Gallstone Growth, Size, and Risk of Gallbladder Cancer: An Interracial Study
Lowenfels A B (Department of Surgery, New York Medical College, Valhalla, New York 10595, USA), Walker A M, Althaus D P, Townsend G and Domellöf L. Gallstone growth, size and risk of gallbladder cancer: An interracial study. International Journal of Epidemiology 1989, 18: 50–54.
To investigate gallstone size, growth, and the relation between stone size and gallbladder cancer we have used cholecystectomy reports from 1676 female subjects (169 Whites, 531 Blacks, and 976 Native American Indians). Although the prevalence of gallstones differs markedly in these groups it appears that the estimated growth rate of gallstones in younger subjects, 2.0 mm per year (95% confidence interval: 1.7–2.3 mm) is homogeneous for all three groups. In both Indian and non-Indian populations the proportion of small stones diminished and the proportion of large stones increased over time. We found a strong relationship between gallstone size and gallbladder cancer. Large stones (≥3 cm) were found in 40% of patients with gallbladder cancer but in only 12% of all subjects of similar age. The relative risk for gallbladder cancer in subjects with stones ≥3 cm was 9.2 compared with subjects with stones <1 cm. (95% confidence interval: 2.3–37). We estimate that one-third of all gallbladder cancers in subjects with calculi will be associated with large (≥3 cm) stones. We believe that stone size might be used to determine the risk of gallbladder cancer in patients with gallstones.
ALBERTO MARINGHINI, M.D.; JACQUES A. MOREAU, M.D.; L. JOSEPH MELTON III, M.D.; VICTORIA S. HENCH, M.S.; ALAN R. ZINSMEISTER, Ph.D.; and EUGENE P. DiMAGNO, M.D.
All 2583 residents of Rochester, Minnesota, who had gallstones initially diagnosed during the years 1950 to 1970 were followed for the development of gastrointestinal malignancies. Although 69 members of the cohort subsequently developed 72 gastrointestinal malignancies, this number of cases did not exceed the 76 cases expected (relative risk, 1.0). The risk for gallbladder cancer was increased threefold, but the increase was significant only in men (p = 0.05; 95% confidence interval, 1.0 to 30.0). The absolute incidence and the total number of men and women who developed gallbladder cancer was low (n = 5). The actual incidence of other gastrointestinal malignancies in our cohort with gallstones did not exceed the expected incidence in the general population of Rochester, Minnesota. Specifically, the risk for colon cancer was not increased, even after cholecystectomy. These data support an association between cholelithiasis and gallbladder cancer. We found, however, no association between cholelithiasis or cholecystectomy and any other gastrointestinal malignancy.
Department of Surgery, New York Medical College, Valhalla, New York 10595, USA.
Abstract
Gallbladder cancer, although rare in most Caucasian populations, is among the most frequently observed cancers in native populations of North and South America, and in the Maori population of New Zealand. In all populations, there is a strong correlation between gallstones and gallbladder cancer: the risk of gallbladder cancer is approximately 4-5 times higher in patients with gallstones, than in patients without gallstones. In those populations where the onset of gallstone disease occurs in the first few decades, the risk is much higher. Obesity, which is also a risk factor for gallstones, increases the risk of gallbladder cancer, as does the consumption of diets high in fats and calories. Other risk factors, such as increased parity, also increase the frequency of gallbladder cancer, most probably explained by the association between gallstones and parity. Prophylactic cholecystectomy for asymptomatic gallstones cannot be justified for the control of gallbladder cancer, but the increasing frequency of this procedure in many countries, secondary to the widespread use of laparoscopic surgical techniques, will clearly lower the incidence and mortality rates for this lethal disease.
Gallbladder cancer is uncommon in most countries and falling in incidence worldwide, with the relevant exceptions of Chile, Japan, Sweden and Finland.1, 2 The Chilean trend toward increasing crude mortality rates for gallbladder cancer has been sharp and uninterrupted over the last 3 decades, going from 3.7/100,000 for both sexes combined in 1970 to 11.7/100,000 in 1999.3 Age adjustment does not change this trend, and the Chilean mortality rate for this cancer ranks first in the world for the period 1981–1986 by far (for both men and women), above that of Japan and some European countries.4 Chile has also a very high and increasing proportion of gallbladder cancers (code 156.0 ICD-9 or C23 ICD-10) compared to choledocal, ampullar and unspecified sites (156.1, 156.2 and 156.9 ICD-9 or C24 ICD-10) and to other countries.5 Cancers originating in the gallbladder have increased from 79% to 94% in the last 3 decades in Chile, instead of the constant 50–60% shown in most countries.6
Several hypotheses have been suggested to explain the high prevalence and high gallbladder location of biliary tract cancers in Chile. There was a sharp and persistent decrease in cholecystectomy rates during the 1970s and the 1980s,7, 8, 9 as has also been shown for some developed countries.10, 11 Other postulated contributing factors are a longer life span, a possible increase in the prevalence of gallstones, deterioration of sanitary conditions in the 1980s with an increase in Salmonella typhi carriers and environmental carcinogens.8
So far, 15 different case-control studies on gallbladder cancer have been published (12 in English) in the world literature.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Our study is the final report of a collaborative project between Japan and Chile, and we explored eventual carcinogenic factors in gallstone carriers, with special emphasis on food.
MATERIAL AND METHODS
Top of page
Abstract
MATERIAL AND METHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
Our hospital-based case-control study was carried out between January 1992 and March 1995 at the Sótero del Río Hospital. This is a teaching facility of 850 beds serving a population of 1.1 million people. The study population comprised 114 patients defined as cases after a surgically and histologically verified gallbladder cancer. Pathologic diagnosis was also verified at the First Department of Pathology, School of Medicine, University of Niigata, by one of the authors (H.W.). Of the patients with diagnosed gallbladder cancer, 96% were also gallstone carriers, as confirmed by ultrasonography, by surgery or at the moment of autopsy. The remaining patients had classical clinical features suggestive of gallstones. A control subject of the same age (3-year bands), gender and hospital was matched to each case. Eligible controls were contemporary cholecystectomized gallstone patients at the same hospital. Hence, cases and controls were matched not only for age and sex but also for gallstone disease with the aim of detecting additional risk factors other than the 3 that are generally accepted.
