Lung cancer in Louisiana: death certificate analysis.

In a search for etiologic clues, a review was made of death certificates of residents in a cluster of Louisiana parishes, mainly in the southern part of the state, where lung cancer mortality was high. A comparison of the statements on occupation for 3,327 patients with lung cancer and those of 3,327 controls (matched by sex, race, age, and parish of residence) during 1960-75 revealed an approximately twofold excess risk associated with transportation equipment manufacture, mainly shipbuilding, and the fishing industry. Smaller elevations of lung cancer risk were found among older men who had been employed in petroleum exploration and production and among male and female residents of towns where the petroleum industry was a major employer. In addition, Acadian ancestry was associated with a higher risk of lung cancer among older male and female residents.

Dietary determinants of gastric cancer in south Louisiana inhabitants.

In south Louisiana, 391 recently diagnosed gastric cancer patients and an equal number of controls were interviewed. Questions asked covered residential and occupational histories, environmental exposures, tobacco use, diet, alcohol consumption, and pertinent demographic characteristics. Elevated relative risks were found for use of tobacco and alcohol products. Diet was found to be the main determinant of gastric cancer risk in south Louisiana. Both dietary patterns and dietary risk factors differed for blacks and whites, although fruits as a group and dietary vitamin C were found to exert strong protective effects for both blacks and whites. Consumption of smoked foods and homemade or home-cured meats increased risk of gastric cancer for blacks but not for whites. The findings are discussed in the light of the prevailing etiologic hypotheses.

Lung cancer and the debrisoquine metabolic phenotype.

In a case-control study, we tested the hypothesis that the genetically determined ability to metabolize debrisoquine is related to risk of lung cancer. Overall, individuals who were extensive metabolizers of debrisoquine were at significantly greater risk of lung cancer than those who were poor or intermediate metabolizers (odds ratio = 6.1; 95% confidence interval = 2.2-17.1). In this study, case patients had lung cancer, and control subjects had either chronic obstructive pulmonary disease or cancers other than lung cancer. Results were adjusted for age, race, asbestos exposure, and smoking. Both black and white individuals who were extensive metabolizers of debrisoquine were at significantly increased risk after similar adjustment (for blacks, odds ratio = 4.5, 95% confidence interval = 1.1-18.1; for whites, odds ratio = 10.2, 95% confidence interval = 2.0-51.4). Significantly increased risk of lung cancer was also present for individuals who were extensive metabolizers when subjects with chronic obstructive pulmonary disease or other cancers were considered separately. These data confirm that the ability to metabolize debrisoquine is a major determinant of susceptibility to lung cancer. Evaluation of the marker in other case-control settings, further exploration of racial differences, and the prospective evaluation of this marker in subgroups at high risk of lung cancer are areas worthy of further study.

Diet in the etiology of oral and pharyngeal cancer among women from the southern United States.

A case-control interview study involving 227 women in North Carolina with oral cavity or pharyngeal cancer and 405 matched controls showed a protective effect of a usual adult diet high in fruits and vegetables. The relative risks of 0.65 for moderate and 0.52 for high (relative to 1.0 for infrequent) consumption of fruits and vegetables were statistically significant and remained after controlling for demographic characteristics, tobacco and alcohol use, relative weight, and intake of other food groups. Risks were lower with higher bread and cereal intake but higher for those women with the lightest weights, adjusted for height. The inverse associations between oral and pharyngeal cancer and intake of fruits and vegetables and intake of breads and cereals could not be attributed to an association with general nutritional status, since meat and fish consumption was related to an increased risk of oral and pharynx cancer. Moreover, dairy and egg consumption was generally unrelated to cancer risk. The reduction in risk with greater fruit and vegetable consumption is consistent with the hypothesis that vitamin C and/or beta-carotene intake is associated with a reduced risk of oral and pharyngeal cancer.

Colorectal cancer in rural Nebraska.

A case-control interview study of colorectal cancer was conducted in two rural counties of eastern Nebraska to determine reasons for the elevated colon cancer mortality rates during 1950 to 1969. Comparison of the information provided by 86 colorectal cancer cases and 176 matched controls (or their next of kin) revealed an increased risk among persons of Czech background, with persons of Bohemian and Moravian extraction predominating in this area. The data suggest an interaction between Bohemian ancestry and certain dietary patterns in the pathogenesis of colon cancer in this region. Colon cancer risk was elevated among commercial beer drinkers regardless of their ethnic background, although Bohemians reported heavier consumption. An excess risk was also associated with intestinal polyps, reported more often by Moravians, and with familial occurrence of gastrointestinal and other cancers. Since 1969, the mortality and incidence rates for colon cancer in this area have declined, possibly as a consequence of acculturation of the American-born descendants of Czech immigrants.

