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Occult metastasis at the time of surgery is a major driver of poor outcomes in intrahepatic cholangiocarcinoma (ICC), yet reliable preoperative biomarkers to identify such patients are lacking. The EXOMIC study aims to develop and validate a circulating exosomal microRNA (exo-miRNA)-based liquid biopsy assay to detect occult metastasis preoperatively in patients with resectable ICC.
Intrahepatic cholangiocarcinoma (ICC) incidence is rising globally, and prognosis remains poor. Patients harboring occult micrometastases that are not detected on preoperative imaging often experience rapid recurrence and significantly worse survival. Tumor-derived exosomes contribute to pre-metastatic niche formation and carry microRNAs that reflect aggressive metastatic potential. Circulating exosomal microRNA profiles may serve as non-invasive biomarkers to reveal occult metastasis before surgery.
Preoperative exosomes will be analyzed using small RNA sequencing (discovery) followed by RT-qPCR validation and machine-learning modeling to develop a predictive score for occult metastasis. The study will evaluate diagnostic performance (sensitivity, specificity, accuracy, AUROC), prognostic relevance (OS/RFS), and clinical utility (decision curve analysis) to establish a biologically informed framework for treatment stratification in ICC.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Training Cohort - ICC with Occult Metastasis | The cohort of ICC patients who had occult metastasis detected at the time of surgery. Preoperative samples were analyzed using the EXOMIC qRT-PCR assay to validate candidate exosomal microRNAs identified in the discovery cohort. |
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| Training Cohort - ICC without Occult Metastasis | The cohort of ICC patients without occult metastasis at the time of surgery. Preoperative samples were analyzed with the EXOMIC qRT-PCR assay to evaluate differential miRNA expression and refine the predictive model for occult metastasis detection. |
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| Validation Cohort - ICC with Occult Metastasis | The cohort of ICC patients with occult metastasis at the time of primary tumor resection. The EXOMIC qRT-PCR assay was applied to confirm the predictive value of the exosomal miRNA panel in identifying occult metastasis prior to surgery. |
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| Validation Cohort - ICC without Occult Metastasis | The cohort of ICC patients without occult metastasis at the time of surgery. Preoperative samples were analyzed with the EXOMIC qRT-PCR assay to evaluate differential miRNA expression and refine the predictive model for occult metastasis detection. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EXOMIC small RNA sequencing | Diagnostic Test | High-throughput small RNA sequencing performed on preoperative serum or plasma samples from patients with intrahepatic cholangiocarcinoma (ICC) to identify exosome-derived microRNAs associated with occult metastasis at the time of surgery. Sequencing data were analyzed to detect differentially expressed miRNAs between patients with and without occult metastasis in the discovery cohort. |
| Measure | Description | Time Frame |
|---|---|---|
| Recurrence Free Survival | The time period from surgery to recurrence of ICC. | 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival | Time from surgery to death from any cause | 5 years |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ajay Goel, PhD | City of Hope Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope Medical Center | Duarte | California | 91016 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38200585 | Background | Huang G, Zhang H, Yang Z, Li Q, Yuan H, Chen P, Xie C, Meng B, Zhang X, Chen K, Yu H. Predictive value of HTS grade in patients with intrahepatic cholangiocarcinoma undergoing radical resection: a multicenter study from China. World J Surg Oncol. 2024 Jan 11;22(1):17. doi: 10.1186/s12957-023-03281-6. | |
| 36905928 | Background |
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Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data.