Hospital controls were selected because they were considered more likely than the general population, which includes healthy subjects, to be aware of antecedent exposures or events, reducing the potential for recall bias. Also, gallstone carriers should have suffered the same intangible selection factors that influenced gallbladder cancer patients to come to our hospital. The institution in which the study was carried out is committed to a specific population, with very similar social, economic and cultural backgrounds, minimizing bias in this matter.
All subjects were interviewed by trained medical students. All interviewers were blinded to the diagnosis on the pathology report as well as to each other's diagnosis. Special care was taken to ensure that the same student who interviewed a case also interviewed the respective matched control, controlling in this way for possible bias. The questionnaire included information about socioeconomic characteristics, family history, lifestyle habits (e.g., smoking, alcohol consumption, intestinal habit) and a problem-oriented medical history. A long-term dietary intake history of the subjects was investigated through an interviewer-administered food-frequency questionnaire (FFQ).
Medical and family background included information about infectious diseases in childhood and prevalence of gallstone disease and/or history of cancer in first-degree relatives. Exposure to agents presumed to be risk factors for gallbladder cancer was also explored. For women, additional questions were added to explore use of oral contraceptives, menstrual and reproductive factors and hormone-replacement therapy. Intestinal habit was classified as normal (daily evacuation), diarrhea (liquid evacuations at least once a day) or constipation (intestinal evacuation after 3 days or more with hardened stools). Socioeconomic status was assessed by the Graffar index, which has 5 categories from V (the highest) to I and considers education, occupation, household and neighborhood characteristics.30 Length of biliary colic was the time between the first episode in life and the current diagnosis, measured in years. Race was established by self-report of the interviewed person or relatives; thus, it is assumed that this factor was biased toward whites, given the Chilean culture.
The FFQ was aimed at detecting the usual diet over the past 15 years either before the diagnosis of cancer (cases) or the surgery (controls). Special emphasis was added to ensure that answers were related to long-term dietary intake; consequently, recent changes in diet were ignored. Typically, most epidemiologic studies estimate intake only over the past 12 months, which could be problematic, particularly when cases are interviewed several months after cancer diagnosis. Estimates of food intake were obtained from cases and controls themselves or from relatives. Subjects were asked to indicate the average frequency of consumption of 60 food items per month, week or day in standard home-portion sizes, following the Chilean guidelines given by the Ministry of Health.
Fat intake was also assessed. Lipid intake was estimated by taking into account not only the intake of fried foods but also the content of seasoning lipids (oils) in different dishes, the frequency of consumption and portion size of each dish, the oil used for cooking and individual fat-intake patterns. We analyzed the data in terms of daily intake (grams) of foods by multiplying the frequency of consumption by the weight of standard portion sizes.
Epiinfo software was used to examine descriptively all variables in the questionnaires. All statistical analyses were done using Stata package, version 7.0 (Stata Corporation, College Station, TX). Primary exposures of interest were fried foods, chili pepper and fresh fruit. Secondary exposures of interest included 60 kinds of vegetable. We used logistic regression to analyze dietary associations with gallbladder cancer. Univariate and conditional multivariate logistic regression analyses were also run, employing variables that were significant (p < 0.05) or of borderline significance. Frequencies were obtained for all variables, and cross-tabulations for each potential risk factor vs. case-control status were built. Variables were retained for further analysis if they had univariate p values < 0.05 (for dichotomous or multilevel variables).
RESULTS
Top of page
Abstract
MATERIAL AND METHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
The study population consisted of 114 patients with verified gallbladder cancer (cases) and 114 patients with verified gallstones by contemporary cholecystectomy at the same hospital and living in the same neighborhoods, characterized as predominantly low medium and low (gallstone controls). As expected, most cases were women, with a male:female ratio of 1:6, mainly middle-aged or older, though almost 20% were aged 49 years and less (Table I). This male:female ratio is common in Chilean surgical data but different from the national mortality ratio, which is about 1:3. Mean age in male cases (65. 8 years) was 4.8 years greater than in female cases.
Table I. Proportion of Study Subjects by Age and Type of Interview
Variable
Cases (%, n = 114)
Controls (%, n = 114)
Gender
Female
81.6
81.6
Age (years)
<40
4.4
3.5
40–49
14.0
15.8
50–59
22.8
18.4
60–69
28.1
33.3
>60
30.7
29.0
Personally interviewed
48.2
88.6
After exploring potential risk factors for gallbladder cancer, socioeconomic status had statistically significant elevated adjusted odds ratios (ORs). Gallbladder cancer cases categorized as having a very low socioeconomic status had an OR of 5.0 [95% confidence interval (CI) 1.5–17.3] compared to those at higher levels. Few cases and controls were in the high socioeconomic categories, and no one was at the highest level. Low educational level was not significant but predominant among gallbladder cancer patients, with an OR of 2.3 (95% CI 0.8–6.2) for less educated people (1–3 schooling years) compared to those with no education. A gradient was observed with descending ORs of 1.8 (95% CI 0.8–4.2) and 0.8 (95% CI 0.3–2.0) for people with 4–6 schooling years and 7 or more, respectively (Table II).
Table II. Risk Factors for Gallbladder Cancer
Variable
Cases (%, n = 114)
Controls (%, n = 114)
OR
95% CI
1
Cases = 84, matched controls = 84.
2
Cases = 93, matched controls = 93.
