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Biliary Tract Diseases

Gastrointestinal Diseases

Gallbladder Diseases

Gallbladder Cancer

Jill E. Koshiol, M.D.

Background:

The gallbladder is a small organ below the liver. Gallbladder cancer is a leading cause of cancer death among women in Chile. Chile also has among the highest rates of gallbladder cancer and death in the world. Researchers in a high-risk region of Chile want to find out more about this type of cancer. They especially want to know how inflammation affects the way it develops.

Objective:

To better understand the causes of gallbladder diseases and factors that may be associated with them.

Eligibility:

Women ages 50 74 with gallbladder cancer who are covered by the Chilean national health system.

Other people over age 21 with gallbladder disease.

Healthy adults over age 21.

Design:

Participants may be screened with an ultrasound. They may be asked questions about their health.

Participants will have an ultrasound of the abdomen. This can be done at the study clinic or in the hospital or at home. The ultrasound uses sound waves to take pictures of the gallbladder.

Participants will have a physical exam.

Participants will have their mouths looked at for tooth loss, dentures, and gum redness.

Participants will give a blood sample or saliva sample.

Participants will be asked for access to their medical history. They may be asked to allow researchers to keep any samples taken during gallbladder surgery.

Participants will answer questions about their medical history. This will include illnesses, surgeries, medicine use, and family history. It will also include diet and lifestyle habits, such as places where they have lived and worked.

Some participants will have 3 follow-up visits over 6 years.

...

Gallbladder cancer is a leading cause of cancer death among women in Chile, which has among the highest reported gallbladder cancer incidence and mortality rates in the world. Gallbladder cancer provides a particularly good model for understanding the role of inflammation in carcinogenesis since the major risk factor, gallstones, causes substantial inflammation in the gallbladder. Chile also has a high prevalence of obesity, diabetes, and metabolic syndrome, which are increasingly understood as inflammatory disorders, but the extent to which their carcinogenic effects are mediated through inflammatory pathways is unknown.

While the vast majority of gallbladder cancer cases have gallstones, only a small fraction of gallstone patients ever develop gallbladder cancer. Since there is no way to identify this small proportion at risk, gallstone cases are cholecystectomized, which, given large absolute numbers of individuals with gallstones, results in overtreatment of some and under-treatment of others in a high-risk area like Chile. While cholecystectomy is standard treatment for symptomatic relief, there are more people who need surgery than there are surgeons to perform them, and individuals aged 34-49 are prioritized for treatment, regardless of symptoms. This practice may lead to overtreatment among 34-49-year-olds and under treatment of individuals aged 50 and above since they have to wait longer for surgery. At the same time, about 30% of patients with a biliary colic attack will never have another attack, and cholecystectomy does not always lead to the cessation of symptoms. In addition, cholecystectomy has been associated with an increased risk of other digestive diseases. Thus, cholecystectomy may not be needed in all gallstone patients and may in fact increase the risk of cancer in some. Better predictors of risk are clearly needed.

As with other cancers, dysplasia is an important epidemiologic endpoint as the immediate precursor to cancer since the vast majority of gallbladder cancers develop through a histologic continuum of chronic cholecystitis, pseudopyloric metaplasia, incomplete intestinal metaplasia, dysplasia, and cancer. Thus, our aim is to identify risk factors for gallbladder dysplasia and cancer (GDC) and potential non-invasive risk stratification methods, such as ultrasound characteristics alone or in combination with inflammatory markers and patient characteristics, to better understand the etiology and natural history of GDC and to help inform strategies for GDC prevention.

Together with collaborators at Pontifica Universidad Catolica (PUC), we successfully completed a pilot study in Chile that was previously reviewed and approved by SAG and provided baseline data for the proposed study. Our pilot demonstrated high recruitment rates in the target enrollment area (80%) and high rates of questionnaire completion (100%), blood collection (78% population-based controls), and participant retention (93% of eligible completed a follow-up visit). Information from the pilot was used to optimize procedures for the longitudinal study. We also found that both gallstones and gallbladder cancer were associated with systemic immune alterations, which as we previously demonstrated, reflect inflammatory changes in the gallbladder detectable in bile. The next step is to demonstrate that these markers precede GDC by longitudinally measuring their levels among gallstone patients.

