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出境医 / 临床实验 / Application of UCAD for Diagnosing Urothelial Carcinoma.

Application of UCAD for Diagnosing Urothelial Carcinoma.

Study Description
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 urothelial cells in urine samples seems a promising method for diagnosing, monitoring, and predicting the prognosis of bladder cancer patients. 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. We 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 help diagnosing and treating bladder cancer patients.

Condition or disease Intervention/treatment
Urothelial Carcinoma Diagnoses Disease Chromosomal Abnormality Urine Marking Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells

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 with 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 urothelial cells from the urine sample for diagnosing and monitoring bladder cancer patients. UCAD is a new method to detecting CIN in the DNA sample from patients, including extracting DNA from urine, analyzing DNA by low-coverage whole-genome sequencing, processing the data by bio-information techniques, and finally optimizing the management of bladder cancer patients.

The investigators intended to conduct a prospective study by analyzing urine samples from bladder cancer patients and control groups that without any tumor in the urinary system or other organs to compare the specificity and sensitivity of UCAD test for diagnosing urothelial carcinoma to other modalities, such as urine cytology or fluorescence in situ hybridization (FISH).

Study Design
Layout table for study information
Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Ultrasensitive Chromosomal Aneuploidy Detection (UCAD) in Urine Exfoliated Cells for Diagnosis of Urothelial Carcinoma in in Urine Exfoliated Cells
Actual Study Start Date : May 5, 2019
Estimated Primary Completion Date : May 5, 2020
Estimated Study Completion Date : May 5, 2020
Arms and Interventions
Group/Cohort Intervention/treatment
Urothelial carcinoma group
Pre-surgery patients with urothelial carcinoma will be the experimental group to determine the sensitivity and specificity of UCAD analysis, the result will be compared with cytology and FISH.
Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells
The level of CIN The extracted DNA from morning urine will be analyzed by UCAD to determine the level of CIN.

Non-cancer participants group
Patients being treated for other diseases but without any tumor will provide a negative control to provide data for determining the sensitivity and specificity of UCAD analysis.
Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells
The level of CIN The extracted DNA from morning urine will be analyzed by UCAD to determine the level of CIN.

Outcome Measures
Primary Outcome Measures :
  1. Sensitivity of urinalysis by UCAD analysis [ Time Frame: Up to 1 years ]
    Number of patients "declared positive" with the UCAD test among the patients suffered from urothelial carcinoma.

  2. Specificity of urinalysis by UCAD analysis [ Time Frame: Through study completion, an average of 12 months ]
    Number of patients "declared negative" with the UCAD test among the patients without cancer.


Secondary Outcome Measures :
  1. Comparison of the sensitivity of the UCAD analysis versus urine cytology [ Time Frame: Up to 1 years ]
    Number of patients "declared positive" with the UCAD analysis versus patients "declared positive" with the urine cytology.

  2. Comparison of the specificity of the UCAD analysis versus urine cytology [ Time Frame: Up to 1 years ]
    Number of patients "declared negative" with the UCAD analysis versus patients " declared negative " with the urine cytology.


Other Outcome Measures:
  1. Identification of the correlation between the level of CIN and the grade of the tumor sample [ Time Frame: Up to 1 years ]
    Level of CIN in the urine sample compared with the grade of the tumor confirmed by histopathologic examination

  2. Identification of the correlation between the level of CIN and the stage of the tumor sample [ Time Frame: Up to 1 years ]
    Level of CIN in the urine sample compared with the stage of the tumor confirmed by histopathologic examination.


Biospecimen Retention:   Samples With DNA
DNA from Urine Exfoliated Cells will be analyzed by Ultrasensitive Chromosomal Aneuploidy Detection

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
Patients diagnosed with urothelial carcinoma or participants in control group in Changhai Hospital from May 2019 till the end of this study.
Criteria

Inclusion Criteria:

  • Patients diagnosed with urothelial carcinoma and planned to undergo surgery.
  • Participants without any tumor disease and willing to attend the study by providing morning urine.
  • Male or female patients aged >= 18 years.
  • Participants signed informed consent form.

Exclusion Criteria:

  • Age under 18 years
  • Individuals unwilling to sign the consent form or unwilling to provide morning urine for test or unwilling to provide the medical record.
  • Individuals unwilling to participate in this trial.
Contacts and Locations

Contacts
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Contact: Shuxiong zeng, M.D., Ph.D +8618930568759 zengshuxiong@126.com