Education (years)
0 y
11.4
15.8
Ref
1–3
24.6
14.9
2.3
0.8–6.2
4–6
43.8
36.8
1.8
0.8–4.2
7+
20.2
32.5
0.8
0.3–2.0
Socioeconomic status
Very low
20.2
9.7
Ref
Low/high
79.8
90.3
5.0
1.5–17.3
Length of biliary colic (years)1
≤24
84.5
95.5
Ref
>24
15.5
4.5
11.0
1.4–85.2
Parity2
≤5 pregnancies
47.3
62.4
Ref
>5 pregnancies
52.7
37.6
1.5
0.8–2.7
Intestinal habit
Diarrhea/normal
64.9
76.3
Ref
Constipation
35.1
23.7
1.8
1.0–3.2
Obesity (BMI)
Up to 24.9
46.5
41.2
Ref
25.0–29.9
36.8
42.1
0.8
0.4–1.4
≥30.0
16.7
16.7
0.9
0.4–1.8
Typhoid fever
Negative self-report
90.3
92.5
Ref
Positive self-report
9.7
7.5
0.5
0.2–1.2
Sugar intake (as soft drinks)
10–15 g/day
35.1
44.7
Ref
3–4 units/week
50.0
50.0
1.2
0.7–2.2
Rarely (<10 g/week)
14.9
5.3
3.6
1.3–10.1
Green chili pepper
<20 g/day
41.2
61.4
Ref
>20 g/day
58.8
38.6
2.9
1.5–5.6
Red chili pepper
<20 g/day
42.1
66.7
Ref
>20 g/day
57.9
33.3
2.9
1.6–5.2
Fried foods
<200 g/day
69.3
84.2
Ref
>200 g/day
30.7
15.8
2.1
1.1–3.8
Fresh fruit
Frequent consumption (2 or more fruits/day)
36.8
44.7
Ref
3–4 Fruits per week
47.4
49.1
1.4
0.7–2.8
Rarely (less than 1 fruit/week)
15.8
6.2
6.4
1.4–30.3
High and similar proportions of both cases and gallstone controls with symptomatic gallstone disease were observed (74% and 77%, respectively), but differences appeared when a comparison was done between groups on the length of history of biliary colic. Some 15.5% of gallbladder cancer cases with diagnosed biliary colic reported a gallstone disease diagnosis more than 24 years earlier compared to 4.5% of gallstone carriers with diagnosed biliary colic but without cancer, yielding an OR of 11.0 (95% CI 1.4–85.2), a wide range and a single cut point that may have maximized the observed statistical power. Grouping below 24 years did not yield significance and was not considered for further analysis (Table II).
Variables found in other studies to be risk factors were only nominally statistically significant for gallstone carriers developing gallbladder cancer in our study. Obesity, parity and sugar consumption as soft drinks were not associated with the odds of gallbladder cancer. Constipation was more frequent in cases but did not reach statistical significance. History of typhoid fever was a nonsignificant, protective factor (Table II).
High consumption of fried foods in gallbladder cancer patients had a weakly significant OR of 2.1 (95% CI 1.1–3.8). A difference was observed with low fresh fruit consumption, which appeared as a strong risk factor for gallbladder cancer. Logistic regression analysis showed that low consumption of fresh fruit was the single most important independent predictor for development of gallbladder cancer (OR = 6.4, 95% CI 1.4–30.3), a wide confidence interval for a random influence (Table II).
Red and green chili peppers conferred significantly higher risk in cases compared to gallstone carriers, with ORs of 2.9 (95% CI 1.5–5.6) and 2.9 (95% CI 1.6–5.2), respectively (Table II).
When a conditional multivariate logistic regression analysis was applied, considering those risk factors that were univariately significant, only very low socioeconomic status and red chili pepper consumption remained as risk factors (Table III).
Table III. Adjusted ORs in a Conditional Logistic Regression Multivariate Analysis (114 Cases and 114 Controls)1
Risk factor
OR
95% CI
p
1
Based on the variables that demonstrated significance in univariate analysis.
Low socioeconomic status
5.6
1.4–20.5
0.014
Red chili pepper consumption
2.5
1.2–5.2
0.016
Green chili pepper consumption
1.4
0.6–3.5
0.792
Fried foods (once or more/day)
1.4
0.7–2.8
0.921
Schooling (6 years or less)
1.0
0.9–1.1
0.994
In the final model, which included only the 2 significant variables, the OR for low socioeconomic status was 6.3 (95% CI 1.7–23.0) and that for red chili pepper consumption was 3.2 (95% CI 1.7–5.9). Despite the significant influence of longstanding gallstones (OR = 11.0, 95% CI 1.4–85.0), this risk factor was removed from the final model because all cases with low and very low socioeconomics status were longstanding gallstones carriers; therefore, the longstanding gallstone OR tends to be endless.
DISCUSSION
Top of page
Abstract
MATERIAL AND METHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
Our finding of excessive chili pepper consumption as a risk factor had not been hypothesized, but it agrees (perhaps randomly) with another case-control study of a different digestive tract cancer that showed a positive relationship with chili pepper consumption.31 Experimental research has shown that capsaicin, an active ingredient of chili pepper, behaves as a carcinogen32 and a mutagen.33 A pathophysiologic explanation for gallbladder cancer could be the association of capsaicin to an increase of bile concentration by increasing the flow of water into the mucosa34 and, thus, the concentration of eventual carcinogens in the bile. Another possibility, not explored in our study, could be that fungus aggregated during the red chili pepper production.
The association of a longer period (>24 years) of symptomatic gallstone disease in cancer patients compared to symptomatic gallstone carriers suggests that gallbladder cancer could be facilitated by physical trauma from gallstones.35 Periods shorter than 24 years showed no significant relationship. Our finding should be related to the inverse relationship between cholecystectomy rates and gallbladder cancer mortality shown in Sweden,10 the United States, England and Wales, Scotland, Canada11 and Chile.8, 9
It is well known that not all gallstone carriers who develop gallbladder cancer are symptomatic. In our study, it appeared that 28% of gallbladder cancer patients were asymptomatic despite an advanced disease that had emerged as acute cholecystitis, cholangitis or a very short period of weight loss. This fact may be related to results showing a strong positive relationship between larger diameter and lasting gallstones with gallbladder cancer.11, 15
Poverty tended to be prevalent and more marked in cases. Education showed an even gradient with descending ORs of 1.8 and 0.8 for people with 4–6 years and 7 or more, respectively. Our finding fits with a Polish study where low education was so important among cases compared to controls that all rates were adjusted for this variable.14
Parity has appeared in the literature as a risk factor for gallbladder cancer;18, 19, 20, 23 but in our study, the OR for gallbladder cancer among women with more than 5 pregnancies was at most borderline, with a value of 1.5 (95% CI 0.8–2.7). Constipation was not significant either (OR = 1.8, 95% CI 1.0–3.2). Obesity was associated with gallbladder cancer in a case-control study in Bolivia;21 but in our study, both overweight and obesity were unrelated to cancer risk, with ORs of 0.8 (95% CI 0.4–1.4) and 0.9 (95% CI 0.4–1.8), respectively.
