Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins.

BACKGROUND: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. METHODS: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. RESULTS: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs. CONCLUSION: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment.

High constant incidence in twins and other relatives of women with breast cancer.

The incidence of breast cancer rises steeply between ages 25 and 50, and more slowly thereafter. In contrast, the incidence in the unaffected (contralateral) breast of women who have had breast cancer remains constant at about 0.7% per year for at least the next 20 years after diagnosis, irrespective of age at first diagnosis. The incidence in relatives of the patients seems to show a similar pattern. The incidence in a prospective study of monozygotic twins of patients was approximately constant at 1.3% per year (77 cases), again about 0.7% per breast. At ages older than a patient's age at diagnosis, her mother and sisters have an incidence of 0.3-0.4% per year. Above the index patient's age at diagnosis, the rate in relatives shows no temporal trend and is independent of the patient's age at diagnosis. A statistically simple explanation is that incidence in susceptible women increases to a high constant level by a predetermined age that varies between families, but this seems inconsistent with conventional models of carcinogenesis and susceptibility. The very high incidence in monozygotic twins of patients indicates that a high proportion, and perhaps the majority, of breast cancers arise in a susceptible minority of women.

Evidence of genetic susceptibility to infectious mononucleosis: a twin study.

Infectious mononucleosis is a clinical manifestation of primary Epstein-Barr virus infection. It is unknown whether genetic factors contribute to risk. To assess heritability, we compared disease concordance in monozygotic to dizygotic twin pairs from the population-based California Twin Program and assessed the risk to initially unaffected co-twins. One member of 611 and both members of 58 twin pairs reported a history of infectious mononucleosis. Pairwise concordance in monozygotic and dizygotic pairs was respectively 12·1% [standard error (s.e.)=1·9%] and 6·1% (s.e.=1·2%). The relative risk (hazard ratio) of monozygotic compared to dizygotic unaffected co-twins of cases was 1·9 [95% confidence interval (CI) 1·1-3·4, P=0·03], over the follow-up period. When the analysis was restricted to same-sex twin pairs, that estimate was 2·5 (95% CI 1·2-5·3, P=0·02). The results are compatible with a heritable contribution to the risk of infectious mononucleosis.

Parallels in the epidemiology of selected anogenital carcinomas.

Characteristics of Los Angeles, Calif., residents in whom carcinomas of the cervix, vulva, vagina, anus, and penis were diagnosed during the period 1972-81 were compared with those of all residents and with those in whom any cancer was diagnosed during the same period. At all five sites, risks for squamous and transitional cell carcinomas generally increased with decreasing social class, were low among Jews (not explained by social class), and were elevated among persons who were separated or divorced at diagnosis compared to married persons. Single men had a striking excess of anal but not penile carcinomas. The five sites represent contiguous and histologically similar tissues, and the clinical literature suggests common risk factors, e.g., sexually transmitted infections and other forms of chronic irritation. These observations are all consistent with the hypothesis that tumors at these sites have common or similar etiologic elements.

Secular trends in histologic types of lung cancer.

The histology pattern of lung cancer in Los Angeles County was reviewed for a 10-year period, 1972-81. In men, the total lung cancer incidence has been fairly constant, but there has been a shift in the histology pattern with an increase in adenocarcinoma and a decrease in "other" cell type (i.e., carcinoma not otherwise specified, large-cell and undifferentiated tumors). This changing histology pattern may be partly due to changes in diagnostic standards and practices. With the assumption that these changes are comparable in men and women, the "true" annual rate of change was estimated for each lung cancer cell type in women. All lung cancer types have increased in women; of the cell types squamous cell carcinoma, small-cell carcinoma, and adenocarcinoma, small-cell carcinoma showed the largest rate of annual increase and adenocarcinoma, the smallest.

Cancer of the gastrointestinal tract among Japanese and white immigrants in Los Angeles County.