Case-control study of diet and mesothelioma in Louisiana.

Data were analyzed from a case-control interview study of malignant mesothelioma in Louisiana, which gathered information on usual diet and on lifetime occupational exposure to asbestos. Thirty-seven patients with malignant mesothelioma of the pleura (n = 32) or peritoneum (n = 5) were matched to controls according to age, sex, race, and factors related to case ascertainment (hospital and date of diagnosis, or parish and date of death). Twenty-one of the 37 cases were judged by masked occupational review to have been exposed to asbestos (57%), compared to seven of 37 controls (19%). Seven additional cases and 10 additional controls had occupational histories suggestive of asbestos exposure. With regard to usual diet before illness, cases reported less frequent consumption of homegrown produce (p = 0.005), cruciferous vegetables (p = 0.005), and all vegetables combined (p = 0.09) than did the controls. An estimate of usual carotene intake was also significantly lower in cases (p = 0.03). Dose-dependent reductions in risk were seen with increasing consumption of vegetables, especially cruciferous vegetables (p for trend = 0.013). These associations were not explained by differences in asbestos exposure as measured by the occupational review. The results indicate that consumption of vegetables or some vegetable-related constituent may have a protective effect on developing mesothelioma.

Occupational risk factors for laryngeal cancer on the Texas Gulf Coast.

Analyses are reported from a case-control interview study of incident laryngeal cancer on the Gulf Coast of Texas. Study subjects were 183 white men with squamous cell carcinoma of the larynx and 250 frequency matched controls. Occupational exposures were examined controlling for potential confounding by cigarette smoking and alcohol consumption. Significantly elevated risks were seen for men employed in the public services industry [transportation, communication, utilities, sanitary service; relative risk (RR), 1.6]; in metal fabricating (RR, 2.1), construction (RR, 1.7), and maintenance (RR, 2.7) occupations; and for workers potentially exposed to paint (RR, 1.8) and diesel or gasoline fumes (RR, 1.5). Elevated risks of border-line significance were seen for men employed as woodworkers/furniture makers (RR, 8.1) and for those with occupational exposure to asbestos (RR, 1.5). When asbestos was categorized by intensity of exposure, a significant positive gradient was found.

Effect of smoking and alcohol consumption on laryngeal cancer risk in coastal Texas.

Data from case-control studies of respiratory cancer conducted in the Texas Gulf Coast region between 1975 and 1980 were used to examine the effects of smoking and alcohol on laryngeal cancer risk. Analyses were limited to living white males, aged 30-79, which included 151 histologically confirmed incident laryngeal cancer cases and 235 population-based controls. A dose-dependent effect for cigarette smoking was observed, with odds ratios ranging from 4.4 for ever smoking up to one-half pack daily, to 10.4 for smoking more than two packs per day. Risks were strongest for current smokers and declined markedly following smoking cessation. Higher risks were associated with smoking nonfiltered than filtered cigarettes. No significantly elevated risks were associated with the use of other tobacco products. Odds ratios for alcohol beverages did not increase linearly with increasing use; instead risks were twofold for consumption of four or more drinks weekly. Patterns of risk associated with beer and hard liquor were not consistent and few participants drank wine. Although the data were sparse, a dose-response effect for alcohol intake was suggested for tumors of the supraglottis (n = 23), while for nonsupraglottic cases, alcohol risks were elevated but did not increase beyond those observed for four drinks per week. Predicted risks for the combined effects of cigarette and alcohol use were intermediate between an additive and multiplicative form of interaction.

The relation of passive smoking to lung cancer.

To evaluate the role of passive smoking in the development of lung cancer among nonsmokers, data were pooled from three large incident case-control interview studies. Ninety-nine lung cancer cases and 736 controls never used any form of tobacco. Overall the adjusted odds ratio for lung cancer among nonsmokers ever living with a smoker was 0.8 (95% confidence interval, 0.5-1.3) rising to 1.2 among those exposed for 40 or more years. Persons living with a spouse who smoked cigarettes were at increased risk (adjusted odds ratio, 1.5; 95% confidence interval, 0.8-2.8). When adjusted for age and gender, there was a significant trend in risk with increasing amounts smoked per week by the spouse (P = 0.05) and with cumulative pack-years of exposure (P = 0.03). This effect was limited to females, especially older women whose husbands were heavy smokers. The elevated risk associated with spouse smoking was restricted to squamous and small cell carcinomas (odds ratio, 2.9; 95% confidence interval, 0.9-9.3), which provides additional evidence linking passive smoking to lung cancer.