Many other variables or potential risk factors, mainly foods, were examined; but no differences were seen when cases were compared to controls matched by age, sex and gallstone disease. The only exception was fresh fruit, which appeared indirectly as protective for gallbladder cancer (OR = 6.4, 95% CI 1.4–30.3) when consumption was low, in agreement with a growing literature that shows antioxidants as protective for many cancers.36, 37 Sugar, measured by soft drink consumption, did not appear to be a risk factor for gallbladder cancer, in agreement with all but 1 previous case-control study.17 Of course, lifetime history of food consumption has to be regarded cautiously because it is influenced by memory bias, which is typical in retrospective studies.
Aymara ethnic background appeared recently as a powerful risk factor for gallbladder cancer.21 In our study, cases who defined themselves as of Indian (Mapuche) origin were slightly more frequent than matched controls, but numbers were too small (5 vs. 2 people) to achieve statistical significance. This was possibly due to biased self-reporting of ethnicity as “white”. Genetic studies have established that the Chilean population is composed of about 70% mestizos (admixture of whites and Indians), 25% Caucasians and only 5% pure Indians. Indigenous origin might, in our perspective, also mean poverty, delayed recognition of disease or lack of accessibility to medical care, reflecting environmental and not genetic differences.38 Furthermore, in the case of Chile, it seems difficult to explain the sharp and constant increase in gallbladder cancer incidence during the last 3 decades based on ethnic changes. Of course, there could be a host susceptibility of the Chilean population to environmental factors.
Typhoid fever is a risk factor for gallbladder cancer,39, 40 but in our analysis it appeared to be protective, though not statistically significant (OR = 0.5, 95% CI 0.2–1.2). A possible explanation is subclinical and undiagnosed typhoid fever cases.
Proxy respondents appeared in relatively high proportion among cases (51.8%) but infrequently in gallstone controls (11.4%), reflecting the poor condition of cancer patients at hospital discharge. Despite the facts that our proportion of direct respondents was higher than in other studies14 and that data obtained from proxy respondents have shown good correlation with past history of patients,41, 42 this is a limitation of our study and errors may exist in some of our findings.
In conclusion, our study, which reports on a relatively large number of cases, suggests that gallbladder cancer is related to longstanding gallstone disease, sometimes asymptomatic, and is more common in poor and less educated people. High consumption of red chili pepper was in our study a significant risk factor for gallbladder cancer. This does not necessarily mean that capsaicin, the active ingredient in chili pepper, is a risk factor; other factors associated with high chili pepper consumption may be important. One of these potential associations could be a high intake of fried foods, as observed in our study. Also, our data suggest that consumption of fresh fruit is a protective factor for gallbladder cancer. Further examination of every potential risk factor is warranted.
Acknowledgements
Top of page
Abstract
MATERIAL AND METHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
We thank Dr. A.K. Diehl (University of Texas, Health Science Center, San Antonio, TX) and Dr. S.I. Bangdiwala (University of North Carolina, Chapel Hill, NC) for careful review of the manuscript.
REFERENCES
Top of page
Abstract
MATERIAL AND METHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
1
Serra I, Yamamoto M, García V, Báez S, Decinti E. Diet, gallstones and gallbladder cancer. Jpn J Cancer Clin1997; 43: 404–12.
2
Aoki K, Kurihara M, Hyakawa N, Suzuki S. Death rates for malignant neoplasms for selected sites by sex and five year group in 33 countries 1953–57 to 1983–87. Nagoya: Nagoya University Press, 1992.
3
National Institute of Statistics. Ministry of Economy, Chile. Annuario de Demografía1999. p. 242.
4
Chen W, Endoh K, Yamamoto M. International comparison of the mortalities of biliary tract cancer. J Aichi Med Univ Assoc1990; 18: 187–92.
5
Serra I, Calvo A, Báez S, Decinti E. Environmental and clinical factors associated with biliary tract cancer in Chile. A preliminary study of 165 cases [in Spanish]. Rev Chil Cir1992; 44: 350–2.
6
Serra I. Has gallbladder cancer mortality decreased in Chile [in Spanish]? Rev Med Chile2001; 129: 1079–84.
PubMed,
CAS,
Web of Science® Times Cited: 14
7
Serra I, Calvo A, Maturana M, Medina E, Sharp A. Changing trends of gall-bladder cancer in Chile, a high-risk area. Int J Cancer1990; 45: 376–7.
Direct Link:
Abstract
PDF(165K)
References
Web of Science® Times Cited: 39
8
Serra I, Calvo A, Maturana M, Sharp A. Biliary-tract cancer in Chile. Int J Cancer1990; 46: 965–71.
Direct Link:
Abstract
PDF(690K)
References
Web of Science® Times Cited: 35
9
Chianale J, del Pino G, Nervi F. Increasing gall-bladder cancer mortality rate during the last decade in Chile, a high-risk area. Int J Cancer1990; 46: 1131–3.
Direct Link:
Abstract
PDF(274K)
References
Web of Science® Times Cited: 22
10
Brodén G, Bengtsson L. Carcinoma of the gallbladder. Its relation to cholelithiasis and to the concept of prophylactic cholecystectomy. Acta Chir Scand1980; 500( Suppl): 15–8.
PubMed
11
Diehl AK, Beral V. Cholecystectomy and changing mortality from gallbladder cancer. Lancet1981; 2: 187–9.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 51
12
Kato K, Akai S, Tominaga S, Kato I. A case-control study of biliary tract cancer in Niigata Prefecture, Japan. Jpn J Cancer Res1989; 80: 932–8.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 58
13
WHO. Combined oral contraceptives and gallbladder cancer. Int J Epidemiol1989; 18: 309–14.
CrossRef,
PubMed
14
Zatonski WA, La Vecchia C, Przewozniak K, Maisonneuve P, Lowenfels AB, Boyle P. Risk factors for gallbladder cancer: a Polish case-control study. Int J Cancer1992; 51: 707–11.
