diseases. Smoking measures were adjusted through direct standardization and regression methods. RESULTS: Despite the decline in smoking, daily cigarette consumption remained high among current smokers. Women's smoking prevalence decreased more slowly than men's and their age at smoking initiation also declined, while the inverse effects on smoking by education and occupation were more pronounced in men than in women. Smoking prevalence was higher, but daily cigarette consumption was lower in blacks compared to caucasians. CONCLUSIONS: Despite an overall downward trend in smoking, lung cancer remains a major public health concern, particularly among women, blacks, and white men with low education. The development of a systematic mechanism for more detailed, regular monitoring of tobacco use by various subpopulations is, therefore, crucial to future public health planning.

Cigarette smoking and prostate cancer: no relation with six measures of lifetime smoking habits in a large case-control study among U.S. whites.

BACKGROUND: The study was undertaken to describe the association between lifetime cigarette smoking habits and prostate cancer. Whereas most case-control and cohort studies report no association, the positive findings from some large cohort studies are difficult to ignore. The available information on lifetime smoking habits from most studies is limited however. METHODS: In a study of 1,097 prostate cancer cases and 3,250 matched controls, admitted between 1969 and 1991 to U.S. hospitals, several ordinal measures of lifetime smoking were compared to look for dose-response or threshold associations. RESULTS: No association was seen between prostate cancer and former or current smoking, age started smoking, number of years smoked, cigarettes per day smoked, the number of years since quitting, and lifetime tar exposure. CONCLUSIONS: Our data provide the most complete dose-response smoking information to date, and support the findings from the majority of studies that prostate cancer is not associated with cigarette smoking.

Wheat bran and psyllium diets: effects on N-methylnitrosourea-induced mammary tumorigenesis in F344 rats.

BACKGROUND: Experimental and epidemiologic evidence suggests that increased dietary fiber is associated with decreased breast cancer risk. Little is known about the role played by different types of fiber and, particularly, mixtures of soluble and insoluble fibers similar to those consumed by human populations in reducing breast cancer risk. High intake of fiber may suppress bacterial hydrolysis of biliary estrogen conjugates to free (absorbable) estrogens in the colon and thus may decrease the availability of circulating estrogens necessary for the development and growth of breast cancers. PURPOSE: The purpose of this study was to evaluate the effect of wheat bran (an insoluble fiber) and psyllium (a soluble fiber) alone and in combination on overall estrogen status, on fecal bacterial beta-D-glucuronidase (a key diet-responsive estrogen-deconjugating enzyme) activity, and on the induction of mammary tumors in rats treated with N-methylnitrosourea (MNU). METHODS: One hundred fifty virgin female F344 rats were fed the NIH-07 diet from 28 days of age until 50 days of age; they were then given a single dose (40 mg/kg of body weight) of MNU by tail vein injection. Three days later, they were randomly assigned to one of five experimental dietary groups (30 animals per group). Soft, white wheat bran (45% dietary fiber content) and psyllium (80% dietary fiber content) were added to a modified (high-fat) American Institute of Nutrition (AIN)-76A diet at the following percents, respectively: 12% + 0% (group 1), 8% + 2% (group 2), 6% + 3% (group 3), 4% + 4% (group 4), and 0% + 6% (group 5). Blood, urine, and feces were collected and analyzed by radioimmunoassay techniques for estrogens. Cecal contents were analyzed for bacterial beta-D-glucuronidase activity. After 19 weeks on the experimental diets, the rats were killed, and mammary tumors were counted and classified by histologic type. Cumulative tumor incidence was evaluated by the Kaplan-Meier life-table method and the logrank test. Tumor number was evaluated by the chi-squared test of association, and tumor multiplicity was evaluated by the Mantel-Haenszel chi-squared test. All statistical tests were two-tailed. RESULTS: As the level of psyllium relative to that of wheat bran increased, the total tumor number and multiplicity of mammary adenocarcinomas in rats decreased as a statistically significant linear trend across groups 1-5 (P < .05). Compared with the group given wheat bran alone, the group given the 1:1 (wheat bran:psyllium) combination had maximum protection against mammary tumorigenesis, while the groups given the 4:1 or 2:1 (wheat bran:psyllium) combination or psyllium alone had intermediate protection. No statistically significant differences in circulating estrogens or urinary estrogen excretion patterns were observed among the five experimental groups. Fecal estrogen excretion, however, decreased with increasing levels of psyllium (P < .01), and cecal beta-D-glucuronidase activity exhibited a decreasing trend with respect to the increasing psyllium content of the diet across groups 1-5 (P < .01). CONCLUSIONS: The addition of a 4%:4% mixture of an insoluble (wheat bran) fiber and a soluble (psyllium) fiber to a high-fat diet provided the maximum tumor-inhibiting effects in this mammary tumor model. Although increasing levels of dietary psyllium were associated with decreased cecal bacterial beta-D-glucuronidase activity, these changes were not reflected in decreased circulating levels of tumor-promoting estrogens. Therefore, the mechanism(s) by which mixtures of soluble and insoluble dietary fibers protect against mammary tumorigenesis remains to be clarified.

