Clearance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection or Liver Transplantation

Abstract

Background: In patients with hepatocellular carcinoma (HCC), a complete clearance of circulating tumor cells (CTCs) early after liver transplantation (LT) or surgical resection (LR) could prevent tumor recurrence. Methods: prospective pilot study including patients with HCC who underwent LR or LT from September 2017 to May 2020. Enumeration of CTCs was performed in peripheral blood samples (7 mL) using the Isoflux® system (Fluxion Biosciences) immediately before surgery, at post-operative day 5 and at day 30. A clinically relevant number of CTCs was defined as >30 CTCs/sample. Results: 41 HCC patients were included (mean age 58.7 ± 6.3; 82.9% male). LR was performed in 10 patients (24.4%) and 31 patients (75.6%) underwent LT. The main etiology of liver disease was chronic hepatitis C (31.7%). Patients undergoing LR and LT were similar in terms of preoperative CTC count (p = 0.99), but clearance of CTCs within the first month was more pronounced in the LT group. Clusters of CTCs at baseline were associated with incomplete clearance of CTCs at day 30 (54.2% vs. 11.8%, p = 0.005), which in turn impacted negatively on survival (p = 0.038). Conclusion: Incomplete clearance of CTCs after surgery could be a surrogate marker of HCC aggressiveness.

Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal

“…Very recently, Hwang et al have shown that CTCs with cancer stemness could predict HCC recurrence when they are detected preoperatively and 1 day after LT using fluorescent activated cell sorter [ 96 ]. We have evaluated the clearance kinetics of CTCs in HCC patients undergoing LT and found that the presence of CTC clusters before surgery was associated with an incomplete clearance of CTCs at postoperative day 30, which in turn predicted mortality due to extrahepatic recurrence of HCC [ 98 ]. The unpredictable evolution of CTCs after LT could be in part explained using immunosuppressive drugs, which are required to prevent graft rejection.…”

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream)

“…The IsoFlux TM system (Fluxion Biosciences, Inc., Alameda, CA, USA) is a semi-automatic platform for the enrichment of CTCs using a combination of immunomagnetic positive selection and microfluidics, and it significantly increases isolation efficiencies compared to the FDA-approved CellSearch ® (Menarini, Italy) system [ 5 ]. An improvement in the recovery rate from 40% to 90% using cancer cell lines was achieved compared with CellSearch ® [ 6 ], and this technology was used to successfully isolate CTCs in bladder [ 7 ], prostate [ 8 ], ovarian [ 9 ], liver [ 10 , 11 , 12 , 13 ] and pancreatic [ 14 ] cancer patients. However, it was only recently that the IsoFlux TM (Fluxion, Biosciences, Inc., Alameda, CA, USA) platform was used to isolate CTCs from colorectal cancer patients to evaluate the relationship between microsatellite instability (MSI) status and peri-operative release of CTCs [ 15 ].…”

Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma?

“…Table 1 summarizes the selected studies. Among 13 articles, only eight studies specifically focused on LT ( 19 – 26 ) ( Table 1 ), including only transplant patients, whereas five other studies investigated CTCs in cohorts of patients receiving various treatments ( 27 – 31 ).…”

“…Recently, Amado et al. studied the kinetics of CTCs clearance after LR and LT, utilizing iFISH ® and collecting sequential blood samples pre-operatively, on post-operative day (POD) 5 and POD30 ( 27 ). Despite a comparable preoperative CTCs count, LT was followed by a significant proportion of CTCs clearance ( p = 0.007), conversely to LR ( p = 0.241).…”