Hepatocellular Carcinoma Nodules Research Articles

Imaging Diagnosis of Hepatocellular Carcinoma: A State-of-the-Art Review.

Hepatocellular carcinoma (HCC) remains not only a cause of a considerable part of oncologic mortality, but also a diagnostic and therapeutic challenge for healthcare systems worldwide. Early detection of the disease and consequential adequate therapy are imperative to increase patients' quality of life and survival. Imaging plays, therefore, a crucial role in the surveillance of patients at risk, the detection and diagnosis of HCC nodules, as well as in the follow-up post-treatment. The unique imaging characteristics of HCC lesions, deriving mainly from the assessment of their vascularity on contrast-enhanced computed tomography (CT), magnetic resonance (MR) or contrast-enhanced ultrasound (CEUS), allow for a more accurate, noninvasive diagnosis and staging. The role of imaging in the management of HCC has further expanded beyond the plain confirmation of a suspected diagnosis due to the introduction of ultrasound and hepatobiliary MRI contrast agents, which allow for the detection of hepatocarcinogenesis even at an early stage. Moreover, the recent technological advancements in artificial intelligence (AI) in radiology contribute an important tool for the diagnostic prediction, prognosis and evaluation of treatment response in the clinical course of the disease. This review presents current imaging modalities and their central role in the management of patients at risk and with HCC.

Human Epidermal Growth Factor Receptor 2 (HER2) Expression by Immunohistochemistry and Its Clinical Significance in Hepatocellular Carcinoma: A Single-Center Analysis.

Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family. It has been identified as an oncogene and is associated with poor outcomes in multiple tumortypes. In hepatocellular carcinoma (HCC), there are contradictory data regarding the HER2 expression and its role in tumor development and progression. Some studies have identified HER2 expression as an early event during tumorigenesis, which decreases with progression and metastasis. Additional data provided evidence that treatment with anti-HER2 therapy resulted in local response and reduction in the metastasis rate in HCC micemodels. Patients with histological diagnoses of HCC between 2010 and 2020 were included. HER2 staining was performed by immunohistochemistry (IHC), and scoring was done in accordance with the gastric cancer guidelines as 0, 1+, 2+, and 3+. Clinicopathological features were accessed by medical records. This study aims to evaluate HER2 expression by IHC in HCCand to correlate this expression with some clinicopathological features such as Barcelona Clinic Liver Cancer (BCLC) staging,number of hepatic lesions,alpha-fetoprotein level, underlying liver disease, presence of livercirrhosis, Child-Pugh score, and tumor recurrence. A total of 57 specimens from 54 patients were included. Of the patients, 85% were men, and the median age at diagnosis was 71 years (interquartile range: 59-75 years). Regarding stage, 61% were at stage 0-A of BCLC. Of the patients,57% had a solitary HCC nodule. Concerning treatment, surgery was performed in 50% of the patients.HER2 expression was identified in seven patients: five in the membrane and two in the cytoplasm. Concerning the membrane staining, HER2 expression was scored as 1+/2+ in 7.4% (n = 4 patients). Of the patients with HER2 expression, fourhad a BCLC stage of 0-A and a single HCC nodule; alpha-fetoprotein was <400 ng/mL in all cases. There was no correlation to clinicopathological features. In one patient with HER2 2+ expressionat diagnosis, this expression was not identified at tumor progression. Median disease-free survival in HER2 with IHC scores 1+/2+ and cytoplasmatic was 38 months versus 22 months in HER2 with a score of 0 (p = 0.604). HER2 expression is a rare event in HCC. It was not possible to identify any relation to clinicopathological features. However, when we relate our data to previous trials, HER2 appears to be an early event in the course of HCC.

Laminin-332 γ2 Monomeric Chain Promotes Adhesion and Migration of Hepatocellular Carcinoma Cells.