Direct Link:
Abstract
PDF(506K)
References
Web of Science® Times Cited: 58
15
Cetta F, Lombardo E, Cariati E. Large stones: association with gallbladder carcinoma. Are they markers of long lasting lithiasis?Gastroenterology1992; 102: A306.
16
Ghadirian P, Simard A, Baillargeon J. A population-based case-control study of cancer of the bile ducts and gallbladder in Quebec, Canada. Rev Epidemiol Sante Publique1993; 41: 107–12.
PubMed,
CAS,
Web of Science® Times Cited: 17
17
Moerman CJ, Bueno de Mesquita HB, Runia S. Dietary sugar intake in the aetiology of biliary tract cancer. Int J Epidemiol1993; 22: 207–14.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 17
18
Lambe M, Trichopoulos D, Hsieh C, Ekbom A, AH, Pavia M. Parity and cancers of the gallbladder and the extrahepatic bile ducts. Int J Cancer1993; 54: 941–4.
Direct Link:
Abstract
PDF(402K)
References
Web of Science® Times Cited: 21
19
Kvalë G, Heuch I, Nilssen S. Parity in relation to mortality and cancer incidence. A prospective study of Norwegian women. Int J Epidemiol1994; 23: 691–9.
CrossRef,
PubMed,
Web of Science® Times Cited: 55
20
Moerman CJ, Berns MPH, Bueno de Mesquita HB, Runia S. Reproductive history and cancer of the biliary tract in women. Int J Cancer1994; 57: 146–53.
Direct Link:
Abstract
PDF(840K)
References
Web of Science® Times Cited: 28
21
Strom BL, Soloway RD, Ríos-Dalenz J, Rodríguez-Martínez HA, West SL, Kinman JL, Polansky M, Berlin JA. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer1995; 76: 1747–87.
Direct Link:
Abstract
PDF(948K)
References
Web of Science® Times Cited: 73
22
Moerman CJ, Bueno de Mesquita HB, Smeets FWM, Runia S. Consumption of foods and micronutrients and the risk of cancer of the biliary tract. Prev Med1995; 24: 591–602.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 16
23
De Aretxabala X, Riedeman P, Burgos L, Roa I, Araya JC, Echeverría X, Toledo MI, Charles M, Espinoza O, Wenzel C. Gallbladder cancer. A case-control study [in Spanish]. Rev Med Chile1995; 123: 581–6.
PubMed,
CAS,
Web of Science® Times Cited: 14
24
Serra I, Báez S, Endoh K, Yamamoto M, Calvo A, Decinti E, Watanabe H, Tajima K, Norambuena R. Gallbladder cancer: a case-control study in Chile [in Spanish]. Rev Chil Cir1996; 48: 139–47.
25
Endoh K, Nakadaira H, Yamazaki O, Yamamoto M, Tajima K, Serra I, Calvo A, Báez S. Risk factors for gallbladder cancer in chilean females [in Japanese]. Jpn J Public Health1997; 44: 113–22.
PubMed,
CAS
26
Fernandez E, La Vecchia C, D'Avanzo B, Negri E, Franceschi S. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev1994; 3: 209–12.
PubMed,
CAS,
Web of Science® Times Cited: 93
27
Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, Jain M, Przewozniak K, Baghurst P, Moerman CJ, Simard A, Howe GR, et al. Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH program of the International Agency for Research on Cancer. J Natl Cancer Inst1997; 89: 1132–8.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 82
28
Khan ZR, Neugut AI, Ahsan H, Chabot JA. Risk factors for biliary tract cancers. Am J Gastroenterol1999; 94: 149–52.
Direct Link:
29
Scott TE, Carroll M, Cogliano FD, Smith BF, Lamorte WW. A case-control assessment of risk factors for gallbladder carcinoma. Dig Dis Sci1999; 44: 1619–25.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 20
30
Graffar M. Une méthode de classification sociale d'échantillons de population. Courrier1956; 6: 455–9.
31
López-Carrillo L, Hernández N, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: a case-control study. Am J Epidemiol1994; 139: 263–71.
PubMed,
Web of Science® Times Cited: 63
32
Toth B, Rogan E, Walker B. Tumorigenicity and mutagenicity studies with capsaicin of hot peppers. Anticancer Res1984; 4: 117–20.
PubMed,
CAS,
Web of Science® Times Cited: 59
33
Agarwal RC, Wiessler M, Hecker E, Bhide SV. Tumour-promoting effect of chili extract in Balb/c mice. Int J Cancer1986; 38: 689–95.
Direct Link:
Abstract
PDF(1424K)
References
Web of Science® Times Cited: 36
34
Fitzgerald S, Desphande YG, Nguyen HQ, Kaminski DL. The effect of capsaicin on gallbladder fluid absorption. Hepatology1991; 14: 660–4.
PubMed,
CAS,
Web of Science® Times Cited: 7
35
Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA1983; 250: 2323–6.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 130
36
Charleux JL. Beta-carotene, vitamin C, and vitamin E: the protective macronutrients. Nutr Rev1996; 54: 109–14.
Direct Link:
Abstract
PDF(616K)
References
37
Kromhout D, Bueno de Mesquita HB. Antioxidant vitamins and stomach cancer: the role of ecologic studies. Cancer Lett1997; 114: 333–4.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 3
38
Serra I, Calvo A, Báez S, Yamamoto M, Endoh K, Aranda W. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer1996; 78: 1515–6.
Direct Link:
Abstract
PDF(224K)
References
Web of Science® Times Cited: 9
39
Caygill CPJ, Hill MJ, Braddick M, Sharp JCM. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet1994; 343: 83–4.
CrossRef,
PubMed,
CAS,
Web of Science® Times Cited: 49
40
Dutta U, Garg PK, Kurmar R, Tandon RK. Thyphoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder. Am J Gastroenterol2000; 95: 784–7.
Direct Link:
41
Humble C, Samet J, Skipper B. Comparison of self- and subrogate-reported dietary information. Am J Epidemiol1984; 119: 86–98.
PubMed,
CAS,
Web of Science® Times Cited: 79
42
Walker A, Velema J, Robins J. Analysis of case-control data derived in part from proxy respondents. Am J Epidemiol1988; 127: 905–14.
Department of Surgery, Tongi Hospital, Tonji Medical University, Wuhan, China.