Salivary analysis for determination of dextromethorphan metabolic phenotype.

Debrisoquin oxidative phenotype is a determinant of pharmacologic response for many drugs. Poor and extensive metabolizers can be identified by the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan). We developed and tested a method to determine debrisoquin phenotype on the basis of the metabolic ratio in saliva. Each of 62 normal volunteers was given a 50 mg capsule of dextromethorphan hydrobromide and collected urine (0 to 8 hours) and saliva (at 3 hours). Dextromethorphan and dextrorphan in saliva and urine were assayed by HPLC. The distributions of paired urinary and 3-hour salivary metabolic ratios of samples from 61 subjects were compared. The urinary and salivary metabolic ratios were distributed trimodally and bimodally, respectively. The Spearman rank correlation coefficient for logarithm of urinary metabolic ratio vs that of salivary metabolic ratio was 0.704. All the poor metabolizers identified by urinary metabolic ratio were also identified by the metabolic ratio in saliva at 3 hours (100% concordance). This study demonstrates that salivary analysis for determination of dextromethorphan metabolic phenotype is feasible.

Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis.

BACKGROUND: The polymorphic metabolism of debrisoquin and sparteine by cytochrome P450IID6 (CYP2D6) is genetically determined. Determination of the CYP2D6 metabolic phenotype with conventional urine analytic methods is not feasible in anuric patients with renal failure. The possibility of using salivary analysis, with dextromethorphan as a probe drug, to determine the CYP2D6 metabolic phenotype in patients with renal failure was evaluated. METHODS AND RESULTS: One hundred four Chinese patients with renal failure were recruited. All 104 patients were receiving hemodialysis. Saliva was collected before and at 3 hours after each patient took a capsule of dextromethorphan hydrobromide (30 mg). Four patients were excluded because of insufficient samples of saliva. The distribution of logarithms of the metabolic ratios (log[MR]) in the 100 patients appeared to be normal. Administration of quinidine sulfate (200 mg twice daily) to nine of the patients significantly and markedly increased the dextromethorphan metabolic ratios. The metabolic ratios of nine patients pretreated with quinidine were higher than any of the 100 patients with renal failure who did not receive quinidine pretreatment. A metabolic ratio of 33 separated these two groups. Genomic deoxyribonucleic acid was extracted from whole blood in a subset of patients. Polymerase chain reaction (PCR)-based methods were used to detect the CYP2D6 and B mutant genes. Mutant B alleles (which are common in white poor metabolizers) of CYP2D6 genes were not detected in any of the 47 subjects tested. A PCR-based test of cytosine (C188) to thymine (T188) polymorphism at 188 base pairs in exon 1 of CYP2D6 genes was performed in 61 patients. Subjects who were homozygous for C188 had significantly (p = 0.0067) lower log[MR] values than those who were homozygous for T188. CONCLUSIONS: Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.

Epidemiology of bronchioloalveolar carcinoma.

Descriptive features of bronchioloalveolar carcinoma (BAC) are presented using Surveillance, Epidemiology and End Results Program population-based incidence data from 1973 through 1987, along with risk factors from histologically confirmed cases of BAC identified in a hospital-based case-control study conducted in Louisiana between 1979 and 1982. Compared to the rising incidence of lung cancer overall, BAC rates have remained relatively constant, accounting for less than 3% of all lung cancer. BAC incidence rates were higher in males, yet it explained proportionately more of the total lung cancer incidence in females. In the case-control study, 21 of the 33 cases originally ascertained from hospital pathology records were histologically confirmed as BAC. Most cases smoked cigarettes, with a 4-fold risk for ever smoking. Risks tended to increase with smoking intensity (reaching 10-fold for more than 1.5 packs/day) and duration (reaching 5-fold for more than 45 years of smoking). Following 10 or more years of employment, there was a 4-fold risk associated with motor freight occupations, along with nonsignificant excesses among construction workers, petroleum manufacturers, and sugar cane farmers. Cases were more likely than controls to have had emphysema or to have had a close family member with lung cancer. Although based on small numbers, this study suggests that BAC shares many of the epidemiological characteristics of lung adenocarcinoma.

Geographic distribution of motor neuron disease and correlation with possible etiologic factors.