With the use of age-adjusted incidence rates and proportional incidence ratios, investigators studied the risk of cancer of the stomach and 3 subdivisions of the large bowel in three race-ethnic groups--Spanish surnamed whites, other whites, and Japanese--and compared Los Angeles County native residents, immigrants, and representative "homeland" populations. The risk pattern for each of the four anatomic sites was quite distinctive, suggesting at least four different etiologic complexes. For each site the observed gradients of risk are nearly identical for each sex, usually with risk for immigrants intermediary between that for homeland residents and that for local natives; the differences between race-ethnic groups are consistent with known international patterns. Particularly notable is the contrast between the low risks of cancer of both the sigmoid and the rectum in Japan and the high risks for Japanese immigrants to Los Angeles, which are nearly double those of their U.S. white neighbors. In all instances, and especially for both the upper and lower colon, the influence of the adult environment predominates over that of the early environment. The environmental determinants of stomach cancer do not always appear in inverse correlation with those of colon cancer, since Japanese immigrants to Los Angeles and their descendants are at high absolute and relative risk of both neoplasms. Our findings suggest that patterns of risk in relation to migration are complex and defy simple dietary or other interpretation. Without more information about the impact of migration to the United States on qualitative and quantitative aspects of lifestyle, it is not possible to put forward simple hypotheses that explain all available facts.

Pancreas cancer and smoking, beverage consumption, and past medical history.

Four hundred and ninety pancreas cancer patients representative of confirmed cases in Los Angeles County residents of working age were compared to healthy controls individually matched by age, sex, race, and neighborhood. Home interviews were conducted on occupation, smoking, food and beverage consumption, and medical history. Cigarette smoking was a strong and consistent predictor of pancreas cancer occurrence; the effect disappeared after a decade of nonsmoking, and there was no increase in risk among current smokers as daily dose increased. There was no link between pancreas cancer and past consumption of tea, carbonated beverages, beer, or spirits; and an association with coffee consumption was inconsistent. A strong association between pancreas cancer and history of subtotal gastrectomy at any past time could not be explained by chance or any other factor. Pancreas cancer patients had experienced fewer allergies of any kind.

Risk factors for invasive cervical cancer among Latinas and non-Latinas in Los Angeles County.

A case-control study among white women in Los Angeles County was conducted to investigate etiologic factors that might explain the high rates of invasive cervical cancer among Latinas. Two hundred patients with invasive squamous cell carcinoma of the uterine cervix and matched (age, sex, preferred language, and neighborhood) controls were interviewed, 98 pairs in English and 102 pairs in Spanish. Seven factors were found to contribute independently and significantly (P less than .01) to risk, each after adjustment for the other six: years since last Pap smear, years of education (protective), frequency-years douching, pack-years of smoking, years of barrier contraceptive use (protective), number of sexual partners before age 20, and recognized episodes of genital warts. An eighth variable, interval in years between menarche and first intercourse, was the second variable to enter the stepwise logistic regression analysis but lost its statistical significance when sexual partners before age 20 entered the model. Together, these eight variables accounted for almost 99% of the risk. There were no significant interactions between any of these variables and age, language of interview, or birth in a Latin country. There was no increased risk associated with use of oral contraceptives, either before or after adjustment for the other significant factors. Compared to English-speaking controls, Spanish-speaking controls smoked less, douched less, had fewer sexual partners before 20, and had essentially the same average interval between menarche and first intercourse and the same average number of episodes of genital warts; however, they had had a longer interval since their last Pap smear, fewer years of barrier contraceptive use, and fewer years of education. Education, presumably a correlate of an inadequately measured etiologic risk factor (possibly papillomavirus infection), was responsible for the greatest difference in risk between the Spanish- and English-speaking cases.

Cigarette smoking, obesity, diuretic use, and coffee consumption as risk factors for renal cell carcinoma.