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| Discovery Cohort - ICC with Occult Metastasis |
Patients with intrahepatic cholangiocarcinoma (ICC) who were found to have occult metastasis at the time of primary tumor resection in the discovery cohort. Preoperative samples were analyzed using small RNA sequencing to identify exosome-derived microRNAs associated with the presence of occult metastasis. |
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| Discovery Cohort - ICC without Occult Metastasis | Patients with ICC who had no occult metastasis at the time of primary tumor resection in the discovery cohort. Preoperative samples from these patients were analyzed by small RNA sequencing and compared with those from patients with occult metastasis to identify candidate microRNAs. |
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| EXOMIC assay (qRT-PCR validation) | Diagnostic Test | Quantitative reverse transcription PCR (qRT-PCR)-based validation of candidate exosomal microRNAs identified through small RNA sequencing. This assay was performed on preoperative serum or plasma samples from independent ICC patient cohorts to validate the predictive value of selected miRNAs for occult metastasis detection prior to surgical resection. |
|
| Swanson K, Wu E, Zhang A, Alizadeh AA, Zou J. From patterns to patients: Advances in clinical machine learning for cancer diagnosis, prognosis, and treatment. Cell. 2023 Apr 13;186(8):1772-1791. doi: 10.1016/j.cell.2023.01.035. Epub 2023 Mar 10. |
| 32881910 | Background | Kojima T, Umeda Y, Fuji T, Niguma T, Sato D, Endo Y, Sui K, Inagaki M, Oishi M, Ota T, Hioki K, Matsuda T, Aoki H, Hirai R, Kimura M, Yagi T, Fujiwara T. Efficacy of surgical management for recurrent intrahepatic cholangiocarcinoma: A multi-institutional study by the Okayama Study Group of HBP surgery. PLoS One. 2020 Sep 3;15(9):e0238392. doi: 10.1371/journal.pone.0238392. eCollection 2020. |
| 35734620 | Background | Feng J, Liang B, Zhang HY, Liu Z, Jiang K, Zhao XQ. Prognostic factors for patients with mass-forming intrahepatic cholangiocarcinoma: A case series of 68 patients. World J Gastrointest Surg. 2022 May 27;14(5):442-451. doi: 10.4240/wjgs.v14.i5.442. |
| 27296525 | Background | Doussot A, Gonen M, Wiggers JK, Groot-Koerkamp B, DeMatteo RP, Fuks D, Allen PJ, Farges O, Kingham TP, Regimbeau JM, D'Angelica MI, Azoulay D, Jarnagin WR. Recurrence Patterns and Disease-Free Survival after Resection of Intrahepatic Cholangiocarcinoma: Preoperative and Postoperative Prognostic Models. J Am Coll Surg. 2016 Sep;223(3):493-505.e2. doi: 10.1016/j.jamcollsurg.2016.05.019. Epub 2016 Jun 11. |
| 33597569 | Background | Yu TH, Chen X, Zhang XH, Zhang EC, Sun CX. Clinicopathological characteristics and prognostic factors for intrahepatic cholangiocarcinoma: a population-based study. Sci Rep. 2021 Feb 17;11(1):3990. doi: 10.1038/s41598-021-83149-5. |
| 31536748 | Background | Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis. J Hepatol. 2020 Jan;72(1):95-103. doi: 10.1016/j.jhep.2019.09.007. Epub 2019 Sep 16. |
| 30910538 | Background | Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P, El-Serag HB, La Vecchia C, Negri E. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019 Jul;71(1):104-114. doi: 10.1016/j.jhep.2019.03.013. Epub 2019 Mar 23. |
| 36860251 | Background | An L, Zheng R, Zhang S, Chen R, Wang S, Sun K, Lu L, Zhang X, Zhao H, Zeng H, Wei W, He J. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma incidence between 2006 and 2015 in China: estimates based on data from 188 population-based cancer registries. Hepatobiliary Surg Nutr. 2023 Feb 28;12(1):45-55. doi: 10.21037/hbsn-21-75. Epub 2021 Jul 21. |
| 33579427 | Background | Sirica AE, Strazzabosco M, Cadamuro M. Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression. Adv Cancer Res. 2021;149:321-387. doi: 10.1016/bs.acr.2020.10.005. Epub 2020 Dec 9. |
| 33922362 | Background | Fiste O, Ntanasis-Stathopoulos I, Gavriatopoulou M, Liontos M, Koutsoukos K, Dimopoulos MA, Zagouri F. The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel). 2021 Apr 22;9(5):422. doi: 10.3390/vaccines9050422. |
| 40446770 | Background | Zhang R, Wang Z, Yang M, Chen B, Liu M, Zheng M, Liu PX, Wang L. Combining traditional analysis and machine learning to predict early, middle, and long-term recurrence of intrahepatic cholangiocarcinoma. Eur J Surg Oncol. 2025 Sep;51(9):110141. doi: 10.1016/j.ejso.2025.110141. Epub 2025 May 9. |
| 33962560 | Background | Zhao B, Cheng Q, Cao H, Zhou X, Li T, Dong L, Wang W. Dynamic change of serum CA19-9 levels in benign and malignant patients with obstructive jaundice after biliary drainage and new correction formulas. BMC Cancer. 2021 May 7;21(1):517. doi: 10.1186/s12885-021-08204-w. |
| ID | Term |
|---|---|
| D018281 | Cholangiocarcinoma |
| C562580 | Cirrhosis, Familial, with Pulmonary Hypertension |
| D012008 | Recurrence |
| D008113 | Liver Neoplasms |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
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