Average annual age-adjusted motor neuron disease (MND) mortality rates were mapped for the first time at the county level in the continental United States. Although the great majority of the rates did not differ significantly from the US average, the highest mortality rates were generally found west of the Mississippi and the lowest rates east of the Mississippi. MND mortality was associated with rural farming and socioeconomic status but not with urbanization, physician-population ratios, lead or mercury exposure, or mortality rates of five kinds of cancer.

Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography.

To determine the mode of inheritance of hypertrophic cardiomyopathy (HC), 367 relatives from 70 families with HC were studied by M-mode and 2-dimensional echocardiography (2-D echo). Inspection of individual family pedigrees suggested that HC was genetically transmitted in 39 pedigrees (56%) and probably sporadic in 31 (44%). Of the 39 pedigrees with familial occurrence, 30 had patterns of inheritance that were most consistent with autosomal dominant transmission. A complex mathematical pedigree analysis determined that patterns of genetic transmission observed in the overall study group were not consistent with known models of autosomal dominant, autosomal recessive, or X-linked inheritance and did not support a unified concept of single-gene Mendelian transmission for all families. The proportion of first-degree relatives affected by HC was 22%, with HC most common in fathers of the proband and least common in offspring. About 20% of the affected relatives (10 of 53) appeared to have inherited a "subclinical" form of HC, in which the sole evidence of HC was the morphologic expression detectable only with echocardiography. Probands and affected relatives differed distinctly with regard to the expression of HC. Probands most often showed functional limitation (81%), subaortic obstruction at rest (53%), particularly diffuse distribution of left ventricular hypertrophy (59%) and marked septal thickening (mean 23 mm). In contrast, affected relatives were characterized by absence of functional limitation (72%) and subaortic obstruction (94%), localized and unusual sites of hypertrophy (60%) and only modest septal thickening (mean 17 mm).(ABSTRACT TRUNCATED AT 250 WORDS)

The logistic modeling of interobserver agreement.

An approach to the logistic modeling of interobserver agreement is described that allows for the estimation of a commonly employed measure of agreement. The dependent variable is defined to be 1 if the two raters agree, and 0 otherwise. Covariates may be included in the regression equation in order to obtain adjusted or subgroup-specific estimates of percent agreement. As an empirical example, logistic models were fitted to data from a validation study of the agreement between interview information and physician records on the history of post-menopausal estrogen use, from a case-control study of breast cancer conducted on Oahu, Hawaii. Variables found to be related to agreement in previous univariate analyses were examined as covariates in the logistic model. The directly calculated estimates of percent agreement agreed well with the modeled estimates derived from the regression coefficients. Thus, the logistic model may provide a useful alternative to existing methods for the description of interobserver agreement.

Lung cancer risk associated with cancer in relatives.

Family history data from an incident case-control study of lung cancer conducted in the Texas Gulf Coast region between 1976 and 1980 were analyzed to evaluate the contribution of cancer in first-degree relatives to lung cancer risk. Odds ratios (OR) increased slightly as the number of relatives with any cancer increased (reaching 1.5 with 4 or more relatives with cancer). Risks were higher for tobacco-related cancers (OR = 1.5 for 2 or more relatives with these tumors) and greatest for first-degree relatives with lung cancer (OR = 2.8 for lung cancer in 2 or more relatives). For cases of squamous cell carcinoma and adenocarcinoma of the lung, risks with 3 or more relatives with any cancer were increased 2-fold (OR = 1.8 and 1.9 respectively), and a significantly elevated risk was found for having a first-degree relative with lung cancer for each histologic type (ORs from 1.7-2.1). Having a spouse with lung cancer increased lung cancer risk (OR = 2.5), and cases with lung cancer reported in a first-degree relative were diagnosed at an earlier age, as were case siblings with lung cancer.

The logistic modeling of sensitivity, specificity, and predictive value of a diagnostic test.

A method is described for modeling the sensitivity, specificity, and positive and negative predictive values of a diagnostic test. To model sensitivity and specificity, the dependent variable (Y) is defined to be the dichotomous results of the screening test, and the presence or absence of disease, as defined by the "gold standard", is included as a binary explanatory variable (X1), along with variables used to define the subgroups of interest. The sensitivity of the screening test may then be estimated using logistic regression procedures. Modeled estimates of the specificity and predictive values of the screening test may be similarly derived. Using data from a population-based study of peripheral arterial disease, the authors demonstrated empirically that this method may be useful for obtaining smoothed estimates of sensitivity, specificity, and predictive values. As an extension of this method, an approach to the modeling of the relative sensitivity of two screening tests is described, using data from a study of screening procedures for colorectal disease as an example.