Extracellular matrix (ECM) has a well-recognized impact on the progression of solid tumors, including hepatocellular carcinoma (HCC). Laminin 332 (Ln332) is a ECM molecule of epithelial basal lamina, composed of three polypeptide chains (α3, β3, and γ2), that is usually poorly expressed in the normal liver but is detected at high levels in HCC. This macromolecule was shown to promote the proliferation, epithelial-to-mesenchymal transition (EMT), and drug resistance of HCC cells. The monomeric γ2 chain is up-regulated and localized preferentially at the invasive edge of metastatic intrahepatic HCC nodules, suggesting its potential involvement in the acquisition of invasive properties of HCC cells. HCC cells were tested in in vitro adhesion, scattering, and transwell migration assays in response to fibronectin and the Ln332 and Ln332 γ2 chains, and the activation status of major signaling pathways involved was evaluated. Here, we show that the Ln332 γ2 chain promotes HCC the cell adhesion, migration, and scattering of HCC cells that express the Ln332 receptor α3β1 integrin, proving to be a causal factor of the EMT program achievement. Moreover, we found that efficient HCC cell adhesion and migration on γ2 require the activation of the small cytosolic GTPase Rac1 and ERKs signaling. These data suggest that the γ2 chain, independently from the full-length Ln332, can contribute to the pro-invasive potential of aggressive HCC cell subpopulations.

Recurrence in patients with totally necrotic nodules of hepatocellular carcinoma after liver transplantation: "totally" an inaccurate description.

Total necrosis of hepatocellular carcinoma (HCC) achieved via locoregional treatment (LRT) is considered to indicate a lack of tumor viability. Nonetheless, there is insufficient evidence of recurrence after liver transplantation (LT) in patients with such a status. The aim of this study was to investigate the prognosis of patients diagnosed with totally necrotic nodules upon explant hepatectomy after LT. We conducted a retrospective study of patients diagnosed with totally necrotic nodules after LT for HCC. A total of 165 patients with HCC who underwent living- or deceased-donor LT from 2000 to 2020 in our hospital were included. A total of 5 patients (3.0%) exhibited HCC recurrence during a median follow-up of 84 months (range, 4-243 months) after LT. The 5-year overall and recurrence-free survival rates of these patients were 92.8% and 92.2%, respectively. Four patients in the HCC-recurrence group (80.0%) died even after further treatment, including transarterial chemoembolization, surgery, and systemic treatment. Both univariate and multivariate analyses of clinicopathological factors identified a maximum diameter of the totally necrotic nodules of >5 cm as the only factor associated with tumor recurrence following LT (P = 0.005 and P = 0.009, respectively). Total necrosis of HCC via LRT yielded excellent survival outcomes for patients undergoing LT. Nevertheless, patients with large tumors should be considered at high risk of recurrence after LT, suggesting the need for their active surveillance during the follow-up period.

Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System in Hepatocellular Carcinoma ≤5 cm: Biological Characteristics and Patient Outcomes

Introduction: The present study aimed to evaluate the influence of biological characteristics of hepatocellular carcinoma (HCC) on the Liver Imaging Reporting and Data System (LI-RADS) v2017 category of contrast-enhanced ultrasound (CEUS) in patients with high risk and compare the outcomes among different categories after radical resection. Methods: Between June 2017 and December 2020, standardized CEUS data of liver nodules were prospectively collected from multiple centers across China. We conducted a retrospective analysis of the prospectively collected data on HCCs measuring no more than 5 cm, as diagnosed by pathology. LI-RADS categories were assigned after thorough evaluation of CEUS features. Then, CEUS LI-RADS categories and major features were compared in different differentiation, Ki-67, and microvascular invasion (MVI) statuses. Differences in recurrence-free survival (RFS) among different LI-RADS categories were further analyzed. Results: A total of 293 HCC nodules in 293 patients were included. This study revealed significant differences in the CEUS LI-RADS category of HCCs among differentiation (p < 0.001) and levels of Ki-67 (p = 0.01) and that poor differentiation (32.7% in LR-M, 12% in LR-5, and 6.2% in LR-4) (p < 0.001) and high level of Ki-67 (median value 30%) were more frequently classified into the LR-M category, whereas well differentiation (37.5% in LR-4, 15.1% in LR-5, and 11.5% in LR-M) and low levels of Ki-67 (median value 11%) were more frequently classified into the LR-4 category. No significant differences were found between MVI and CEUS LI-RADS categories (p > 0.05). With a median follow-up of 23 months, HCCs assigned to different CEUS LI-RADS classes showed no significant differences in RFS after resection. Conclusions: Biological characteristics of HCC, including differentiation and level of Ki-67 expression, could influence major features of CEUS and impact the CEUS LI-RADS category. HCCs in different CEUS LI-RADS categories showed no significant differences in RFS after resection.

