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Protein Biomarker in Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT00465842
Recruitment Status : Terminated (Loss of funding due to difficulty with recruitment and participant retention.)
First Posted : April 25, 2007
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
Singapore Cancer Society
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:

Hepatocellular carcinoma (HCC) is the fifth commonest cancer in the world with poor prognosis, as the annual mortality is almost equivalent to the incidence. This is mainly due to late diagnosis and co-morbid liver dysfunction. HCC is prevalent in our region than in the West due to prevalent Hepatitis B infection and carriers. At the time of diagnosis, only 10 - 20% of HCC patients are candidates for liver resection or transplantation. Almost 40-50% of patients have such poor liver function and co-morbid conditions that only supportive cares are offered. Thus the median survival time is 18-24 months for resectable disease, 6 months for unresectabe disease and 3 months for metastatic disease.

Current screening methods for HCC in high risk patients depend on alpha-fetoprotein (AFP) and ultrasound of the liver. Neither test is sensitive or specific enough for early detection. Therefore, early diagnosis with novel protein biomarkers is needed urgently and may provides hope to improve treatment outcome.

Our preliminary study in 49 HCC patients have identified several proteins such as truncated complement C3a, albumin, B2 microglobulin, may be potentially helpful in early diagnosis. We have started a large prospective and longitudinal study in July 2006, with nearly 100 patients accrued. This application is to extend and expand our current study. We aim to (i) identify and validate novel protein biomarkers for early diagnosis of HCC (ii) conduct longitudinal proteomics with most up-to-date methods to discover new biomarker for early detection and prognostication of HCC (iii) set up gene and plasma depository and clinical database for HCC in collaboration with Singapore Tissue Network.


Condition or disease
Normal Volunteers Hepatitis Liver Cirrhosis Hepatocellular Carcinoma

Detailed Description:

Up to 40% of HCC patients have normal AFP. Moreover, AFP can also be elevated in patients with cirrhosis or exacerbation of chronic hepatitis. Prospective studies evaluating the value of AFP in HCC surveillance have reported sensitivities of 39-64%, specificity of 76-91% and positive predictive values of 9 -32% 9-11.

Recently, a small handful of biomarkers were identified in the blood of 49 HCC patients by SELDI / MS proteomic analysis of their blood with specificity and sensitivity both at 90% 12, 13. These were truncated complement C3a, albumin, B2 microglobulin, and histidine-rich glycoprotein. In addition, insulin growth factor (IGF) and its binding protein have been shown to be novel biomarkers of HCC 14-17. A larger prospective study is necessary to validate these findings.

Other investigators have also used Surface-enhanced laser desorption / ionization time-of-flight mass spectrometry (SELDI) to study proteomics in HCC. Most of the studies included small numbers of patients and did not include independent test set or report on reproducibility most of the time. Thus, controversies continue on both the technology of SELDI and validation of the findings. Nevertheless, Ward et al reported that Kappa and Lumda immunoglobulin light chains were elevated by an average pf 50% in the serum of HCC patients (p < 0.001, sensitivity 94%, specificity 86%) with Hepatitis C related cirrhosis 18. Schwegler et al reported that SELDI-TOF MS profiling of serum can distinguish chronic Hepatitis C from HCV- related HCC with a sensitivity of 61% and a specificity of 76%. Sensitivity and specificity can be improved with the addition of AFP, des-gamma carboxyprothrombin, and GP73 19. Other reports also indicated potential marker of heat-shock protein 27 20 and complement C3a 21. However, all studies lack prospective and longitudinal follow-up with multiple serum samples from same patient. Our trial is designed to test the changes of proteomic overtime to identify the earliest possible biomarkers for HCC.

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Study Type : Observational
Actual Enrollment : 211 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Protein Biomarkers for Early Detection and Prognostication in Hepatocellular Carcinoma (HCC)
Actual Study Start Date : June 20, 2006
Actual Primary Completion Date : August 14, 2013
Actual Study Completion Date : August 14, 2013

Resource links provided by the National Library of Medicine


Group/Cohort
A - Normal Volunteers

Normal volunteers without any history of liver disease and with normal liver functions test (LFT), including total protein/Albumin, LDH, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin and do not belong to group B.

Volunteers will be screened using questionnaires. Those deemed suitable will then be asked to have the blood test done. All blood tests are done free of charge to subjects.

B - Hepatitis B or C carriers with normal liver functions
C - Hepatitis B or C carriers with abnormal liver functions
D - Liver Cirrhosis
Liver cirrhosis, proven by liver biopsy or on clinical evidences, such as varices on CT scan indicative of portal hypertension.
E - Hepatocellular Carcinoma (HCC) with Resection
HCC patients with resection.
F - Unresectable HCC
Unresectable HCC patients with treatment
G - Malignant HCC
HCC patients with active malignant disease and only palliative care are offered.



Primary Outcome Measures :
  1. Number of participants with presence of serum protein markers [ Time Frame: Day 1 ]
    Number of participants with truncated complement C3a, albumin, B2-microglobulin and histidine-rich glycoprotein, IGF-I, and IGF-II on first blood sample.


Secondary Outcome Measures :
  1. Number of participants with hepatocellular carcinoma (HCC) with presence of protein markers. [ Time Frame: up to 5 years ]
    To study the prospective and longitudinal value of these protein markers in detecting HCC by regular measurement of these proteins and follow up with routine clinical practice in high-risk patients.

  2. Number of participants with presence of serum protein markers with resectable and unrsectable HCC. [ Time Frame: up to 5 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
HCC patients, normal volunteers and patients with hepatitis with/without cirrhosis
Criteria

Inclusion Criteria:

  • Group A: Normal volunteers without any history of liver disease and with normal liver functions test (LFT), including total protein/Albumin, LDH, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin and do not belong to group B. Volunteers will be screened using questionnaires. Those deemed suitable will then be asked to have the blood test done. All blood tests are done free of charge to subjects.
  • Group B: Hepatitis B or C carriers with normal liver functions.
  • Group C: Hepatitis B or C carriers with abnormal liver functions.
  • Group D: Liver cirrhosis, proven by liver biopsy or on clinical evidences, such as varices on CT scan indicative of portal hypertension.
  • Group E: HCC patients with resection.
  • Group F: Unresectable HCC patients with treatment.
  • Group G: HCC patients with active malignant disease and only palliative care are offered.
  • Signed Informed Consent

    -≥ 18 years of age

  • In this trial, diagnosis of HCC is established with either (a) known hepatitis B or C carrier, and space occupying lesion(s) in the liver and AFP > 400ng/ml or (b) cytological or histological confirmation by biopsy

Exclusion Criteria:

There is no exclusion criteria


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00465842


Locations
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Singapore
Johns Hopkins Singapore International Medical Center
Singapore, Singapore, 308433
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Singapore Cancer Society
Investigators
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Principal Investigator: Alex Chang, MD Johns Hopkins Singapore
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00465842    
Other Study ID Numbers: JS0541
NA_00037477 ( Other Identifier: JHM IRB )
First Posted: April 25, 2007    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Hepatitis
Liver Cirrhosis
HCC
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Hepatitis
Liver Cirrhosis
Fibrosis
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Diseases
Digestive System Diseases
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Pathologic Processes