Locations
Layout table for location information
China, Shanghai
Changhai Hospital Recruiting
Shanghai, Shanghai, China, 200433
Contact: Shuxiong Zeng, M.D. Ph.D    +8618930568759    zengshuxiong@126.com   
Sponsors and Collaborators
Changhai Hospital
Investigators
Layout table for investigator information
Study Chair: Chuangliang Xu, M.D., Ph.D Changhai Hospital
Tracking Information
First Submitted Date June 19, 2019
First Posted Date June 26, 2019
Last Update Posted Date June 26, 2019
Actual Study Start Date May 5, 2019
Estimated Primary Completion Date May 5, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 25, 2019)
  • Sensitivity of urinalysis by UCAD analysis [ Time Frame: Up to 1 years ]
    Number of patients "declared positive" with the UCAD test among the patients suffered from urothelial carcinoma.
  • Specificity of urinalysis by UCAD analysis [ Time Frame: Through study completion, an average of 12 months ]
    Number of patients "declared negative" with the UCAD test among the patients without cancer.
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: June 25, 2019)
  • Comparison of the sensitivity of the UCAD analysis versus urine cytology [ Time Frame: Up to 1 years ]
    Number of patients "declared positive" with the UCAD analysis versus patients "declared positive" with the urine cytology.
  • Comparison of the specificity of the UCAD analysis versus urine cytology [ Time Frame: Up to 1 years ]
    Number of patients "declared negative" with the UCAD analysis versus patients " declared negative " with the urine cytology.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 25, 2019)
  • Identification of the correlation between the level of CIN and the grade of the tumor sample [ Time Frame: Up to 1 years ]
    Level of CIN in the urine sample compared with the grade of the tumor confirmed by histopathologic examination
  • Identification of the correlation between the level of CIN and the stage of the tumor sample [ Time Frame: Up to 1 years ]
    Level of CIN in the urine sample compared with the stage of the tumor confirmed by histopathologic examination.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title Application of UCAD for Diagnosing Urothelial Carcinoma.
Official Title Ultrasensitive Chromosomal Aneuploidy Detection (UCAD) in Urine Exfoliated Cells for Diagnosis of Urothelial Carcinoma in in Urine Exfoliated Cells
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 urothelial cells in urine samples seems a promising method for diagnosing, monitoring, and predicting the prognosis of bladder cancer patients. 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. We 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 help diagnosing and treating bladder cancer patients.
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 with 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 urothelial cells from the urine sample for diagnosing and monitoring bladder cancer patients. UCAD is a new method to detecting CIN in the DNA sample from patients, including extracting DNA from urine, analyzing DNA by low-coverage whole-genome sequencing, processing the data by bio-information techniques, and finally optimizing the management of bladder cancer patients.

The investigators intended to conduct a prospective study by analyzing urine samples from bladder cancer patients and control groups that without any tumor in the urinary system or other organs to compare the specificity and sensitivity of UCAD test for diagnosing urothelial carcinoma to other modalities, such as urine cytology or fluorescence in situ hybridization (FISH).

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
DNA from Urine Exfoliated Cells will be analyzed by Ultrasensitive Chromosomal Aneuploidy Detection
Sampling Method Non-Probability Sample
Study Population Patients diagnosed with urothelial carcinoma or participants in control group in Changhai Hospital from May 2019 till the end of this study.
Condition
  • Urothelial Carcinoma
  • Diagnoses Disease
  • Chromosomal Abnormality
  • Urine Marking
Intervention Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells
The level of CIN The extracted DNA from morning urine will be analyzed by UCAD to determine the level of CIN.
Study Groups/Cohorts
  • Urothelial carcinoma group
    Pre-surgery patients with urothelial carcinoma will be the experimental group to determine the sensitivity and specificity of UCAD analysis, the result will be compared with cytology and FISH.
    Intervention: Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells
  • Non-cancer participants group
    Patients being treated for other diseases but without any tumor will provide a negative control to provide data for determining the sensitivity and specificity of UCAD analysis.
    Intervention: Diagnostic Test: Low-coverage whole-genome sequencing of urine exfoliated cells
Publications *
  • Wadhwa N, Mathew BB, Jatawa SK, Tiwari A. Genetic instability in urinary bladder cancer: An evolving hallmark. J Postgrad Med. 2013 Oct-Dec;59(4):284-8. doi: 10.4103/0022-3859.123156. Review.
  • Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe'er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018 Jan 25;553(7689):467-472. doi: 10.1038/nature25432. Epub 2018 Jan 17.
  • Liu H, He W, Wang B, Xu K, Han J, Zheng J, Ren J, Shao L, Bo S, Lu S, Lin T, Huang J. MALBAC-based chromosomal imbalance analysis: a novel technique enabling effective non-invasive diagnosis and monitoring of bladder cancer. BMC Cancer. 2018 Jun 15;18(1):659. doi: 10.1186/s12885-018-4571-7.
  • Hieronymus H, Murali R, Tin A, Yadav K, Abida W, Moller H, Berney D, Scher H, Carver B, Scardino P, Schultz N, Taylor B, Vickers A, Cuzick J, Sawyers CL. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife. 2018 Sep 4;7. pii: e37294. doi: 10.7554/eLife.37294.
  • Zeng S, Ying Y, Xing N, Wang B, Qian Z, Zhou Z, Zhang Z, Xu W, Wang H, Dai L, Gao L, Zhou T, Ji J, Xu C. Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA. Clin Cancer Res. 2020 Nov 1;26(21):5646-5654. doi: 10.1158/1078-0432.CCR-20-0401. Epub 2020 Oct 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Estimated Enrollment
 (submitted: June 25, 2019)
300
Original Estimated Enrollment Same as current
Estimated Study Completion Date May 5, 2020
Estimated Primary Completion Date May 5, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients diagnosed with urothelial carcinoma and planned to undergo surgery.
  • Participants without any tumor disease and willing to attend the study by providing morning urine.
  • Male or female patients aged >= 18 years.
  • Participants signed informed consent form.

Exclusion Criteria:

  • Age under 18 years
  • Individuals unwilling to sign the consent form or unwilling to provide morning urine for test or unwilling to provide the medical record.
  • Individuals unwilling to participate in this trial.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers Not Provided
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries China
Removed Location Countries  
 
Administrative Information
NCT Number NCT03998371
Other Study ID Numbers CH-urology-bladder marker-002
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: We will try to protect the information of the included participants
Responsible Party Shuxiong Zeng, Changhai Hospital
Study Sponsor Changhai Hospital
Collaborators Not Provided
Investigators
Study Chair: Chuangliang Xu, M.D., Ph.D Changhai Hospital
PRS Account Changhai Hospital
Verification Date June 2019

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