One hundred sixty incident cases of renal cell carcinoma under the age of 55 years and an equal number of age-(within 5 yr), race-, and sex-matched neighborhood controls were interviewed. Cigarette smoking was a risk factor for renal cell carcinoma in males [relative risk (RR) = 2.1, one-sided P = .02] but not in females (RR = 1.1, P = .50). Obesity was a significant risk factor in both males and females: The RR for a 4th quartile compared to a 1st quartile Quetelet's Index 10 years ago was 2.5 for males and 3.3 for females. Additional risk factors in females were diuretic use (RR = 4.5, P = .002) and daily coffee consumption (RR = 2.3, P = .06).

DDT and related compounds and risk of pancreatic cancer.

BACKGROUND: A cohort mortality study among 5886 chemical manufacturing workers was completed in 1987 and showed increased mortality due to pancreatic cancer. PURPOSE: We conducted a nested case-control study of pancreatic cancer among these chemical manufacturing workers to identify risk factors for this disease. METHODS: Twenty-eight verified cases of pancreatic cancer and 112 matched controls were studied. Next of kin of each subject were interviewed to determine lifestyle factors, including tobacco, alcohol, and coffee consumption. Written work records and interviews with co-workers were used to determine chemical exposures at the plant under study. RESULTS: DDT was associated with pancreatic cancer (risk ratio [RR] for ever exposed compared with never exposed = 4.8; 95% confidence interval = 1.3-17.6). Among subjects who had a mean exposure to DDT of 47 months, the risk was 7.4 times that among subjects with no exposure. Two DDT derivatives, Ethylan and DDD, were additionally associated with pancreatic cancer (RR = 5.0 and 4.3, respectively); exposures to these two chemicals were correlated, and it was not possible to determine whether each acted independently of the other. Smoking was identified as an independent risk factor, but controlling for smoking (and other potential confounders) in the analyses did not appreciably alter the risks seen for DDT, DDD, or Ethylan. CONCLUSIONS: Exposure to DDT was associated with pancreatic cancer. The association was not explained by exposure to lifestyle factors or other chemicals, and risk increased with both duration of exposure and latency since first exposure. IMPLICATIONS: These results may indicate that DDT can cause pancreatic cancer in humans under circumstances of heavy and prolonged exposure.

Increased frequency of adenocarcinoma of the uterine cervix in young women in Los Angeles County.

By hypothesizing that oral contraceptives (OC's) might have a carcinogenic effect on glandular cells of the cervix if given during periods of active metaplasia (e.g., postmenarchal adolescence), an increasing rate of cervical adenocarcinoma was predicted in young women who had been teenagers when OC's were introduced roughly 20 years ago. Secular trends for cervical carcinomas in non-Hispanic whites were examined by age, histologic type, and social class by using data from the Los Angeles County population-based tumor registry. Between 1972 and 1982, the frequency of invasive cervical adenocarcinoma in women under 35 years of age increased from about 2 to about 5 annually, amounting to an average rate of change of 8% per year (P less than .01). There was essentially no trend for women over 35 years old; the frequency of other invasive carcinomas (and of squamous carcinoma in situ) decreased at average rates of about 3% per year in women under 35 years of age and decreased more rapidly in older women. The increase in adenocarcinoma, unlike risk from cervical cancer generally, was most striking among young women residing in middle-to-upper income neighborhoods, who were the first to use OC's; in this subgroup the average rate of increase was 16% per year (P less than .05). These findings are compatible with our hypothesis and merit further study.

Estrogen-progestin replacement therapy and endometrial cancer.

BACKGROUND: It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. PURPOSE: We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. METHODS: A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. RESULTS: The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects). CONCLUSIONS: The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.

Tobacco, alcohol, diet, occupation, and carcinoma of the esophagus.

