Reinhold Bergström

Association between Body Mass and Adenocarcinoma of the Esophagus and Gastric Cardia

The reasons for the increase in the incidence of esophageal and gastric cardia adenocarcinoma in several industrialized countries (1-4) are largely unknown (5). In the United States, the relative increase in the incidence of esophageal adenocarcinoma exceeds that of any other type of cancer (1). Obesity, which has been found to be linked with a moderately increased risk for adenocarcinoma in some (6-9) but not all (10, 11) previous epidemiologic studies, is one factor that could explain this epidemic because the prevalence of obesity has increased concomitantly (12-14). No evidence shows a link between obesity and squamous-cell carcinoma (the other main histologic type of esophageal cancer) or adenocarcinoma of the distal stomach (9). As part of a nationwide casecontrol study of risk factors for esophageal and gastric cardia adenocarcinoma, we analyzed body measures in relation to the risk for developing these tumors. Our primary aim was to precisely estimate the strength of the association while adjusting for potential confounding factors. We also examined the effects of body mass early in life compared with its effects late in life and assessed the relative importance of physical activity and energy intake. Methods Participants Our methods have been described in detail previously (15). The study base consisted of all Swedish residents who had been born in Sweden, were younger than 80 years of age, and lived in Sweden from 1995 through 1997. All persons in the study base who developed new esophageal or cardia adenocarcinomas and persons who developed esophageal squamous-cell carcinoma and were born on even dates were eligible as case-patients. We included 189 patients with esophageal adenocarcinoma, 262 patients with cardia adenocarcinoma, and 167 patients with esophageal squamous-cell carcinoma. These persons constituted 87%, 83%, and 73%, respectively, of all eligible patients in the study base. Physical disorders, mental disorders, or early death prevented participation in 12% to 22% of the eligible patients, and 1% to 5% of patients declined to participate. The 820 population-based controls represented 73% of those originally selected; of these persons, 19% declined to participate, 6% had physical or mental disorders, and 2% could not be contacted. The proportions of men among patients with esophageal adenocarcinoma, cardia adenocarcinoma, and esophageal squamous-cell carcinoma were 87%, 85%, and 72%, respectively; 83% of controls were men. The median ages for both sexes in these four groups were 69 years, 66 years, 67 years, and 68 years, respectively. The study was approved by all regional ethics committees in Sweden, and individual informed consent was obtained from each participant before the interview. Exposure Information At face-to-face interviews conducted by trained professional interviewers, participants were asked about height and weight at 20 years of age and at 20 years before the interview. Body mass index (BMI) (16) was calculated as body weight in kilograms divided by the square of body height in meters (kg/m2). To obtain an independent measure of body fat, we asked each interviewee to choose the picture that best resembled his or her body build 20 years ago from a pictogram that showed nine somatotypes ranging from very lean to grossly obese. The Spearman correlation coefficient with BMI is 0.5 to 0.8 (17). Weight change between 20 years of age and 20 years before the interview was calculated in kilograms and in percentage of body weight at 20 years of age. Meal sizeself-reported by each participant by using photographs of seven common disheswas divided into three categories and used as a measure of energy intake. This method gives an acceptably valid representation of energy intake (18, 19). Physical activity was divided into four levels by using a combination of 12 variables, including usual activities, such as standing, walking, and climbing stairs; physical activities during leisure time; and physical exertion at work. The interviewers could not be blinded to the casecontrol status of the interviewees, but they were completely blinded to the study hypothesis and were urged to treat patients and controls equally. Clinical Information All 195 hospital departments involved in the diagnosis or management of these patients collaborated in the recruitment of patients. The regional tumor registries helped us to identify missed cases. We used a common protocol for uniform documentation and classification of the tumors. At endoscopy, we measured the distances between the gastroesophageal junction (defined as the point at which the proximal longitudinal mucosal folds begin in the stomach) and the upper and lower borders of the tumor. The protocol also prescribed that serial biopsy specimens should be taken at points 2 cm apart, from the proximal stomach, through the gastroesophageal junction, and into the esophagus until normal squamous-cell epithelium was reached. Additional specimens were to be obtained proximal, distal, and lateral to the tumor. Surgeons and pathologists were required to provide standardized, detailed descriptions of the location of the cancer in the 424 patients in whom surgery was performed. In addition, 97% of all biopsy and surgical specimens were reexamined by one pathologist. Barrett esophagus was defined as columnar-cell metaplasia of the specialized type, with goblet cells and villiform surface configuration of the mucosa resembling the features of the intestines. Cancer of the gastric cardia had to have its center within 2 cm proximal, or 3 cm distal, to the gastroesophageal junction. If Barrett esophagus was detected adjacent to the tumor, it was classified as esophageal regardless of its location. We classified squamous-cell carcinomas as esophageal even if they were located in the gastric cardia. Population-based controls were randomly selected from age and sex strata in the complete and continuously updated population register to obtain an age and sex distribution similar to that of patients with esophageal adenocarcinoma. Statistical Analysis Logistic regression was used in univariate and multivariate analyses of the relation among anthropometric measures, potential confounding variables, and cancer risk. Patients in each category of cancer were compared with all controls. Model variables were estimated by the maximum likelihood method (20) and converted to odds ratios and 95% CIs. In the baseline model, adjustments were made for age (in 5-year classes) and sex; in the multivariate analyses, we further adjusted for tobacco smoking (never-smokers, former smokers, and current smokers 2 years before the interview), alcohol use (grams of pure alcohol in four classes), years of formal education (in four classes), reflux symptoms (heartburn or regurgitation at least once per week occurring at least 5 years before the interview), intake of fruit and vegetables (in four classes), meal size, and physical activity. Variables were considered in both categorized and continuous form. Wald tests and likelihood ratio tests were used. The relation of BMI to physical activity and meal sizeadjusted for age, sex, and diagnostic groupwas analyzed by linear regression analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Esophageal Adenocarcinoma We found a positive association between BMI 20 years before the interview and risk for esophageal adenocarcinoma. This association was dose-dependent across the entire range of BMI values (Table 1). The multivariate-adjusted odds ratio was 7.6 (95% CI, 3.8 to 15.2) among persons in the highest BMI quartile compared with those in the lowest BMI quartile. The highest BMI quartile included both overweight and obese persons, as defined according to World Health Organization criteria (21). We therefore reanalyzed the association using more commonly applied BMI cutoff points. Obese persons (persons with BMI>30 kg/m2) had an odds ratio of 16.2 (CI, 6.3 to 41.4) compared with persons whose BMI was less than 22 kg/m2. Table 1. Body Measures and Risk for Esophageal Adenocarcinoma The association between esophageal adenocarcinoma and BMI was supported by our finding of a dose-dependent relation between esophageal adenocarcinoma and somatotype (P for trend<0.001). The adjusted odds ratio among persons who reported that their body build 20 years before the interview corresponded to one of the four obese somatotypes in our pictogram was 4.1 (CI, 2.6 to 6.7) compared with persons reporting one of the three lean somatotypes. Weight gain after 20 years of age, both in absolute values and expressed as percentage of weight at 20 years of age, increased the risk monotonically (P for trend<0.001); after adjustments for BMI 20 years before the interview, however, this effect disappeared almost entirely. Height was inversely and significantly (P=0.03) associated with risk. A 50% risk reduction was found among the tallest persons compared with the shortest persons. Stratified analyses showed a seemingly stronger association between BMI and risk for esophageal adenocarcinoma among persons 60 to 69 years of age compared with those in other age strata and among women compared with men; however, the CIs were wide and the differences were not statistically significant (Table 2). No important confounding was caused by any of the seven additional covariates. The presence of reflux symptoms at least 5 years before the interview did not affect the association between BMI and esophageal adenocarcinoma. Therefore, BMI was a risk factor independent of the occurrence of gastroesophageal reflux. The strength of the association with BMI was equally strong among the 118 patients with histologically verified Barrett esophagus and the 71 patients without this metaplasia (data not shown). Table 2. Stratified Analyses of the Association between

