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Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

ABSTRACT: Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was performed on a panel of 597 selected genes. Images of the patients who underwent MRI with hepatospecific contrast media during the study period were retrospectively re-evaluated (imaging was not part of the prospective study). cfDNA was detected in the plasma of 36 patients with LC. NGS-based analyses identified 20 variants in different combinations. Re-evaluation of the MRI images that were available for a proportion of the patients (n = 27) confirmed the absence of lesions in 8 cases carrying cfDNA without variants. In 6 of 19 patients with identified variants and MRI images available, MRI revealed a precursor lesion compatible with HCC and new lesions were discovered at follow-up in two patients. These precursor lesions were amenable for curative treatments. Mutation analysis revealed selective HCC related gene mutations in a subset of patients with LC, raising the suspect that these patients were at an increased risk for HCC development. MRI findings confirmed suspect nodular lesions of early stage HCC not detected with current standard screening procedures, which were only seen in patients carrying cfDNA variants. This opens a perspective for an HCC screening strategy combining both liquid biopsy and MRI in patients with LC.

SUBMITTER: Alunni-Fabbroni M

PROVIDER: S-EPMC7866376 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

Alunni-Fabbroni Marianna M Weber Sabine S Öcal Osman O Seidensticker Max M Mayerle Julia J Malfertheiner Peter P Ricke Jens J

Cancers 20210129 3

Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was perf ...[more]

PMID: 33572923

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Project description:BackgroundUltrasonography (US) is recommended as a standard surveillance tool for patients with a high risk of developing hepatocellular carcinoma (HCC). However, the low sensitivity of US for small HCC can lead to surveillance failure, resulting in advanced stage tumor presentations. For the early detection of HCC in high-risk patients and to improve survival and prognosis, a new efficient imaging tool with a high sensitivity for HCC detection is needed. The purpose of this study is to evaluate and compare the feasibility and efficacy of non-contrast magnetic resonance imaging (MRI) with US as a surveillance tool for HCC in patients with liver cirrhosis.MethodsMAGNUS-HCC is a prospective, multicenter clinical trial with a crossover design for a single arm of patients. This study was approved by six Institutional Review Boards, and informed consent was obtained from all participants. All patients will undergo liver US every 6 months and non-contrast liver MRI every 12 months during a follow-up period of 3 years. If a focal liver lesion suspected of harboring HCC is detected, dynamic liver computed tomography (CT) will be performed to confirm the diagnosis. After the last surveillance round, patients without suspicion of HCC or who are not diagnosed with HCC will be evaluated with a dynamic liver CT to exclude false-negative findings. The primary endpoint is to compare the rate of detection of HCC by US examinations performed at 6-month intervals with that of yearly non-contrast liver MRI studies during a 3-year follow-up. The secondary endpoint is the survival of the patients who developed HCC within the 3-year follow-up period.DiscussionMAGNUS-HCC is the first study to compare the feasibility of non-contrast MRI with US as a surveillance tool for the detection of HCC in high-risk patients. We anticipate that the evidence presented in this study will establish the efficacy of non-contrast MRI as a surveillance tool for HCC in high-risk patients.Trial registrationThe date of trial registration ( NCT02551250 ) in this study was September 15, 2015, and follow-up is still ongoing.