HCC treated with immune checkpoint inhibitors: a hyper-enhanced rim on Sonazoid-CEUS Kupffer phase images is a predictor of tumor response.

We aimed to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody therapy by assessing the hyper-enhanced rim phenomenon of hepatocellular carcinoma (HCC) on Sonazoid-contrast-enhanced ultrasound (CEUS) Kupffer phase images. This retrospective study included 61 patients with HCC who received anti-PD-1/PD-L1 antibody therapy from August 1, 2020, to January 31, 2022. We compared the progression-free survival (PFS) of patients with hyper-enhanced rim+ and hyper-enhanced rim-nodules and the time to nodule progression (TTnP) of hyper-enhanced rim+ and hyper-enhanced rim- nodules. Thirty-nine patients received postoperative therapy, and 22 patients had unresectable HCC. The mean PFS was 11.8 months (95% confidence interval [CI]: 8.7-14.9) for patients with hyper-enhanced rim+ HCC nodules and 16.5 months (95% CI: 14.9-18.1) for patients with hyper-enhanced rim- HCC nodules in the surgery group (p = 0.017). The mean PFS was 9.2 months (95% CI: 3.6-14.8) for patients with hyper-enhanced rim+ HCC nodules and 17.8 months (95% CI: 14.9-20.6) for patients with hyper-enhanced rim- HCC nodules in the non-surgery group (p = 0.015). For hyper-enhanced rim+ HCC nodules, TTnP for each nodule exceeding the specified threshold was 10.1 months, whereas that for hyper-enhanced rim- HCC nodules was 17.6 months (p = 0 .018). The disease control rate was 42.9% (3/7) for hyper-enhanced rim+ HCC nodules and 85.7% (21/24) for hyper-enhanced rim- HCC nodules (p = 0.013). The presence of hyper-enhanced rim on the Kupffer phase images obtained via the non-invasive Sonazoid-CEUS is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 therapy in patients with HCC. • The mean progression-free survival was 11.8 months for patients with hyper-enhanced rim+ HCC nodules and 16.5 months for patients with hyper-enhanced rim- HCC nodules in the surgery group. • The mean progression-free survival was 9.2 months for patients with hyper-enhanced rim+ HCC nodules and 17.8 months for patients with hyper-enhanced rim- HCC nodules in the non-surgery group. • The disease control rate was 42.9% for hyper-enhanced rim+ HCC nodules and 85.7% for hyper-enhanced rim- HCC nodules (p = 0.013).

Efficacy and safety of no-touch radiofrequency ablation for small hepatocellular carcinoma-a systematic review and single-arm meta-analysis

ObjectiveThe purpose of this study was to report the efficacy and safety of no-touch radiofrequency ablation (NT-RFA) in the treatment of small hepatocellular carcinoma (HCC). MethodsWe systematically searched for eligible studies in PubMed, Embase and Cochrane library until June 1, 2022. Random effect model was applied to synthesize the pooled proportions of local tumor progression-free survival (LTP), recurrence-free survival (RFS) and overall survival (OS) respectively, as well as adverse events, for small HCC treated by NT-RFA. ResultsOf the 10 included studies, 3 of them reported local tumor recurrence. One reported local tumor recurrence at 19 months (range, 12–24), and 2 studies had no tumor recurrence with 24-months of follow-up. The 1- and 2-year LTP pooled proportions were 99.3% (95%CI, 97.5–100) and 97.8% (95%CI, 94.6–99.6) respectively, and two studies reported a 3-year LTP rate of 96.4% (204/212, 36/37). The 1-yearRFS rates was 91.3% (95%CI, 84.1–98.4), 2-year was 86.4% (95%CI, 75.3–97.5). The 1-, 2- and 3- year OS rates were 92.4% (95%CI, 82.8–92.7), 84.1% (95%CI, 74.7–93.6) and 81.8% (116/181, 33/36) respectively, and only one study reported a 5-year OS rate of 47.0% (85/181). The ablative success rate of the HCC nodules was 96.6% (95%CI, 91.3–99.5) and the proportions of mild and severe adverse events following ablation were 18.3% (95%CI, 8.1–41.6) and 5.0%, respectively. ConclusionNT-RFA provides safely very high rate of sustained local control for the treatment of HCC up to 5 cm.