Find all citations in this journal (default).
Orfilter your current search
Zhonghua wai ke za zhi [Chinese Journal of Surgery][2000, 38(11):805-808]
Type: Journal Article
Abstract
Highlight Terms
OBJECTIVE: To make clear the relationship between gallstones and gallbladder cancer, the relationship between the size of gallstones and gallbladder cancer, the course of gallbladder cancer, and the relationship among adenoma and carcinoma of gallbladder and ascariasis in the biliary tract.
METHODS: A total of 3,922 cases of gallbladder cancer from 28 provinces in china from 1986 to 1998 were reviewed, according to a standard protocol called "the clinical epidemiological list of gallbladder cancer". RESULTS: Gallbladder cancer accounted for 0.4% - 3.8% of bile tract disease in the same period, averaging 1.53%.Gallbladder cancer accounted for 0.1% - 1.1% of abdominal surgery in the same period. Gallstones were found in 46.7% of the cases of gallbladder cancer, the related risk (RR) of gallbladder cancer with gallstones was 13.7. The average course with gallstones was 10 - 15 years. The gallstone in gallbladder was 3 cm or above in diameter. The ratio of the progression from adenoma to carcinoma of gallbladder was 1.5%. Only 4 cases of ascariasis was reported. CONCLUSIONS: Gallbladder cancer and gallstones are closely associated. Patients with gallstone of 3 cm or above in diameter and a course of 10 - 15 years are usually at an increased risk for cancer. We found the adenoma and carcinoma of gallbladder are closely related, and there is no relationship between gallbladder cancer and ascariasis in our group.
↵3 Departments of Surgery and Preventive Medicine, New York Medical College, Valhalla, NY 10595.
↵4Address reprint requests to Dr. Lowenfels, Department of Surgery, New York Medical College, Westchester County Medical Center, Munger Pavilion, Valhalla, NY 10595.
↵5 Department of Pathology, University of Lund, Malmö General Hospital, Malmö, Sweden.
↵6 Phoenix Indian Medical Center, Phoenix, AZ 85016.
↵7 Department of Surgery, Louisiana State University School of Medicine, New Orleans, LA 70112.
Received November 19, 1984.
Accepted March 8, 1985.
Abstract
The relationship between gallstones and gallbladder cancer was investigated in a case-control study in 131 subjects with gallbladder cancer and 2,399 subjects without gallbladder cancer. Included in the study were male and female subjects from 3 racial groups: white, black, and Southwestern American Indian. For the non-Indian group there was a significant relationship between gallstones and gallbladder cancer, with an overall estimated relative risk (RR) of 4.4 (95% confidence interval, 2.6–7.3). For the Indian population the overall estimated RR was much higher: RR = 20.9; 95% confidence interval = 8.1–54. By the combination of the RR, the prevalence of gallstones, and the overall incidence of gallbladder cancer, the risk of gallbladder cancer was calculated in each population for subjects with untreated gallstones. In older subjects with gallstones the estimated 20-year cumulative risk for gallbladder cancer ranged from 0.13% in black males to 1.5% in Indian females. It was concluded that the risk of gallbladder cancer in untreated subjects with gallstones is heterogeneous, depending on race and sex as well as the period of exposure to gallstones.
SHOULD I HAVE MY
GALLBLADDER REMOVED? IS GALLBLADDER REMOVAL
REALLY NECESSARY? Over 1/2 million people in America have their
gallbladders removed every year. Is it necessary? Not that often it isn't.
Sometimes it is absolutely necessary, but not always. How do you know for sure?
That's not easy to determine. Most doctors advise gallbladder removal with any
diagnosis of a gallbladder problem. Large gallstones, small gallstones,
low-functioning gallbladder, few symptoms, no symptoms. If the diagnosis
warrants surgery, you are advised to take it out. But the same diagnosis in
thousands of people does not mean the same condition exists. For example,
gallstones can be silent which means you are unaware of any probelm going on.
There are no symptoms at all and the gallstones are found by routine lab tests
done for a separate issue. You may eventually develop symptoms or you could live
a long life and never experience symptoms of gallstones. Or you may be one of
those people who have frequent attacks and on-going pain who just can't live
with it. The majority of people we hear from here at GallbladderAttack are in
the middle. They had an attack; it's behind them now, but they still have
discomfort that gets worse when they are under stress or when they eat the wrong
foods. If you are in that camp, you have a choice to make. Part of that choice
involves whether or not you are willing to make both lifestyle and dietary
changes.
If you do opt for gallbladder removal, will your digestion be
perfect afterwards? That's what everybody's hoping for, to be pain free, gas
free, bloat-free and to be able to eat whatever they like. You have a 60% chance
of that happening. Out of every 10 cholecystectomies, 4 people will still have
symtpoms. Those symptoms are rarely, if ever, equal to that of the previous
gallbladder attack. They are more often discomfort, or dull pain. But you need
to be aware.
So read the research and find out what your chances are of
that happening before you give your body parts up. And scroll over to the right
of this page to read what my readers are saying about their experiences. And if
you've had a good experience and are symptom-free 2 and 3 years after surgery,
please write and tell us about it. We want to hear from you too. I say 2 or 3
years because it sometimes happens that uncomfortable symptoms resolve after a
year or so.
The most frequently asked question I am asked from people who
have had surgery is this: "Why is that that I still have pain even though my
gallbladder has been removed?" If you think of your problem as a biliary (bile)
problem as opposed to a "gallbladder" problem you are more on the right track to
understanding how to take care of it. Removing the gallbladder does not always
address the problem in the body that is causing these symptoms. In order to
break down and digest fats, your body must produce bile, which is done in the
liver. Your gallbladder is merely a sac for holding some of the bile that the
liver produces. Whether or not you have had your gallbladder removed, your liver
is still producing bile in order to digest fats. Without the gallbladder,
however, the bile is not as readily secreted in the body, and the liver can
become overwhelmed when faced with large amounts of any fats, especially
saturated fats and hydrogenated fats. And for some people even small amounts of
fats can cause discomfort.
One of the side effects of gallbladder
removal can be the dumping of bile which is now not as easily regulated and can
send someone running to the bathroom immediately after eating. A more common
side effect is a decrease in the secretion of bile. If the bile produced by the
liver becomes thick and sluggish, painful symptoms and bile stones can occur.