Differences in lung cancer risk between men and women: examination of the evidence.

BACKGROUND: Lung cancer incidence is gradually leveling off in U.S. men but is continuing to rise in U.S. women. This increase in U.S. women exceeds that expected from a slower decline of smoking among women. Recent epidemiologic and biochemical studies suggest gender differences in susceptibility to tobacco carcinogens. PURPOSE: We conducted an up-to-date, more in-depth evaluation of our earlier observation of a potential gender difference in relative risk (RR) of lung cancer due to smoking. We added information from several additional case and control subjects and included more precise histologic classification of the cancer type, accurate quantitation of smoke exposure, and adjustments for body size. METHODS: The present investigation was a part of an ongoing hospital-based, case-control study by the American Health Foundation. It included data from 1889 case subjects (1108 males and 781 females) with lung cancer of squamous/epidermoid, small-cell/oat cell, large-cell, and adenocarcinoma types and 2070 control subjects (1122 males and 948 females) with diseases unrelated to smoking. The case and control subjects were admitted to participating hospitals from 1981 to 1994 and were pair-matched by age, sex, hospital, and the time of hospital admission. Ex-smokers and non-Caucasians were excluded from analyses to avoid confounding. The RRs and 95% confidence intervals were estimated from adjusted odds ratios (ORs) by use of unconditional multiple logistic regression analysis, and statistical significance was determined by two-sided tests. The ORs for major histologic types were estimated at increasing levels of exposure to cigarette smoke. RESULTS: Our results indicated that women were more likely to be never-smokers than men, particularly those with the squamous/epidermoid-type cancer (8.3% for women versus 2.9% for men 55 years old or older). Men started smoking earlier, reported inhaling more deeply, and smoked more cigarettes per day than women. In contrast, dose-response ORs over cumulative exposure to cigarette smoking were 1.2-fold to 1.7-fold higher in women than in men for the three major histologic types; these differences were more pronounced for small-cell/oat cell carcinomas and adenocarcinomas than for squamous/epidermoid carcinomas. Adjustments for weight, height, or body mass index did not alter the ORs. CONCLUSIONS: These results confirm our earlier finding that the ORs for major lung cancer types are consistently higher for women than for men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in base-line exposure, smoking history, or body size, but it is likely due to the higher susceptibility to tobacco carcinogens in women.

Differences in nutritional risk factors for breast cancer among New York City white, Hispanic, and black college students.

Breast cancer incidence is significantly lower in Hispanic and black women than in non-Hispanic white women. Since diet has been suggested as an important determinant of breast cancer risk, we compared the food intake of college students sampled from these three racial-ethnic groups in New York City to evaluate the potential role of diet as a determinant of the observed differences in breast cancer risk. A semiquantitative food frequency questionnaire and a general health and demographic questionnaire were administered to 89 Hispanic, 67 black, and 58 white premenopausal female college students randomly selected from among those waiting to register for the fall semester at Lehmann College in Bronx, New York. The food frequency questionnaire was designed to assess usual eating habits over the past year. With regard to specific foods and food groups, Hispanics and blacks consumed more vegetables, citrus fruits, and fish than did whites. The intake of beans among Hispanics was twice that of either whites or blacks. Consumption of carotenoid-containing fruits and vegetables was substantially higher in blacks than in the other two groups, and alcohol consumption was higher in whites compared to blacks and Hispanics. Interestingly, no significant differences were found in total fat or fiber intake, although the sources of fat and fiber differed significantly among the three groups. The results suggest that the variation in risk by racial-ethnic background may, in part, be a reflection of protective agents present in greater amounts in the diets of Hispanics (beans) and blacks (fruits and vegetables) than of whites.