The Risk of Stomach Cancer in Patients with Gastric or Duodenal Ulcer Disease

BACKGROUND Helicobacter pylori infection, now considered to be a cause of gastric cancer, is also strongly associated with gastric and duodenal ulcer disease. The discovery of these relations has brought the long-controversial connection between peptic ulcers and gastric cancer into focus. METHODS We estimated the risk of stomach cancer in a large cohort of hospitalized patients with gastric or duodenal ulcers, as recorded in the Swedish Inpatient Register between 1965 and 1983. Altogether, 57,936 patients were followed through 1989, for an average of 9.1 years. The standardized incidence ratio--the ratio of the observed number of cancers to the number expected on the basis of the incidence in the Swedish population at large--was used as a measure of relative risk. RESULTS After peaking in the first 3 years of follow-up, the standardized incidence ratio for gastric cancer among 29,287 patients with gastric ulcers leveled off at 1.8 (95 percent confidence interval, 1.6 to 2.0) and remained significantly increased throughout follow-up, which was as long as 24 years for some patients. Prepyloric ulcer, diagnosed in 8646 patients, was not associated with a significant excess risk (standardized incidence ratio, 1.2; 95 percent confidence interval, 0.8 to 1.6). In the cohort of patients with duodenal ulcers (24,456 patients), the incidence of gastric cancer was significantly lower than expected. After the second year of follow-up, the standardized incidence ratio was only 0.6 (95 percent confidence interval, 0.4 to 0.7) and remained stable thereafter. CONCLUSIONS Gastric ulcer disease and gastric cancer have etiologic factors in common. A likely cause of both is atrophic gastritis induced by H. pylori. By contrast, there appear to be factors associated with duodenal ulcer disease that protect against gastric cancer.