Bile stones can form in the liver as well as the gallbladder. One woman had her
gallbladder removed only to end up back in surgery again two or three days later
where they found stones in the bile ducts of the liver causing her alot of
pain.
However, removing the gallbladder may be an absolute medical
necessity. But, unless it is diseased, ruptured or otherwise sick, know that
just having cholelithiasis or gallbladder stones does not mean you have to take
it out. If you have gallbladder attacks, pain or discomfort or digestive
problems but not a diseased gallbladder, this does not mean you necessarily have
to have gallbladder surgery. Get a second opinion. You do have an option of
cleaning up your diet, doing some work on your gallbladder and liver and keeping
your organ of fat digestion. If you happen to think that nature made a mistake
and that you don't need it anyway, you probably wouldn't be reading this page in
the first place.
What's the worst thing that can happen? You try to fix a
huge contributing factor which is based on cleaning up your diet and eating real
food and real fats and not the "pretend food" that can sit on a shelf for 6
months to 2 years. What kind of a food takes two years to go bad? Nothing that
will give health to your body, that's for sure. And if the gallbladder still
needs to come out later, you've only gained by eating better anyway.
The
gallbladder does facilitate and regulate the flow of bile in your body. When
that facilitator is taken away it is quite possible that the flow will be not as
efficient, ie. too much at one time, or more commonly, not
enough.
Whether you choose gallbladder surgery or not, consider taking
products and changing your diet as well as doing a series of gallbladder and
liver flushes to take care of the root of your gallbladder problem.
The
most common problems, apart from actual pain are impaired digestion: bloating,
gas, heartburn, constipation or diarrhea. You are/were already having trouble
digesting fats. So why would removing the organ that regulates the metabolizer
of fats improve your digestion? It may help with the pain, but
know that 34% of people who have their gallbladder removed still experience some
abdominal pain. (4)
The easiest way to avoid this is to take a supplement of
bile salts or choline with meals to help your body with the digestion of
fats. And do a series of gallbladder flushes. Flushes are especially helpful
after gallbladder removal to help flush out the bile ducts. Supplemental bile
salts, (unless you are experriencing bile dumping) available separately or in
the After Gallbladder Removal
Kit, should be taken frequently along with the digestive stimulant
(also in the kit) to help stimulate your own digestive juices. Alternating the
dosage of bile salts will help to mimic the body's way of secreting bile. For
example, take one with breakfast, two at lunch, three at dinner, two with
breakfast the next day, and so on in rotation.
If you have the less
common, but not unusual side effect after gallbladder removal of needing to run
to the bathroom immediately after eating, you are probably getting too much bile
instead of too little. This, unfortunately is much harder to control. Try the
Dumping Syndrome
Kit. Read more about postcholecystectomy diarrhea towards the bottom of
this page. CAN I FUNCTION WITHOUT A GALLBLADDER Yes you can. The bile will
still be produced in the liver and find its way to the small intestine. It will
continue to break down your dietary fats and to remove toxins from the liver.
What is different is that the bile will no longer be as concentrated (the
gallbladder removes 90% of the water from the bile) and its function as a
regulator will be gone. Some people have no problem with this at all; others
have problems with getting the right amount of bile at the right time, either
too much or too little. IS GALLBLADDER SURGERY
EFFECTIVE What is meant by effective? Will you never have another gallbladder
attack? I mean, how could you if you have no gallbladder, right? Will you never
suffer from indigestion again? Will your gas and bloating disappear? Will the
constipation go away? Will diarrhea resolve?
The answer to all of the
above is "sometimes". Actual attacks are rare, but other forms of pain and
discomfort are possible and new symptoms can also develop. Read
on...
Let's look at gallbladder attacks. Gallstones can also be found in
the liver and the bile ducts leading to the gallbladder. The attack is often
(but not always) caused by a stone blocking a duct. And yes, this can still
happen. As seen by research above, stones are formed partly due to what we eat.
If we take the gallbladder out and continue to eat the same lithogenic forming
diet that we did before, why should stones not form? They will. You may never
know it. You may be asymptomatic for the rest of your life. Or, you may get a
stone stuck in a bile duct. This is one of the reasons for the most frequently
asked question on this site: "I had my gallbladder removed months (or years)
ago. Why do I still have pain?" (See testimonials to the right for examples.)
Removing the gallbladder does not always address the problem in the body that is
causing these or other symptoms listed above. It has probably taken years for
your body to form these stones. Your fat digestion has been impaired for a long
time. In order to break down and digest fats, your body must produce bile, which
is done in the liver. To address the root of the problem you must study and
reflect on the causes of gallbladder disease.
There could be
an underlying thyroid problem which research connects with both gallstones and a
low-functioning gallbladder. Food allergies may also be a big part of it and
stress as well.
Another thing to keep in mind is that you could have
another gallbladder disease that has not yet been diagnosed. For example, if an
ultrasound is done and gallstones found, a cholecystectomy or gallbladder
removal will be recommended without doing any further exploration. This is
because the most obvious and easily diagnosed cause of gallbladder attacks is
gallstones or cholelithiasis. And ultrasound is quick and non-invasive. However,
if your gallbladder is ejecting bile below 33%-40% which is considered normal
range, you would be diagnosed with a low-functioning gallbladder or biliary
dyskinesia. This can only be determined with a HIDA scan which is an invasive procedure using
radioactive dye. Symptoms of biliary dyskinesia are not always resolved with
cholecystectomy either for various known and unknown reasons. One reason is that
the problem could be with the Sphincter of Oddi rather than the gallbladder
itself. DIET AFTER GALLBLADDER
SURGERY If you understand that co-existant with your gallbladder disease is
usually a problem of stagnant bile, cholestasis, or some imbalance in the bile
composition itself, you will realize that most people are not out of the woods
after surgery or able to eat anything they like. Treat your lack of a
gallbladder as you would any gallbladder disease and eat the same way. Exactly
what that means depends upon your symptoms. Some people have surgery having had
few symptoms and others were in bad shape. If you are in the latter category,
and are now still having some discomfort, you may be most comfortable giving
your gallbladder a rest by following the strict 30-60 Day Gallbladder Menu Plan.