The association between body mass index and the relative frequencies of diseases in a sample of hospitalized patients.

Body mass index (BMI) is known to differ among the various diseases, potentially due to etiologic causes, which can lead to bias in estimating the effects of other risk factors. The relationship between BMI and disease must be identified to control for this potential bias in epidemiological investigations. We used the data from our large hospital-based case-control study to analyze the difference in BMI (computed as kg/m2) by diagnosis, separately in males (n = 20,011) and females (n = 9,083) admitted to the hospital between 1977 and 1992. The difference in BMI between diagnoses is most clearly represented through the quartile distributions, whereas the mean tends to camouflage it. Although some associations between BMI and disease differed between the sexes, in general, fractures and diseases of the respiratory tract were associated with the lowest BMI and arthritis, cataract/glaucoma, and endometrial cancer with the highest BMI. Potential disease risk factors, including alcohol use, smoking, and education, showed a strongly negative and age a strongly positive association with BMI in females, but little or no association was found between BMI and these factors in males. The data presented provide information on the correlation between BMI and several diseases and the potential distortion of etiologic factors that can occur as a result of these correlations. The reported associations with BMI can be useful in the evaluation of independent risk factors or when selecting appropriate controls in epidemiological investigations of diseases.

Race and sex differences in lung cancer risk associated with cigarette smoking.

Despite the extreme differences in the incidence of lung cancer between black and white Americans of each sex, little information is available on the sex-race-specific lung cancer risk due to tobacco use. In the current study, case-control data were examined for sex-race differences in the lung cancer risk associated with cigarette smoking. Results indicate that Kreyberg I lung cancers (squamous cell and oat cell carcinomas) are associated with heavier intensity of smoking than Kreyberg II lung cancer (adenocarcinomas and alveolar cell carcinomas); blacks are at higher risk than whites (relative risk = 1.8), and women are at higher risk than men for a given level of smoking (RR = 1.7). Our findings indicate the existence of important differences in the smoking-associated risk for lung cancer which depend upon sex, race, and histology.

Cigarette smoking and occupational status: 1977 to 1990.

OBJECTIVES: In this study we examined the relationship between occupational status and smoking habits in men and women during the period from 1977 to 1990. METHODS: Cigarette smoking and occupational history were obtained from 8045 men and women who served as controls for a hospital-based study of tobacco-related diseases. RESULTS: There was an association between increasing occupational status and tobacco exposure in men, but not in women. The quit rate increased over time in all sex-occupational groups except for male laborers, whose quit rate remained constant. Nicotine-dependent smokers are likely to find it difficult to quit. Male nicotine-dependent smokers were consistently found in greater numbers among blue collar workers throughout the study period. Initially, female nicotine-dependent smokers were more often found among blue collar workers, but in recent years became more frequent among white collar workers. CONCLUSION: These trends provide clues to the future epidemiological distribution of lung cancer and other tobacco-related diseases. An understanding of gender differences in the occupational profile of cigarette smokers can provide guidelines for effective antismoking interventions.

Cumulative tar exposure. A new index for estimating lung cancer risk among cigarette smokers.

A new index for estimating lifetime exposure to tar from cigarette smoking was found to be the best measure of the relative risk for Kreyberg type I (KI) and Kreyberg type II (KII) lung cancer in a case-control study of 2296 cases (1274 KI and 1022 KII) and 4667 controls. There is a steep, near-linear dose-response of lung cancer risk of both histologic types to cumulative exposure to tar, although the odds ratios are three to five times higher for KI than for KII. The odds ratios for lung cancer in women are consistently higher than those in men with the same level of exposure to tar, particularly among long-term smokers who smoke heavily. Based on their estimates of odds ratios associated with tar exposure, the authors projected an approximate 15-20% decrease in KI lung cancer risk among long-term smokers who smoked heavily for every 10-mg decrease in tar in the cigarettes they smoked.

Oral contraceptives and breast cancer risk: a case-control study.

The association between breast cancer risk and oral contraceptive use was examined in 401 breast cancer patients and 519 hospital controls interviewed in New York City during 1979-1981. Control subjects were ascertained utilizing variable ratio matching to the cases (2:1 or 1:1) by sex, age, hospital, and time of diagnosis. No evidence of a positive association was found between cancer risk and the duration of use in either parous or nulliparous women. The odds ratios obtained by comparing users to non-users in women under 50 years of age after adjusting for other risk factors were 0.8 (95% CI = 0.4-1.4) for less than five years duration and 0.4 (95% CI = 0.2-0.8) for five or more years duration (P less than 0.05 when tested for decreasing trend). There was also no evidence of effect modification between oral contraceptive use and other breast cancer risk factors (viz. family history, nulliparity, late age at first pregnancy, or abstention from breastfeeding). Our results do not indicate that the use of oral contraceptives increases the risk of breast cancer.