The Role of Immediate Post-Procedural Cone-Beam Computed Tomography (CBCT) in Predicting the Early Radiologic Response of Hepatocellular Carcinoma (HCC) Nodules to Drug-Eluting Bead Transarterial Chemoembolization (DEB-TACE).

The purpose of this study was to evaluate the efficacy of unenhanced cone-beam computed tomography (CBCT) performed at the end of drug-eluting bead transarterial chemoembolization (DEB-TACE) in predicting HCC nodules’ early radiologic response to treatment, assessed using mRECIST criteria with a 30−60 day four-phase contrast-enhanced CT follow-up. Fifty-nine patients (81 lesions) subjected to DEB-TACE as exclusive treatment for HCC lesions (naive/relapse) between February 2020 and October 2021 were prospectively enrolled. In a post-interventional unenhanced CBCT procedure, two experienced radiologists evaluated for each lesion the overall intensity of the contrast media deposit, the homogeneity of the enhancement, and the presence of smooth and complete margins. The univariate analysis found that lesions with complete response (CR+) had a significantly higher incidence of clear and complete margins than CR− lesions (76.9% vs. 17.2%, p = 0.003) and a higher intensity score (67.3% vs. 27.6%, p = 0.0009). A Dmax <30 mm was significantly more common among CR+ than CR− lesions (92.3% vs. 69%, p = 0.01). These features were confirmed as significant predictors for CR+ by multivariate binary logistic regression. The homogeneity of the enhancement did not affect the DEB-TACE outcome. Post-interventional unenhanced CBCT is effective in predicting early radiological response to DEB-TACE, since the presence of an intense contrast media deposit with clear and complete margins in treated HCC lesions is associated with CR.

Surgical resection versus transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the gold standard treatment in intermediate hepatocellular carcinoma (HCC), but long-term disease control rates remain low. Herein, we compared results of TACE followed by hypofractionated radiotherapy (TACE-hRT) to surgical resection (SR) in early single or paucinodular intrahepatic HCC. Between June 2004 and November 2016, data on 160 consecutive patients with Barcelona Clinic Liver Cancer (BCLC) stageA Child-PughA HCC treated with SR or TACE-hRT in our expert center were retrospectively reviewed. Time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were evaluated. Clinical outcomes were compared using the stabilized-weights inverse probability of treatment weighting propensity score. Ninety-eight patients underwent SR and 62were treated by TACE-hRT. Median total dose of RT was 54 Gy (interquartile range [IQR] 54-54) in 3‑Gy fractions. Median OS follow-up was 93months. TTP did not significantly differ between patients following SR and TACE-hRT, with 1‑year rates of 68.2% and 82.6% (p = 0.17), respectively. In contrast, PFS and OS were lower in the TACE-hRT group (p = 0.015 and p = 0.006), with amedian OS of 37vs. 63months for patients with surgery and TACE-hRT, respectively. In multivariate analysis, asignificant negative impact on PFS and OS was seen for age at diagnosis, on TTP for alcohol-related liver disease, and on OS for total number of HCC nodules. Symptomatic grade ≥ 3 adverse events were presented by42 (42.9%) SR and19 (30.6%) TACE-hRT patients (p = 0.17). In patients presenting Child-PughA BCLC‑A HCC with high risk for surgical complications, TACE-hRT can be an effective and safe treatment. However, surgical management remains the standard of care whenever possible.

Prediction of Protumorigenic Effects after Image-Guided Radiofrequency Ablation of Hepatocellular Carcinoma Using Biomarkers