We propose to prospectively assess risk factors and early detection markers for GDC by conducting the Chile Biliary Longitudinal Study (BiLS), a cohort study of 6250 individuals with gallstones from the high- risk southern-central region of Chile. Because women are twice as likely to have gallstones and twice as likely to have gallbladder cancer as men, we plan to maximize our screening efficiency and number of outcomes by screening and enrolling women only. This approach is reasonable given that the female gender bias for gallbladder cancer is largely thought to be due to the gender bias for gallstones,1-3 suggesting that in the presence of gallstones, the risk of gallbladder cancer is the same for men and women. In addition, Chile is conducting a general population cohort in a small town in the high-risk area, and we can use the men with gallstones enrolled by the Chilean study to compare to the women in our study. We plan to enroll women with gallstones over 2 years and follow them for 6 years, conducting visits every other year to collect data on the primary exposures of interest, inflammatory markers and ultrasound characteristics, as well as additional exposures of interest, such as infections, genetics, and environmental exposures (e.g., aflatoxin, pesticides).

Chile Biliary Longitudinal Study

Our major exposures of interest are patterns, levels, and changes in inflammatory markers and ultrasound characteristics, with Gallbladder Dysplasia and Cancer as the primary outcome of interest.

National Cancer Institute (NCI)

Biliary Tract Cancer

Patients undergoing cholecystectomy for gall stones

The key aims of this study include estimation of possible risk associated with a history of gallstones, bacterial infection for the biliary tract, other medical history, diet, use of tobacco and alcohol, obesity, reproductive factors, and family history of cancer. Information will be used to examine risk patterns a) seperately by anatomic subsite; b) among patients with gallbladder cancer vs. controls undergoing cholecystectomy for gallstones; c) among the patients with bile duct cancer vs. Hospital controls without cancer who undergo surgery for removal of bile duct stones. We will also attempt to ascertain reasons for cancer who undergo surgery for removal of bile duct stones. We will also attempt to ascertain reasons for the rising incidence of biliary tract cancers in Shanghai. Serum collected from all subjects will be analyzed for estrogens and other hormones, vitamins C and E, cholesterol, and bacterial antibodies (including salmonella typhi, paratyphi, and escherischia coli). Bile fluid will be cultured for aerobic bacteria, and gallstones analyzed for color, cholesterol, and evidence of bacteria infection. A major challenge in biliary tract cancer research is to determine how cancer risk factors differ from those for gallstones or biliary duct stone disease, since many people have gallstones (or biliary duct stones) but few develop cancer....

The key aims of this study include estimation of possible risk associated with a history of gallstones, bacterial infection for the biliary tract, other medical history, diet, use of tobacco and alcohol, obesity, reproductive factors, and family history of cancer. Information will be used to examine risk patterns a) seperately by anatomic subsite; b) among patients with gallbladder cancer vs. controls undergoing cholecystectomy for gallstones; c) among the patients with bile duct cancer vs. Hospital controls without cancer who undergo surgery for removal of bile duct stones. We will also attempt to ascertain reasons for cancer who undergo surgery for removal of bile duct stones. We will also attempt to ascertain reasons for the rising incidence of biliary tract cancers in Shanghai. Serum collected from all subjects will be analyzed for estrogens and other hormones, vitamins C and E, cholesterol, and bacterial antibodies (including salmonella typhi, paratyphi, and escherischia coli). Bile fluid will be cultured for aerobic bacteria, and gallstones analyzed for color, cholesterol, and evidence of bacteria infection. A major challenge in biliary tract cancer research is to determine how cancer risk factors differ from those for gallstones or biliary duct stone disease, since many people have gallstones (or biliary duct stones) but few develop cancer.

A Population-Based Case-Control Study of Biliary Tract Cancers in Shanghai, China

Women from the cohort with gallbladder cancer

Women from Chile screened for gallbladder cancer with and without gallstones

Background:

- Chile has the highest diagnosis and death rates of gallbladder cancer in the world. Gallbladder cancer is also the leading cause of cancer death in Chilean women. High rates of gallstones and obesity, as well as genetic concerns, may explain these high rates. Researchers want to study gallbladder cancer in more depth in Chile. A small study must be done to see if a full-scale study is feasible.

Objectives:

- To test the methods and procedures of a small-scale study of gallbladder cancer in Chile.

Eligibility:

* Individuals at least 18 years of age who have gallbladder cancer or gallstones, or are healthy control volunteers.
* Participants will be recruited from four clinical centers in Chile.

Design:

* Participants will be screened with a physical exam and medical history. Because gallbladder cancer has a high fatality rate, family members may be asked to provide additional medical history information if study participants die or become too ill to provide this information.
* Participants will provide blood, urine, stool, hair, fingernail, and saliva samples.
* Gallstones, bile, and tissue samples will be collected from those who have gallbladder removal surgery. Normal and tumor tissue samples will be collected as needed.
* Treatment will not be provided as part of this protocol. This is a data collection study only.