Breast-cancer risk following long-term oestrogen-and oestrogen-progestin-replacement therapy

While use of hormone‐replacement therapy (HRT) effectively alleviates menopausal symptoms and prevents osteoporosis and possibly cardiovascular disease, there is concern of a detrimental impact on breast‐cancer risk. There is a particular lack of data regarding the effect of long‐term use of oestrogen‐progestin combinations on breast‐cancer risk. We conducted a large epidemiological study in Sweden, where combined oestrogen‐progestin treatment has been predominant, to examine the influence of different regimens of menopausal hormone therapy on breast‐cancer risk. In this population‐based case‐control study, 3,345 women aged 50 to 74 years with invasive breast cancer (84% of all eligible) and 3,454 controls of similar age (82% of all selected) were included. Mailed questionnaires and telephone interviews were used to collect detailed information on use of hormone replacement and on potential confounding factors. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multiple logistic regression. There was a trend of increasing breast‐cancer risk with duration of oestrogen/oestrogen‐progestin use (OR for women treated at least 10 years, 2.43; 95% CI, 1.79–3.30, as compared to never‐users), with statistically significant estimates only for women with BMI < 27 kg/m2. Excess risks were observed to current use and use that ceased more than 10 years ago (OR for women treated at least 5 years, OR was 2.68, 95% CI, 2.09–3.42, and OR 2.57, 95% CI, 1.28–5.15, as compared with never‐users, respectively). A positive association which was noted for use of oestrogen combined with testosterone‐derived progestins appeared especially pronounced with continuously combined regimens. Long‐term use of replacement oestrogens with or without progestins may substantially increase the incidence of post‐menopausal breast cancer, particularly among non‐obese women. Int. J. Cancer 81:339–344, 1999.

The risk of acute myocardial infarction after oestrogen and oestrogen‐progestogen replacement

Objective To determine the relative risk of developing a first acute myocardial infarction after treatment with oestrogens alone or oestrogen‐progestogen combinations.

The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia

While tobacco and alcohol are established risk factors for oesophageal squamous‐cell carcinoma, their roles in the aetiology of the increasingly common oesophageal adenocarcinoma remains uncertain. We tested the association between tobacco, snuff and alcohol use and the risk of oesophageal and cardia cancer in a nationwide, population‐based case‐control study in Sweden. Face‐to‐face interviews were conducted with 618 (81% of all eligible) patients (189 oesophageal adenocarcinoma, 262 cardia adenocarcinoma and 167 oesophageal squamous‐cell carcinoma) and 820 control subjects. Odds ratios (OR) were calculated by logistic regression with multivariate adjustments for potential confounding. The risk of oesophageal adenocarcinoma was not associated with snuff or alcohol use, and the association with smoking was weak or absent. Gastric cardia adenocarcinoma was dose‐dependently associated with smoking (OR=4.2, 95% CI=2.5–7.0 among heavy smokers compared with never‐smokers), but not with alcohol or snuff use. Oesophageal squamous‐cell carcinoma was strongly associated with tobacco, moderately with alcohol, but not with snuff use; combined use of tobacco and alcohol entailed a strongly increased risk (OR=23.1, 95% CI=9.6–56.0 among heavy users compared with never‐users). We conclude that tobacco smoking, a strong risk factor for oesophageal squamous‐cell carcinoma and cardia adenocarcinoma, does not play an important role in the aetiology of oesophageal adenocarcinoma. None of the studied exposures can explain the increasing incidence of oesophageal adenocarcinoma. Int. J. Cancer 85:340–346, 2000. ©2000 Wiley‐Liss, Inc.

Helicobacter pylori Infection: Independent Risk Indicator of Gastric Adenocarcinoma

BACKGROUND Helicobacter pylori has been implicated as a possible etiologic factor in gastric cancer. This case control study was performed to determine the association between H. pylori and gastric cancer, taking into account the possibility of confounding by other background factors. METHODS Sera were collected from 112 incident case patients with gastric cancer and 103 control patients with nongastroenterological diseases, who were frequency-matched with respect to age and sex. Immunoglobulin G antibodies to H. pylori were identified using the HM-CAP immunoassay (Enteric Products Inc., Wesbury, NY). RESULTS The prevalence of H. pylori seropositivity was significantly higher (P = 0.002) among case patients than control patients. The odds ratio (OR) was 2.60 (95% confidence interval, 1.35-5.02). The increased OR associated with H. pylori infection was confined to tumors with a noncardia location (OR, 3.06) and men (OR, 4.27). OR increased with decreasing age at cancer diagnosis to reach 9.33 in patients < 60 years of age. Multivariate logistic regression analysis was used as control for potential confounding, but the elevated OR associated with H. pylori infection remained significantly increased. CONCLUSIONS The results support the hypothesis of H. pylori infection as an independent risk indicator of gastric cancer.

Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.

Fracture of the distal forearm as a forecaster of subsequent hip fracture: a population-based cohort study with 24 years of follow-up.

SummaryObjective: To determine the long-term risk of hip fracture following fracture of the distal forearm. Design: Registry-based cohort study comparing patients with a fracture of the distal forearm with a population-based cohort. Fracture cohort: All women and men above 40 years of age with a radiologically verified fracture of the distal forearm during a 5-year period. 1968–1972, in all 1,126 women and 212 men. Control cohort: An equal number of population-based, age-and sex-matched control persons selected from a population register. Measurements: All cohort members were followed up individually through record linkage until the first hip fracture, emigration, death, or the end of 1991. The cohort members contributed a total of 40,832 person-years of observation, and altogether 365 cases of hip fractures were observed. Results: Both women and men with a fracture of the distal forearm ran an increased risk of sustaining a subsequent hip fracture. The overall relative hazard for the women was 1.54 and for men 2.27. The increased risk in the women was independent of age at inclusion, but that in the men was more pronounced in the younger age groups. Conclusions: Patients with a fracture of the distal forearm run an increased risk of sustaining a subsequent hip fracture. They therefore appear to constitute a group in which appropriate prophylactic measures against osteoporosis and fractures should be considered.

Sternal wound complications-incidence, microbiology and risk factors

OBJECTIVE Sternal wound complications, i.e. instability and/or infection (mediastinitis), are important causes of morbidity in patients undergoing cardiac surgery via median sternotomy. Coagulase negative staphylococci, a normal inhabitant of the skin, have evolved as a cause of sternal wound infections. Since these opportunistic pathogens often are multiresistant, they can cause therapeutic problems. METHODS From 1980 through 1995 open heart surgery, was performed on 13,285 adult patients. Reoperation necessitated by sternal wound complications occurerd in 203 patients (1.5%). The incidence was 1.7% (168/9987) after coronary artery bypass grafting (CABG group) and 0.7% (35/3413) after heart valve surgery with or without concomitant CABG (HVR group). RESULTS Factors independently related to sternal complications in the CABG group (variable odds ratio [95% C.I.]): year of surgery, 1.9 [1.3-2.8] in 1990-1992, 2.0 [1.4-2.9] in 1993-1995; female sex, 0.4 [0.2-0.6]; diabetic disease, 1.8 [1.2-2.5]; bilateral ITA procedure, 3.3 [1.1-7.7]; and postoperative dialysis, 3.1 [1.4-6.9]. In the HVR group they were: use of ITA graft, 3.7 [1.7-7.7]; early re-exploration because of bleeding 3.0 [1.1-8.2]; and postoperative dialysis 3.1, [1.4-9.3]. Multivariate models were used to compute the risk for sternal complications in each patient. However, the prognostic models based on these risk scores provided low sensitivity and low predictive value. Patients with sternal wound complications showed no increased early mortality but worse long-term survival even after adjustment for other factors (relative hazard in CABG group 1.9 [1.2-2.8]; in HVR group 2.1 [1.1-4.3]. CONCLUSIONS The use of ITA grafts seems to be one of the most important factors related to sternal wound complications. However, patients at truly increased risk for this complication could not be identified on the basis of the risk factors considered in this study.

NATURAL HISTORY OF LOCALISED PROSTATIC CANCER: A Population-based Study in 223 Untreated Patients

In a population-based study, disease progression and survival were evaluated in untreated patients with newly diagnosed cancer of the prostate without distant metastases. Complete follow-up was achieved in 223 of 227 (98%) consecutively diagnosed, eligible patients of all ages. After 5 years, the cumulative progression-free survival (with 95% confidence interval) was 71.8 (65.5-78.1)% and survival corrected for causes of death other than prostatic cancer was 93.8 (88.3-97.6)%. Univariate and multivariate analyses showed no association between age at diagnosis and the natural course. Local progression was less common in localised, non-palpable tumours than in larger tumours. The rate of progression was 18.7 (6.1-57.1) times higher and that of disease-specific death 216.0 (31.2-1496) times higher in patients with poorly than in those with highly differentiated tumours. It is concluded that tumour grade at diagnosis is an excellent predictor of local and distant progression. The low death rate, especially in patients with highly and moderately differentiated tumours, means that any local or systemic therapy intended for patients with early prostatic cancer must be evaluated in clinical trials with untreated controls for comparison.