PurposeTo perform radiofrequency (RF) ablation of hepatocellular carcinoma (HCC) and to assess serological and histopathological markers of tumorigenesis in distant untreated tumors to determine whether these were associated with unfavorable outcomes such as early relapse and increased biological aggressiveness. Materials and MethodsThe study cohort comprised 13 patients from a prospective single-arm study. All patients underwent 2 ablation sessions of multifocal HCC nodules 14 days apart. Core biopsy samples of untreated tumors were acquired at baseline and at the time of the second ablation session. Samples were stained immunohistochemically with Ki-67 (proliferation) and CD34 (microvasculature). Blood plasma was obtained at baseline and 2 days after the initial ablation session and analyzed for hepatocyte growth factor (HGF), vascular endothelial growth factor C, and angiopoietin-2 using an enzyme-linked immunosorbent assay. The clinical follow-up period ranged from 7 to 25 months. Patients were stratified as responders (complete remission or limited and delayed recurrence at >6 months; n = 6) or nonresponders (any recurrence within 6 months or >3 new tumors or any new tumor of >3 cm thereafter; n = 7). ResultsIn 3 of 7 nonresponders, the Ki-67 index markedly increased in untreated tumors, whereas Ki-67 was stable in all responders. Microvascular density strongly increased in a single nonresponder only. HGF and angiopoietin-2 increased by >30% in 3 of 7 and 4 of 7 nonresponders, respectively, whereas they were stable or decreased in responders. Overall, ≥2 biomarkers were elevated in 6 of 7 (85.7%) nonresponders, whereas 4 of 6 responders demonstrated no increased biomarker and 2 patients demonstrated increase in 1 biomarker only (P = .002). ConclusionsRF ablation of HCC can produce protumorigenic factors that induce effects in distant untreated tumors. These may potentially function as biomarkers of clinical outcome.

Can DKI-MRI predict recurrence and invasion of peritumoral zone of hepatocellular carcinoma after transcatheter arterial chemoembolization?

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Transcatheter arterial chemoembolization (TACE) has been performed as a palliative treatment for patients with HCC. However, HCC is easy to recur after TACE. Magnetic resonance imaging (MRI) has clinical potential in evaluating the TACE treatment effect for patients with liver cancer. However, traditional MRI has some limitations. To explore the clinical potential of diffusion kurtosis imaging (DKI) in predicting recurrence and cellular invasion of the peritumoral liver zone of HCC after TACE. Seventy-six patients with 82 HCC nodules were recruited in this study and underwent DKI after TACE. According to pathological examinations or the overall modified response evaluation criteria in solid tumors (mRECIST) criterion, 48 and 34 nodules were divided into true progression and pseudo-progression groups, respectively. The TACE-treated area, peritumoral liver zone, and far-tumoral zone were evaluated on DKI-derived metric maps. Non-parametric U test and receiver operating characteristic curve (ROC) analysis were used to evaluate the prediction performance of each DKI metric between the two groups. The independent t-test was used to compare each DKI metric between the peritumoral and far-tumoral zones of the true progression group. DKI metrics, including mean diffusivity (MD), axial diffusivity (DA), radial diffusivity (DR), axial kurtosis (KA), and anisotropy fraction of kurtosis (Fak), showed statistically different values between the true progression and pseudo-progression groups (P < 0.05). Among these, MD, DA, and DR values were higher in pseudo-progression lesions than in true progression lesions, whereas KA and FAk values were higher in true progression lesions than in pseudo-progression lesions. Moreover, for the true progression group, the peritumoral zone showed significantly different DA, DR, KA, and FAk values from the far-tumoral zone. Furthermore, MD values of the liver parenchyma (peritumoral and far-tumoral zones) were significantly lower in the true progression group than in the pseudo-progression group (P < 0.05). DKI has been demonstrated with robust performance in predicting the therapeutic response of HCC to TACE. Moreover, DKI might reveal cellular invasion of the peritumoral zone by molecular diffusion-restricted change.

Indocyanine Green as a Navigational Adjunct for Laparoscopic Ablation of Liver Tumors.

Minimally invasive operative approaches for resection and thermal ablation (eg, microwave, radiofrequency) of hepatocellular carcinoma (HCC) have been successfully implemented over the last two decades, although identifying tumors can be challenging. Successfully performing laparoscopic ablation requires real-time visualization and ultrasonography skills for direct placement of the ablation probe. In this study, we introduce a novel adjunct to ultrasound imaging for tumors located near or on the surface of the liver via intravenous delivery of indocyanine green (ICG) dye. Non-resectable lesion(s) not amenable to percutaneous ablation were considered for laparoscopic microwave ablation. Each patient initially received a dose of .3125mg ICG via peripheral IV. A total of 17 patients were included. There was brisk uptake of ICG throughout the liver parenchyma in under 2minutes in 15 of 17 patients; the remaining 2 required a second dose of ICG. In 14 cases, a hypo-fluorescent perfusion pattern in the tumor was clearly identified. Integrating ICG and fluorescent imaging provides a complementary adjunct to ultrasound in identifying HCC nodules. While previous applications of ICG typically require injections several days prior to surgery or segmental injections, this study demonstrates a novel real-time application of ICG to aid surgeons with various experiences in laparoscopic-assisted ablation procedures for HCC.

