Initial Study of Gallbladder Cancer in Chile
Condition: Gallbaldder Cancer
MeSH terms: Gallbladder Neoplasms
Study type: Observational

Summary: 
      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.
    

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 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.
    

Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Target neighborhoods in Chile in the study areas.
      
Keywords: Gallbaldder; Gallstones; Inflammation; Cholecystectomy; Cancer; Gallbaldder Cancer