Gallbladder cancer is a leading cause of cancer death among women in Chile, which has among the highest reported gallbladder cancer incidence and mortality rates in the world. Gallbladder cancer provides a particularly good model for understanding the role of inflammation in carcinogenesis since the major risk factor, gallstones, causes substantial inflammation in the gallbladder. Chile also has a high prevalence of obesity, diabetes, and metabolic syndrome, which are increasingly understood as inflammatory disorders, but the extent to which their carcinogenic effects are mediated through inflammatory pathways is unknown.

While the vast majority of gallbladder cancer cases have gallstones, only a small fraction of

gallstone patients ever develop gallbladder cancer. Since there is no way to identify this small

proportion at risk, gallstone cases are cholecystectomized, which, given large absolute numbers of individuals with gallstones, results in overtreatment of some and under-treatment of others in a high-risk area like Chile. While cholecystectomy is standard treatment for symptomatic relief, there are more people who need surgery than there are surgeons to perform them, and individuals aged 34-49 are prioritized for treatment, regardless of symptoms. This practice may lead to overtreatment among 34-49-year-olds and under treatment of individuals aged 50 and above since they have to wait longer for surgery. At the same time, about 30% of patients with a biliary colic attack will never have another attack, and cholecystectomy does not always lead to the cessation of symptoms. In addition, cholecystectomy has been associated with an increased risk of other digestive diseases. Thus, cholecystectomy may not be needed in all gallstone patients and may in fact increase the risk of cancer in some. Better predictors of risk are clearly needed.

As with other cancers, dysplasia is an important epidemiologic endpoint as the immediate precursor to cancer since the vast majority of gallbladder cancers develop through a histologic continuum of chronic cholecystitis, pseudopyloric metaplasia, incomplete intestinal metaplasia, dysplasia, and cancer. Thus, our aim is to identify risk factors for gallbladder dysplasia and cancer (GDC) and potential non-invasive risk stratification methods, such as ultrasound characteristics alone or in combination with inflammatory markers and patient characteristics, to better understand the etiology and natural history of GDC and to help inform strategies for GDC prevention.

Together with collaborators at Pontifica Universidad Catolica (PUC), we successfully completed a pilot study in Chile that was previously reviewed and approved by SAG and provided baseline data for the proposed study. Our pilot demonstrated high recruitment rates in the target enrollment area (80%) and high rates of questionnaire completion (100%), blood collection (78% population-based controls), and participant retention (93% of eligible completed a follow-up visit). Information from the pilot was used to optimize procedures for the longitudinal study. We also found that both gallstones and gallbladder cancer were associated with systemic immune alterations, which as we previously demonstrated, reflect inflammatory changes in the gallbladder detectable in bile. The next step is to demonstrate that these markers precedeGDC by longitudinally measuring their levels among gallstone patients.

We propose to prospectively assess risk factors and early detection markers for GDC by conducting the Chile Biliary Longitudinal Study (BiLS), a cohort study of 6250 individuals with gallstones from the high- risk southern-central region of Chile. Because women are twice as likely to have gallstones and twice as likely to have gallbladder cancer as men, we plan to maximize our screening efficiency and number of outcomes by screening and enrolling women only. Since Chile is conducting a general population cohort in a small town in the high-risk area, will we benefit from the infrastructure that is already in place and be able to compare the women in our study to a set of men with gallstones enrolled by the Chilean study. We plan to enroll women with gallstones over 2 years and follow them for 6 years, conducting visits every other year to collect data on the primary exposures of interest, inflammatory markers and ultrasound characteristics, as well as additional exposures of interest, such as infections, genetics, and environmental exposures (e.g., aflatoxin, pesticides). The cohort will be complemented by an incident case-control study of 300 women with gallbladder cancer and 600 controls with and without gallstones obtained from the cohort participants.

Study title	NCT ID	Conditions	Eligibility	Organization
Chile Biliary Longitudinal Study	NCT02692911	Gallbladder Can... Nutritional and...	50 Years - 74 Years	National Institutes of Health Clinical Center (CC)
A Population-Based Case-Control Study of Biliary Tract Cancers in Shanghai, China	NCT00339560	Biliary Tract C...	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)
Initial Study of Gallbladder Cancer in Chile	NCT01520259	Gallbaldder Can...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Initial Study of Gallbladder Cancer in Chile	NCT01520259	Gallbaldder Can...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for gallbaldder

Every month we try and update this database with for gallbaldder cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gallbaldder

Every month we try and update this database with for gallbaldder cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gallbaldder cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.