Radiological Features of Microvascular Invasion of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

Background: The aim of the present study was to evaluate the presence and the prognostic value of the radiological signs of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: Between January 2015 and December 2017, all patients (91 patients) with de novo HCC or HCC recurrence occurring at least 2 years after the last treatment in NAFLD (36 patients) or with hepatitis C virus (HCV) liver disease (55 patients) were included. Each HCC was treated with liver resection and transplantation to obtain the anatomopathological confirmation of MVI. All patients had at least one available computed tomography (CT) scan or magnetic resonance imaging (MRI) performed no more than one month prior to the treatment. The clinical data of each patient, tumor burden (diameter, margins, two-trait predictor of venous invasion (TTPVI), and peritumoral enhancement), the recurrence rate (RR) after a 1-year follow-up, and the time to recurrence (TTR) were collected. Results: The NAFLD–HCC nodules were larger as compared to HCV–HCC (51 mm vs. 36 mm, p = 0.004) and showed a higher prevalence of TTPVI (38.9 vs. 20.0%, p = 0.058). At multivariate analysis, nodule diameter &gt;50 mm was found to be the only independent prognostic factor of TTPVI (hazard ratio: 21.3, 95% confidence interval: 4.2–107.7, p &lt; 0.001), and the presence of TTPVI was confirmed to be the only independent prognostic factors of recurrence (hazard ratio: 2.349, 95% confidence interval: 1.369–4.032, p = 0.002). No correlations were found between TTR and irregular tumor margins or peritumoral enhancement. Conclusion: The NAFLD–HCC patients had larger tumors at diagnosis and showed a more frequent presence of radiological signs of MVI as compared to the HCV–HCC patients. The MVI was related to a more rapid recurrence after curative treatments, demonstrating the prognostic value of this radiological diagnosis.

Efficacy and safety of microwave ablation and radiofrequency ablation in the treatment of hepatocellular carcinoma: A systematic review and meta-analysis.

Background:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Surgical resection is often only possible in the early stages of HCC and among those with limited cirrhosis. Radiofrequency ablation and Microwave ablation are 2 main types of percutaneous thermal ablation for the treatment of HCC. The efficacy and safety between these 2 therapy methods are still under a debate.Objective:To compare the efficacy and safety of Radiofrequency ablation and Microwave ablation in treating HCC.Methods:PubMed, EMBASE, the Cochrane databases and Web of Science were systematically searched. We included randomized controlled trials and cohort studies comparing the efficacy and safety of Radiofrequency ablation and Microwave ablation in HCC patients. Outcome measures on local tumor progression, complete ablation, disease-free survival, overall survival, or major complications were compared between the 2 groups. The random effect model was used when there was significant heterogeneity between studies, otherwise the fixed effect model was used.Results:A total of 33 studies, involving a total of 4589 patients were identified, which included studies comprised 7 RCTs, 24 retrospective observational trials, and 2 prospective observational trial. Microwave ablation had a lower local tumor progression than Radiofrequency ablation in cohort studies (OR = 0.78, 95% CI 0.64–0.96, P = .02). Complete ablation rate of Microwave ablation was higher than that of Radiofrequency ablation in cohort studies (OR = 1.54, 95% CI 1.05–2.25, P = .03). There was no significant difference in overall survival and disease-free survival between the 2 groups. Meta-analysis showed that there was no significant difference in the main complications between Microwave ablation and Radiofrequency ablation.Conclusions:Microwave ablation has higher complete ablation and lower local tumor progression than Radiofrequency ablation in the ablation treatment of HCC nodules. There was no significant difference in overall survival between the 2 therapy methods.

Two-Phase MDCT Protocol for the Screening of Small Hepatocellular Carcinoma.