Human T-cell lymphotropic virus type III infection in a cohort of homosexual men in New York City.

Using blood samples collected since 1978, we investigated the epidemiology of human T-cell lymphotropic virus type III (HTLV-III), the etiologic agent of the acquired immunodeficiency syndrome, in a group of 378 homosexually active men who have resided in New York City since the acquired immunodeficiency syndrome epidemic began. The anti-HTLV-III prevalence was 6.6% in sera from 1978 or 1979, and the subsequent annual incidence of seroconversion among susceptible men ranged between 5.5% and 10.6%. The highest incidences were in recent years, even though these men reported a decrease in their sexual activity during this time. These data demonstrate the continuing risk of HTLV-III infections in the homosexual population studied and emphasize the need for more effective prevention of transmission. The year during which antibody was first present was the only factor identified that was associated with altered cell-mediated immunity in antibody-positive men. Men who became antibody positive in 1981 or earlier currently had significantly lower OKT4/OKT8 ratios than did those who seroconverted more recently. Further follow-up will be necessary to establish the reasons for this association.

Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.

We evaluated the immunogenicity and efficacy of hepatitis B vaccine (Heptavax-B) in a randomized, double-blind, placebo-controlled trial involving 1311 patients receiving hemodialysis in the United States. After three doses of vaccine (40 micrograms each) had been administered, 63 per cent of the patients were antibody-positive. After correction for possible passive transfer of antibodies by blood transfusion, only 50 per cent of vaccine recipients were considered vaccine responders. The incidence of hepatitis B viral infection during the 25 months of the trial was much lower than had been anticipated and was virtually the same in the vaccine and placebo recipients (6.4 and 5.4 per cent, respectively). Four cases of hepatitis B occurred in patients who had an apparent antibody response to the vaccine, but in each case either antibody had reached low or undetectable levels before hepatitis B surface antigen was detected or the patient had been receiving immunosuppressive therapy. This study did not demonstrate the efficacy of the vaccine in a population of patients receiving dialysis in whom both the rate of antibody response to hepatitis B vaccine and the viral attack rate were low. Other measures to control transmission of hepatitis B virus in dialysis units, including surveillance for hepatitis B surface antigen and isolation of patients who are positive for the antigen, must be continued.

Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection.

We evaluated the efficacy of hepatitis B vaccine (Heptavax-B) containing only the ad subtype in a randomized, placebo-controlled, double-blind trial among 865 staff members of 43 hemodialysis units in the United States. Surface antibody developed in 92.6 per cent of the subjects after two doses of vaccine and in 96 per cent after the six-month booster. The incidence of infections with hepatitis B virus (with or without hepatitis) was 9.9 per cent in placebo recipients and 2.2 per cent in vaccine recipients (P less than 0.01). The two cases of hepatitis B among vaccine recipients did not occur in subjects in whom antibody had developed. In 81 per cent of the hepatitis events, the virus was of the ay subtype. The indicence of ay virus was 8.2 per cent among placebo recipients and 1.2 per cent among vaccine recipients (P less than 0.005). We conclude that these data confirm the efficacy of the vaccine and demonstrate subtype cross-protection.

A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report.

A controlled, randomized, double-blind trial in 1,083 homosexual men from New York confirmed that a highly purified, formalin-inactivated vaccine against hepatitis B prepared from HBsAg positive plasma, is safe immunogenic, and highly efficacious. Over 95% of vaccinated subjects developed antibody against the surface antigen. Vaccine-induced antibody persisted for the entire 24-month follow-up period. The attack rate of all hepatitis B virus infections (excluding conversions of anti-HBc alone) was 3.2% in vaccine recipients compared with 25.6% in placebo recipients (p less than 0.0001). In those who received all three doses of vaccine, of 40 micrograms each, the protective efficacy rate was close to 100%. The vaccine protects against acute hepatitis B, asymptomatic infection, and chronic antigenemia. There is reason to assume that the vaccine is also partially effective when given postexposure.