A Prospective Study of UCAD for Diagnosing Benign or Malignant Biliary Obstruction and Follow-up

Study Overview
=================
Brief Summary
-----------------
Chromosomal instability (CIN) refers to ongoing chromosome segregation errors throughout consecutive cell divisions. CIN is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. Analyzing CIN of the DNA extracted from bile tract exfoliated cells in bile samples seems a promising method for diagnosing, monitoring, and predicting the prognosis of patients with malignant biliary obstruction, including biliary tract cancer (BTC), pancreatic head carcinoma. CIN can be assessed using experimental techniques such as bulk DNA sequencing, fluorescence in situ hybridization (FISH), or conventional karyotyping. However, these techniques are either time-consuming or non-specific. The investigators here intend to study whether a new method named Ultrasensitive Chromosomal Aneuploidy Detection (UCAD), which is based on low-coverage whole-genome sequencing, can be used to analyze CIN thus helping diagnose malignant biliary obstruction and assessing follow-up.

Detailed Description
-----------------
CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. It will generate genomic heterogeneity that acts as a substrate for natural selection. Furthermore, it is proved that tumors with aneuploidies and polyploidy resulting from whole-genome doubling are related to metastasis, treatment resistance, and decreased overall survival. It is estimated that 60%-80% of human tumors exhibit chromosomal abnormalities suggestive of CIN. CIN positively correlates with tumor stage and is enriched in relapsed as well as metastatic tumor specimens. Due to the ubiquity of CIN in cancer cells, it is a potentially non-invasive way to detect CIN in the bile tract exfoliated cells in bile samples for diagnosing and monitoring malignant biliary obstruction patients. UCAD is a new method to detect CIN in the DNA sample from patients, including extracting DNA from bile, analyzing DNA by low-coverage whole-genome sequencing, processing the data by bio-information techniques, and finally optimizing the management of malignant biliary obstruction patients. The investigators intended to conduct a prospective, single-blinded study by analyzing bile samples from malignant biliary obstruction patients and control groups without any tumor in the biliary system or other organs to compare the specificity and sensitivity of the UCAD test for diagnosing malignant biliary obstruction to other modalities, such as bile cytology. The investigators also intend to investigate the potential of UCAD in malignant biliary obstruction patient follow-up by analyzing the CIN level and following malignant biliary obstruction patients for up to 2 years to determine if there is a correlation between CIN level and patient prognosis

Official Title
-----------------
A Prospective, Multi-centre, Single-blinded Study of UCAD for Diagnosing Benign or Malignant Biliary Obstruction and Follow-up

Conditions
-----------------
Biliary Tract Neoplasms, Pancreatic Carcinoma, Gallbladder Cancer, Pancreatic Head Carcinoma

Intervention / Treatment
-----------------
* Diagnostic Test: The level of CIN


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients diagnosed with malignant biliary obstruction and planned to undergo ERCP(endoscopic retrograde cholangiopancreatography), PTCS(percutaneous transhepatic cholangioscopy) or surgery. Malignant biliary obstruction patients confirmed by operation or biopsy. Participants without any tumor disease and willing to attend the study. Male or female patients aged >= 18 years. Participants signed informed consent form. Exclusion Criteria: Patients diagnosed with malignant biliary obstruction and planned to undergo ERCP, PTCS or surgery. Malignant biliary obstruction patients confirmed by operation or biopsy. Participants without any tumor disease and willing to attend the study. Male or female patients aged >= 18 years. Participants signed informed consent form.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| malignant biliary obstruction<br>Pre-surgery patients with malignant biliary obstruction will be the experimental group to determine the sensitivity and specificity of UCAD analysis, the result will be compared with cytology. | Diagnostic Test: The level of CIN<br>* The extracted DNA from bile will be analyzed by UCAD to determine the level of CIN. And the patient will be followed for up to 2 years.<br>|
| Benign biliary obstruction<br>Patients being treated for other biliary diseases but without any tumor will provide a negative control to provide data for determining the sensitivity and specificity of UCAD analysis. | Diagnostic Test: The level of CIN<br>* The extracted DNA from bile will be analyzed by UCAD to determine the level of CIN. And the patient will be followed for up to 2 years.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and Specificity of UCAD analysis | number of patients declared positive with the UCAD test among the patients who suffered from malignant biliary obstruction and number of patients declared negative with the UCAD test among the patients without cancer | through study completion, an average of 30 months | 
| Assess the value of UCAD for malignant biliary obstruction patient follow-up | Compare the CIN level with the patient information gathered by follow-up to determine whether there is a correlation between CIN level and patient prognosis , like PFS(progression-free survival), five-year survival rate. | through study completion, an average of 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of the correlation between the level of CIN and the grade of the tumor sample | level of CIN in the bile sample compared with the grade of the tumor confirmed by histopathologic examination, like Grade 1-4. | through study completion, an average of 30 months | 
| Identification of the correlation between the level of CIN and the stage of the tumor sample | level of CIN in the bile sample compared with the TNM stage of the tumor confirmed by histopathologic examination, like Stage 0-IV. | through study completion, an average of 30 months | 
| Comparison of the sensitivity and specificity of the UCAD analysis versus bile cytology | number of patients declared positive with the UCAD analysis versus patients declared positive with the bile cytology and number of patients declared negative with the UCAD analysis versus patients  declared negative  with the bile cytology | through study completion, an average of 30 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diagnosis, follow-up