Chile Biliary Longitudinal Study
Condition: Gallbladder Cancer; Nutritional and Metabolic Diseases
MeSH terms: Gallbladder Neoplasms; Metabolic Diseases
Study type: Observational

Summary: 
      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.

      ...
    

Detailed description: 
      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).
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subject identification will begin with a census of the target neighborhoods in Chile in the
        study areas. Potential participants will be contacted by study staff (healthcare
        assistants), who will conduct home visits. If participant is eligible, study staff will
        invite the individual to participate and obtain written informed consent. She will then
        schedule an appointment at the study center for the screening ultrasound and give her the
        instructions to prepare for the examination.
      
Keywords: Gallbaldder; Cancer; Gallstones; Cholecystectomy; Inflammation