Information on occupation, smoking, food and beverage consumption, and medical history were compared between 275 incident cases of carcinoma of the esophagus and 275 neighborhood controls who were matched to the cases on age (within 5 years), race, and sex. Tobacco use, mainly cigarette smoking, was a significant risk factor for carcinoma of the esophagus. Ex-smokers of cigarettes showed a reduced risk relative to those who continued to smoke, and current smokers of two or more packs per day displayed a higher risk than those who smoked less. Alcohol consumption was another significant risk factor for carcinoma of the esophagus; there was a highly significant trend with average daily dose of ethanol. Relative to controls, cases also consumed significantly more fried bacon or ham, less fresh fruits and raw vegetables, and were more likely to prefer white than whole grain bread. Finally, there was a significant association between carcinoma of the esophagus and long-term occupational exposure to metal dust; this association was largely confined to the lower one-third section of the esophagus.

Life-style, workplace, and stomach cancer by subsite in young men of Los Angeles County.

A case-control study involving interviews with 137 incident male cases of stomach cancer under the age of 55 yr and an equal number of age- (within 5 yr), race-, and sex-matched neighborhood controls in Los Angeles County was conducted. Cases were more likely to be foreign born and had less education compared with controls. Any use of tobacco products conferred a 2-fold increase risk for stomach cancer; the effect was present in all subsites: the cardia; fundus/body; and antrum/pylorus. Weekly use of alcoholic beverages was also a risk factor, but the effect was not observed in the antrum/pylorus. In comparison with controls, cases had a significantly higher intake of beef (cardia only) and barbecued/smoked foods, had a lower intake of fresh fruits/vegetables, and were more likely to prefer white than whole grain bread. Occupational exposure to metal dust was associated with a 70% increased risk of stomach cancer, with an increase in risk as the duration of exposure increased. This association was most pronounced for tumors in the antrum and pylorus. Subjects with a history of stomach or duodenal ulcer showed a 2-fold increased risk of stomach cancer. The effects of smoking, alcohol, intake of white bread, history of ulcer, and exposure to metal dust remained statistically significant when these variables were examined simultaneously in multivariate analyses and when the multivariate analyses were confined to directly interviewed subjects.

A case-control study of occupational and dietary factors in colorectal cancer in young men by subsite.

With the hope that exposures responsible for colorectal cancer might be especially obvious among those in whom it develops early, 147 men with colorectal carcinomas first diagnosed between the ages of 25 and 44 years were compared to neighborhood controls. Physical activity on the job was protective for tumors located in the transverse and descending portions of the colon. Rectal cancer and to a lesser extent sigmoid cancers were associated with jobs in which dusts or fumes were inhaled, especially if those jobs were held for long periods in young adulthood. While risk for rectal cancer did not seem to be limited to any particular type of dust or fume, the excess risk was strongest for wood and metal dusts. Consumption of fruits and vegetables and a preference for whole grain breads were protective for colon but not rectal cancers, while consumption of deep fried foods and barbecued/smoked meats increased risk at specific subsites. Beef intake, alcohol consumption, and cigarette smoking appeared to play little or no role at any subsite.

North-American twins with IDDM. Genetic, etiological, and clinical significance of disease concordance according to age, zygosity, and the interval after diagnosis in first twin.