Project description:The aims of this study were to observe the pattern of transient motion after gadoxetic acid administration including incidence, onset, and duration, and to evaluate the clinical feasibility of free-breathing gadoxetic acid-enhanced liver magnetic resonance imaging using golden-angle radial sparse parallel (GRASP) imaging with respiratory gating.In this institutional review board-approved prospective study, 59 patients who provided informed consents were analyzed. Free-breathing dynamic T1-weighted images (T1WIs) were obtained using GRASP at 3 T after a standard dose of gadoxetic acid (0.025 mmol/kg) administration at a rate of 1 mL/s, and development of transient motion was monitored, which is defined as a distinctive respiratory frequency alteration of the self-gating MR signals. Early arterial, late arterial, and portal venous phases retrospectively reconstructed with and without respiratory gating and with different temporal resolutions (nongated 13.3-second, gated 13.3-second, gated 6-second T1WI) were evaluated for image quality and motion artifacts. Diagnostic performance in detecting focal liver lesions was compared among the 3 data sets.Transient motion (mean duration, 21.5 ± 13.0 seconds) was observed in 40.0% (23/59) of patients, 73.9% (17/23) of which developed within 15 seconds after gadoxetic acid administration. On late arterial phase, motion artifacts were significantly reduced on gated 13.3-second and 6-second T1WI (3.64 ± 0.34, 3.61 ± 0.36, respectively), compared with nongated 13.3-second T1WI (3.12 ± 0.51, P < 0.0001). Overall, image quality was the highest on gated 13.3-second T1WI (3.76 ± 0.39) followed by gated 6-second and nongated 13.3-second T1WI (3.39 ± 0.55, 2.57 ± 0.57, P < 0.0001). Only gated 6-second T1WI showed significantly higher detection performance than nongated 13.3-second T1WI (figure of merit, 0.69 [0.63-0.76]) vs 0.60 [0.56-0.65], P = 0.004).Transient motion developed in 40% (23/59) of patients shortly after gadoxetic acid administration, and gated free-breathing T1WI using GRASP was able to consistently provide acceptable arterial phase imaging in patients who exhibited transient motion.

Project description:Background & aimsReinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%.MethodsFrench patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs.ResultsAmong 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective.ConclusionsIn the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection.Lay summaryThe early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.

Project description:BackgroundLiver cirrhosis, as the terminal phase of chronic liver disease fibrosis, is associated with high morbidity and mortality. Traditional methods for assessing liver function, such as clinical scoring systems, offer only a global evaluation and may not accurately reflect regional liver function variations. This study aimed at evaluating the diagnostic potential of whole-liver histogram analysis of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) for predicting the progression of cirrhosis.MethodsIn this retrospective study, 265 consecutive patients with cirrhosis admitted to the Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University from August 2012 to September 2019 were enrolled. After the exclusion criteria were applied, 117 patients (84 males and 33 females) were divided into Child-Pugh A cirrhosis (n=43), Child-Pugh B cirrhosis (n=49), and Child-Pugh C cirrhosis (n=25). After correction for liver signal intensity with the spleen was completed, 19 histogram features of the whole liver were extracted and modeled to evaluate liver function, with the Child-Pugh class being incorporated as a clinical parameter. Receiver operating characteristic (ROC) curves were used to assess the diagnosis capability and determine the optimal cutoffs after a mean follow-up of 42.3±19.1 (range, 8-93) months. The association between significant histogram features and the cumulative incidence of hepatic insufficiency was analyzed with the adjusted Kaplan-Meier curve model.ResultsAmong 117 patients (12%), 14 developed hepatic insufficiency through a period of follow-up. Five features, including the median (P<0.01), 90th percentile (P<0.01), root mean squared (P<0.01), mean (P<0.01), and 10th percentile (P<0.05), were significantly different between the groups with and without hepatic insufficiency according to the Kruskal-Wallis test; in the ROC curve analysis, the area under the curve (AUC) of these features was 0.723 [95% confidence interval (CI): 0.653-0.793], 0.722 (95% CI: 0.652-0.792), 0.722 (95% CI: 0.652-0.792), 0.721 (95% CI: 0.651-0.791), and 0.674 (95% CI: 0.600-0.748) after correction, respectively (all P values <0.05). Median, 90th percentile, root mean squared, and mean were found to be significant factors in predicting liver insufficiency. The adjusted Kaplan-Meier curves revealed that patients with a feature level less than the cutoff, as compared to those with a level above the cutoff, showed a statistically shorter progression-free survival and higher incidences of hepatic insufficiency for significant features of median (cutoff =26.001; 21.28% versus 5.71%; P=0.02), 90th percentile (cutoff =86.263; 20.41% versus 5.88%; P<0.01), root mean squared (cutoff =1,028.477; 19.15% versus 7.14%; P=0.049), and mean (cutoff =27.484; 19.15% versus 7.14%; P=0.049). Patients with a 10th percentile less than -39.811 also showed a higher cumulative incidence of hepatic insufficiency than did those with a value higher than the cutoff (0.18% versus 7.46%; P=0.22).ConclusionsWhole-liver histogram analysis of Gd-BOPTA-enhanced MRI may serve as a noninvasive analytical method to predict hepatic insufficiency in patients with cirrhosis.

Dataset Information

Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

Publications

Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

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