Screening programmes for cirrhotic patients are based on ultrasound (US) examinations at 6-month intervals, but a US sensitivity of 47% has recently been reported. The aim of this study was to evaluate a two-phase MDCT protocol in terms of hepatic nodule detection within a hepatocellular carcinoma (HCC) screening situation and to evaluate a reduction in irradiation dose for the 6-monthly checks compared to the classic four-phase protocol. In total, 373 patients with 498 nodules that were suspected to be HCC and ranged from 10 to 30 mm in size were prospectively included. All patients underwent four-phase MDCT with an unenhanced phase, arterial phase (AP), portal phase (PP) and delayed phase (DP). The cumulative irradiation from the repeated 6-monthly MDCT protocol was calculated. Of the 498 nodules, only 4 (0.008%) were only seen in the PP and not in the AP or AP. Of the 319 HCC nodules, 270 (84.6%) had AP hyperenhancement, while 115 had washout in the PP and 224 had washout in the DP. Overall, 222 of the 224 (99.1%) HCC nodules with typical features were seen in the AP and DP. The dose reduction was estimated at 55.4% when using the two-phase protocol (AP and DP). The cumulative irradiation of the two-phase protocol, which was performed every 6 months over 5 years, was 96.5 mSv. MDCT with the two-phase protocol could offer an alternative to ultrasound screening with an interesting risk–benefit trade-off.

Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation.

The role of heat shock protein 70 and glypican 3 expression in early diagnosis of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths in the world and accounts for ~90% of primary liver carcinoma cases. This study aimed to evaluate the combination of two markers (HSP70 and GPC3) immunohistochemical expression in early detection of HCC. Materials and methods This study included 56 cases of primary hepatic lesions, five cases of focal nodular hyperplasia, five cases of hepatic adenoma, 33 cases of small vaguely nodular lesions (five of dysplastic nodule and 28 of early HCC), and 13 cases of late HCC. Results The sensitivity, specificity, and positive and negative predictive values of HSP70 for HCC detection were 78.2, 100, 100, and 24.1%, respectively. The sensitivity, specificity, and positive and negative predictive values of GPC3 for HCC detection were 60, 100, 100, and 36.8%, respectively. The sensitivity, specificity, and positive and negative predictive values for this combination (HSP70+GPC3) were 100, 100, 100, and 100%, respectively. Conclusion The immunoexpression of the two markers HSP70 and GPC3 is valuable in distinguishing between dysplastic nodules and early HCC. When the two markers are positive, the optimal sensitivity and specificity for detection of early HCC are obtained. The results of our study strikingly support the combination of the two markers together in the diagnostic distinction of nonconfirmed hepatic lesions of malignancies but do not support the use of both separately.

Long-term outcomes of living-donor liver transplantation, hepatic resection, and local therapy for hepatocellular carcinoma with three

Background and AimTreatment for small hepatocellular carcinoma (HCC) is determined based on the results of a liver function test and the tumor location and spread. The present study compared the outcomes among local therapy, hepatic resection (HR), and living‐donor liver transplantation (LDLT) for small HCC in a single institute.MethodsWe compared the overall survival, recurrence‐free survival, and cancer‐specific survival rates in patients with three HCC nodules <3 cm in size among local therapy, which included radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and transarterial chemoembolization (TACE), and surgical treatment (HR and LDLT).ResultsOne hundred and ninety‐seven patients with local therapy (109 RFA, 26 PEI, and 78 TACE), 107 with HR, and 66 with LDLT were enrolled in this study. There was no significant difference in OS among these groups. The recurrence‐free, cancer‐specific survival (CSS) of LDLT was superior to local therapy and HR. The prognostic factors for the survival were Child–Pugh (CP) Grade B and tumor marker for local therapy and multiple tumors and elevated ALT levels for HR.ConclusionsFor CP grade B patients with HCC of three <3‐cm nodule, LDLT could be considered because it resulted in better survival and CSS rates than local therapy.

Kupffer Phase Radiomics Signature in Sonazoid-Enhanced Ultrasound is an Independent and Effective Predictor of the Pathologic Grade of Hepatocellular Carcinoma.