Conditioning-related toxicity and acute graft-versus-host disease in patients given methotrexate/cyclosporine prophylaxis.

Intensive chemoradiotherapy conditioning regimens and acute graft-versus-host disease (GVHD) are both associated with significant morbidity and mortality after bone marrow transplantation. In this study, we investigated whether the conditioning regimen affected the development of acute GVHD. Thirty-four patients, four with severe aplastic anemia and 30 with a lymphohemopoietic malignancy, were prepared for transplantation either with cyclophosphamide (CY) alone, with CY combined with total body irradiation (TBI) or CY combined with etoposide and either TBI or busulfan. GVHD prophylaxis included methotrexate (MTX 10 mg/m2) given on days 1, 3 and 6, and daily cyclosporine (CSP) on days--1 through 180. The overall incidence of acute GVHD was 36% (15% for HLA identical, 87% for HLA non-identical recipients). However, when assessed by the severity of conditioning regimen-related toxicity, the incidence of GVHD grades II-IV (HLA identical; HLA non-identical) was 0% (0%; 0%), 37% (20%; 67%) and 50% (22%; 100%) for patients with mild, moderate and severe toxicity, respectively. Compliance with GVHD prophylaxis declined with increasing intensity and toxicity of the conditioning regimen. These data suggest that a regimen of three doses of MTX and daily CSP is as effective as four doses of MTX/CSP for GVHD prophylaxis in patients given HLA identical marrow grafts. However, GVHD regimen compliance and efficacy of GVHD prevention are inversely related to the intensity of the conditioning regimen.

Some but not all benefits of intravenous immunoglobulin therapy after marrow transplantation appear to correlate with IgG trough levels.

Multiple benefits of intravenous immunoglobulin (IVIG) therapy after marrow transplantation have been reported, including decreased incidence of acute graft-versus-host disease (GVHD), infection, sepsis, cytomegalovirus (CMV) pneumonitis and platelet use. To test the hypothesis that the observed beneficial effects of IVIG are related to the serum IgG levels achieved, we followed IgG levels (pre-infusion, 1 h and 24 h post-infusion) in 45 consecutive marrow transplant recipients. IVIG 500 mg/kg was given weekly for six doses starting day -8 pre-transplant, then every other week for a total of 11 doses. Forty-one patients (22 allogeneic, 17 autologous, two syngeneic) were evaluable. Patients with acute GVHD had significantly lower serum IgG trough levels (less than 1200 mg/dl) noted at day +20 post-transplant and afterwards than patients without GVHD (greater than or equal to 1200 mg/dl). Pharmacokinetic modeling of the data indicates that IgG half-life between day -8 and day +6 may predict which recipients are at increased risk of acute GVHD. Allogeneic recipients in the group with trough levels less than 1200 mg/dl required more platelet transfusions. Although there was no significant difference in fungal infection rates or bacteremia, sepsis was noted in only two recipients (one allogeneic, one autologous), both with serum IgG trough levels less than 1200 mg/dl. In addition, three allogeneic recipients had cytomegalovirus pneumonitis, all in the group with lower IgG trough levels. Thus, while serum IgG trough levels less than 1200 mg/dl appear to be strongly associated with acute GVHD, low levels may also be associated with increased platelet utilization, with cytomegalovirus pneumonitis, and sepsis, but not with the overall incidence of infection.

Cytogenetics in hereditary malignant melanoma and dysplastic nevus syndrome: is dysplastic nevus syndrome a chromosome instability disorder?

Analysis of peripheral blood lymphocyte Giemsa-banded karyotypes was performed on 163 family members from 13 melanoma-prone families. Patients were classified regarding the presence of cutaneous melanoma and dysplastic nevi (a well characterized melanoma precursor), and each karyotype was scored for the number of cells containing the following: major structural, minor structural, and numerical abnormalities. No clonal cytogenetic abnormalities were observed. Cutaneous malignant melanoma and dysplastic nevi syndrome patients each had increased abnormalities of all types combined, compared with pooled controls (i.e., normal family members, and spouses; respectively, chi 2 = 6.02, p = 0.01; chi 2 = 5.29, p = 0.02). There was a statistically significant p-value for major structural abnormalities for melanoma patients and numerical abnormalities for the dysplastic nevi patients. Minor structural abnormalities did not differ in any of the groups. In addition, studies of ultraviolet induced sister chromatid exchange, in vitro tetraploidy, and extended prophase banding were performed on a limited number of patients. No significant differences between cases and controls were observed in these tests. Our data suggest that a chromosome instability abnormality may contribute to the pathogenesis of hereditary melanoma.