In 224 twin pairs (132 monozygotic, 86 dizygotic, and 6 of uncertain zygosity) in whom the index twin had developed IDDM before 30 yr of age, 51 of the co-twins (38 monozygotic, 10 dizygotic, and 3 of uncertain zygosity) subsequently became diabetic. On the basis of concordance ratios, which were significantly discrepant (P < 0.01) between monozygotic and dizygotic twins, the substantial genetic role in IDDM etiology is confirmed. For the monozygotic co-twin of an IDDM case, the relative risk is significantly related to an early age at proband diagnosis (P < 0.01 for 0-4 vs. 5-9 yr of age). However, among monozygotic co-twins at any age, IDDM risk decreases as time passes after the proband diagnosis (P < 0.01 for 0-23 vs. > or = 24 mo after a proband diagnosis at 5-9 yr of age). Moreover, a structural-equation analysis suggests a profound contribution to liability (as much as 79%) from the twins' shared environment. Risk to like-sex male dizygotic co-twins is as high as that to monozygotic co-twins, significantly higher than that to like-sex female dizygotic co-twins (P < 0.005), and even higher than that to male co-twins in unlike-sex dizygotic pairs (P < 0.05). Overall, the risk to the dizygotic co-twin of a case is significantly higher (P < 0.001) than that to a non-twin sibling, as reported in the literature. The observed male excess is consistent with reported patterns of IDDM in experimental animals, and in certain circumstances in humans. Taken together, these observations suggest an important early acquired determinant of IDDM, independent of genetic determinants. On the basis of Kaplan-Meier IDDM-free survival curves, if the proband is diagnosed before 15 yr of age, the long-term risk to the co-twin is estimated at 44% (monozygotic) and 19% (dizygotic); it reaches 65% for the co-twin of a monozygotic proband diagnosed before 5 yr of age. An IDDM discordant period of no more than 3 yr was observed in 60% of the pairs destined to become concordant, offering a very brief window for intervention following the recognition of high risk.

Risk patterns of Hodgkin's disease in Los Angeles vary by cell type.

Over the period 1972-1985, 2729 cases of Hodgkin's disease were diagnosed in Los Angeles County, and 2492 were subclassified using the Rye classification. The occurrence of these cases was examined in relation to age, sex, race, place of birth, social class, occupation, and year of diagnosis. The pattern of nodular sclerosis occurrence conformed to expectations, supporting the polio model of etiology for this subtype. However, the risk pattern of mixed cell disease was quite distinct from that of nodular sclerosis, suggesting that the two may not share a common etiology. The pattern of lymphocyte predominance in Hodgkin's disease, with a special prominence in younger blacks, resembled neither that of nodular sclerosis nor that of mixed cell disease. The cases of lymphocyte-depletion Hodgkin's disease showed no distinctive epidemiological features, and its continued classification with nodular sclerosis and/or mixed cellularity can be justified solely by histological or biological evidence.

Postmenopausal carcinoma as a result of estrogen treatment: survey of evidence.

Recent studies concerning the relationship of exogenous estrogens and endometrial cancer have been reviewed and the objections to their conclusions discussed. Even considering the most serious of these reservations, it is difficult to avoid the tentative conclusion that estrogens are causally linked to endometrial cancer and that the attributable risk is numerically sizable. Whether the medical costs will be ultimately shown to outweigh the benefits of estrogen replacement therapy will depend largely on whether or not a relationship to breast cancer is shown and on the magnitude of the effect of estrogens in preventing serious complications of ovarian failure. For the time being, treatment of menopausal symptoms with estrogens should be brief as possible, should use the lowest dose possible, and should probably be given in cyclic fashion, particularly to women with intact uteruses. Every attempt should be made to give patients a quantitative understanding of both potential risks and benefits before they decide in favor of or against estrogen therapy.

Urogenital tract abnormalities in sons of women treated with diethylstilbestrol.

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices. The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).

Re-evaluating the role of progestogen therapy after the menopause.

An estrogen-progestogen regimen of hormone replacement therapy has become widely used in recent years, primarily as a means to protect the endometrium from the carcinogenic effects of unopposed estrogen therapy (ERT). In this article, we evaluate the probable effects of this regimen on mortality from endometrial cancer as well as mortality from other chronic diseases. We conclude from this analysis that ERT is to be preferred to combination therapy for postmenopausal women without a uterus, primarily because it is predicted that ERT confers a significantly greater benefit on heart disease risk. In women with a uterus, if progestogens are to be prescribed, they should be given in the lowest possible dose needed to achieve the desired histologic changes in the endometrium, since the predicted loss in heart disease benefit from adding the progestogen is substantial.