We conduct this study to investigate the value of Kupffer phase radiomics signature of Sonazoid-enhanced ultrasound images (SEUS) for the preoperative prediction of hepatocellular carcinoma (HCC) grade. From November 2019 to October 2021, 68 pathologically confirmed HCC nodules from 54 patients were included. Quantitative radiomic features were extracted from grayscale images and arterial and Kupffer phases of SEUS of HCC lesions. Univariate logistic regression and the maximum relevance minimum redundancy (MRMR) method were applied to select radiomic features best corresponding to pathological results. Prediction radiomic signature was calculated using each of the image types. A predictive model was validated using internal leave-one-out cross validation (LOOCV). For discrimination between poorly differentiated HCC (p-HCC) and well-differentiated HCC/moderately differentiated HCC (w/m-HCC), the Kupffer phase radiomic score (KPRS) achieved an excellent area under the curve (AUC = 0.937), significantly higher than the other two radiomic signatures. KPRS was the best radiomic score based on the highest AUC (AUC = 0.878), which is prior to gray and arterial RS for differentiation between w-HCC and m/p-HCC. Univariate and multivariate analysis incorporating all radiomic signatures and serological variables showed that KPRS was the only independent predictor in both predictions of HCC lesions (p-HCC vs. w/m-HCC, log OR 15.869, P < 0.001, m/p-HCC vs. w-HCC, log OR 12.520, P < 0.05). We conclude that radiomics signature based on the Kupffer phase imaging may be useful for identifying the histological grade of HCC. The Kupffer phase radiomic signature may be an independent and effective predictor in discriminating w-HCC and p-HCC.

Abstract 255: Peroxidasin deficiency recruits pro-healing macrophages into the liver and inhibits NAFLD progression to HCC

Abstract Introduction: During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix (ECM) proteins. ECM stabilization influences the speed of tissue recovery. Here, we used a mouse model of nonalcoholic fatty liver disease (NAFLD) to study the function of peroxidasin (PXDN), a peroxidase that uses H2O2 to cross-link collagen IV, during liver fibrosis progression to hepatocellular carcinoma (HCC). Method: Pxdn-/- and Pxdn+/+ mice were fed with a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) for 16 weeks to create a NAFLD-HCC preclinical model. Liver histology, collagen content, flow cytometry, immunostaining of immune cells, RNA-seq, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. Results: Using Fe-PyC3A as an MRI contrast agent, we detected a higher content of ROS in Pxdn-/- livers (healthy) that was not necessarily directly toxic but could activate hypoxia-related molecular pathways. Genome-wide expression analysis of liver tissue and differential gene expression (DGE) combined with Gene Ontology (GO) analysis identified significant upregulation of genes associated with hypoxia and TNFα signaling pathways already in Pxdn-/- sham livers (without injury). In addition, we observed an upregulation of genes involved in the innate immune response, leukocyte activation, and chemotaxis. After 16 weeks of CDAHFD, gross analysis of collected liver showed no HCC nodule formation in Pxdn-/- mice while 60% of the WT mice had HCC tumors. Collagen deposition showed less collagen accumulation in Pxdn-/- mice. Flow cytometry of macrophages showed Pxdn-/- mice had increased pro-healing M2 macrophages recruitment in early- and mid-stage NAFLD (4 weeks and 8 weeks on CDAHFD) compared to WT controls. In addition, we observed a significant decrease in the number of CD3+ T cells and CD8+ cytotoxic T cells in the late-stage of NAFLD in Pxdn KO mice. DGE analysis revealed that IL-12 is highly expressed in Pxdn-/- injured livers. Additionally, multiple other T cell-related molecules such as IL-10, IL-6, CCL2, IL-7, and CD4 were elevated in Pxdn-/- injured liver. Elevation of these cytokines is an indicator for higher recruitment of pro-healing and anti-HCC macrophage to the site of injury. Conclusion: Our findings demonstrate that PXDN deficiency is associated with the induction of the hypoxia and TNFα signaling pathways and the recruitment of pro-healing and anti-HCC macrophages to the liver. This results in significantly decreased collagen stabilization during liver fibrosis and accelerates fibrosis reversal. In addition, recruited macrophages-controlled T cell response and inhibited HCC formation in Pxdn-/- mice. Citation Format: Mozhdeh Sojoodi, Stephen C. Barrett, Derek J. Erstad, Shadi Salloum, Shijia Zhu, Tongqi Qian, Selene Colon, Eric Gale, Veronica Clavijo Jordan, Yongtao Wang, Shen Li, Michael Lanuti, Lawrence Zukerberg, Peter Caravan, Yujin Hoshida, Raymond T. Chung, Gautam Bhave, Georg M. Lauer, Bryan C. Fuchs, Kenneth K. Tanabe. Peroxidasin deficiency recruits pro-healing macrophages into the liver and inhibits NAFLD progression to HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 255.