Most people after surgery will be able to start with the 2nd Menu Plan which is
more relaxed. Others will be comfortable just following the Gallbladder Foods Guidelines in the Helpful and To Be
Avoided lists.
There is a whole page on gallbladder diet with foods
that are good for the gallbladder (think "bile") and liver and foods that are
hard on the biliary system. You still have a biliary system. Treat it gently and
feed it nourishing foods. Of particular importance is the understanding of good
fats and harmful fats. Follow the links on gallbladder diet for more information on
both of these. When should the gallbladder be
removed?
Many doctors recommend gallbladder removal if you have had
only one attack. Others will do so if you have repeated attacks. Some will do so
if you have stones; others will say unless you are having attacks with the
stones you can leave it. This is a place to get a second opinion and above all,
to educate yourself; read all you can.
If your doctor finds that you have
an infected gallbladder it will almost certainly
have to come out. If it bursts you are in similar danger as with a burst
appendix. Infection is then lose in the peritoneal cavity. This is like an
explosion of infection from a place of contaiment to the body at large and is
difficult to clean up.
If you have a motility
problem or a problem with gallbladder contraction or low-functioning (see
biliary dyskinesiaunder gallbladder diseases) gallbladder surgery is also
recommended. Yet some doctors do not recommend gallbladder removal for biliary
dyskinesia. Complications of surgery Apart from complications
of surgery such as damage to the common bile duct with laparoscopic surgery (due
to lack of visibility) or infection from an incision, one may develop
postcholecystectomy syndrome.(See
below.) "During laparoscopic cholecystectomy, gallbladder
perforation with leakage of bile and/or gallstones into the abdominal cavity
occurs frequently." or 33% according to this study. However, there were no
complications of infection or blockages in any of the
subjects.(3)
POSSIBLE SIDE EFFECTS FROM
GALLBLADDER REMOVAL
LIFE AFTER GALLBLADDER
SURGERY Abdominal pain, nausea, gas, bloating, and diarrhea are common
following surgery. Postcholecystectomy syndrome (after gallbladder
removal syndrome) may include all of the above symptoms plus indigestion,
nausea, vomiting and constant pain in the upper right abdomen. Sound familiar?
You're right -- gallbladder attack symptoms. Up to 40% of people who undergo
gallbladder surgery will experience these symptoms for months or years after
surgery. How is this possible? You no longer have a gallbladder and that was the
problem, right? Look to the whole biliary tract. Now that the gallbladder is no
longer present to act as a reservoir for bile, the common bile duct may expand
as the bile backs up in the bile duct between the sphincter or muscular opening
at the small intestine and the liver from which it flows. If it drips constantly
into the small intestine this can cause problems of a different kind. However,
this syndrome with accompanying pain appears to have the flow of bile obstructed
by either a narrowing of the sphincter or a malfunction of the
sphincter.(1) "Functional biliary pain in the absence of gallstone
disease is a definite entity and a challenge for clinicians." which is to say
that at this point in time, they don't really know what to do with gallbladder
problems that aren't related to gallstones (2) and "Often, following
cholecystectomy, biliary pain does not resolve..." (2) which means after
gallbladder surgery you may just be stuck with the pain.
So in
conclusion, your best bet may be to try and fix what is wrong if that is
possible, before taking it out. Sometimes, that is just not
possible. Postcholecystectomy Diarrhea or Bile Dumping
Syndrome
The uncomfortable and inconvenient side effect that some
people experience following the removal of their gallbladder is that of running
to the bathroom immediately or soon after eating. For some it is rather
explosive. Whatever its presentation, it is an increased transit time which
means that absorption of nutrients is impaired. Not a good situation for your
overall health. You may find help from the Dumping Syndrome Kit on this site. It
helps to bind the bile salts that accumulate in the intestine along with extra
fluid. However, this quote from a British medical journal suggests that perhaps
IBS is part of the problem and may have been there, if somewhat less
problematic, before the surgery. If that is the case, try our Dumping Syndrome
Kit, by all means. It can be helpful for all sorts of etiologies. But you may
also want to read up on IBS and try some products specifically for an irritable
bowel condition. I like the products at www.diverticulitisinfo.com.
"13-40% of patients have
persisting abdominal pain after cholecystectomy although the vast majority
regard their operation as a success. Up to 12% of post-cholecystectomy patients
when questioned feel that they have diarrhoea as a consequence of their
operation, and at least 4-5% of patients have a definite deterioration in their
perceived diarrhoea or perceive that they have developed diarrhoea for the first
time. Objective assessments postoperatively, however, rarely demonstrate new
onset diarrhoea. Some of these patients may have the irritable bowel
syndrome."6 IS THERE SOMETHING I COULD DO FOLLOWING GALLBLADDER
REMOVAL THAT WOULD BE HELPFUL Of course! Always keep
following a clean, sensible gallbladder diet that includes good fats, lots of
organic fruits and vegetables and lean meats and fish. And for at least 2 or 3
months immediately afterwards, follow the diet religiously and if you haven't
done a Gallbladder Starter
Kit, do so now to give your digestion and your fat metabolism a kit
start. I also suggest a series of coffee
enemasabout a month after surgery (even years after if it's been that
long) to flush all the bile ducts including those of the liver. Your biliary
tree can benefit from this at any time as can your liver. I suggest one per day,
if possible, for 21 days. Then order the
After Gallbladder Removal Kit
and stay on it from now on. You will need the assistance in
digestion that it offers, especially for digesting fats. That is the ideal. If
it is beyond your means to do this, at least use bile salts with every meal.
(1)Torsoli A, Corazziari E, Habib FI, Cicala M. Scand
J Gastroenterol Suppl. 1990;175:52-7 Pressure relationships within the human
bile tract. Normal and abnormal physiology.
(2) Shaffer E., Dig Liver
Dis. 2003 Jul;35 Suppl 3:S20-5
(3) Surgical Endoscopy Publisher: Springer
New York ISSN: 0930-2794 (Paper) 1432-2218 (Online) DOI:
10.1007/BF00188454Issue: Volume 9, Number 9 Date: September 1995 Pages: 977 -
980
