Background/Aim s: Although the Barcelona Clinic Liver Cancer staging system seems to underestimate the impact of curative-intent surgical resection for multifocal hepatocellular carcinoma (HCC), recent studies have indicated favorable results for the surgical resection of multiple HCC. This study aimed to assess clinical outcomes and feasibility of surgical resection for multifocal HCC with up to three nodules compared with single tumor cases.
Methods Patients who underwent surgical resection for HCC with up to three nodules between 2009 and 2020 were included, and those with the American Joint Committee on Cancer (AJCC) 8th edition, T1 and T4 stages were excluded to reduce differences in disease distribution and severity. Finally, 81 and 52 patients were included in the single and multiple treatment groups, respectively. Short- and long-term outcomes including recurrence-free survival (RFS) and overall survival (OS), were evaluated.
Results All patients were classified as Child-Pugh class A. RFS and OS were not significantly different between the two groups (P=0.176 and P=0.966, respectively). Multivariate analysis revealed that transfusion and intrahepatic metastasis were significantly associated with recurrence (P=0.046 and P=0.005, respectively). Additionally, intrahepatic metastasis was significantly associated with OS (hazard ratio, 1.989; 95% confidence interval, 1.040-3.802; P=0.038).
Conclusions Since there was no significant difference in survival between the single and multiple groups among patients with AJCC 8th stage T2 and T3, surgical resection with curative intent could be considered with acceptable long-term survival for selected patients with multiple HCC of up to three nodules.
Han Ah Lee, Sangheun Lee, Hae Lim Lee, Jeong Eun Song, Dong Hyeon Lee, Sojung Han, Ju Hyun Shim, Bo Hyun Kim, Jong Young Choi, Hyunchul Rhim, Do Young Kim
J Liver Cancer. 2023;23(2):362-376. Published online September 14, 2023
Background/Aim Despite the increasing proportion of elderly patients with hepatocellular carcinoma (HCC) over time, treatment efficacy in this population is not well established.
Methods Data collected from the Korean Primary Liver Cancer Registry, a representative cohort of patients newly diagnosed with HCC in Korea between 2008 and 2017, were analyzed. Overall survival (OS) according to tumor stage and treatment modality was compared between elderly and non-elderly patients with HCC.
Results Among 15,186 study patients, 5,829 (38.4%) were elderly. A larger proportion of elderly patients did not receive any treatment for HCC than non-elderly patients (25.2% vs. 16.7%). However, OS was significantly better in elderly patients who received treatment compared to those who did not (median, 38.6 vs. 22.3 months; P<0.001). In early-stage HCC, surgery yielded significantly lower OS in elderly patients compared to non-elderly patients (median, 97.4 vs. 138.0 months; P<0.001), however, local ablation (median, 82.2 vs. 105.5 months) and transarterial therapy (median, 42.6 vs. 56.9 months) each provided comparable OS between the two groups after inverse probability of treatment weighting (IPTW) analysis (all P>0.05). After IPTW, in intermediate-stage HCC, surgery (median, 66.0 vs. 90.3 months) and transarterial therapy (median, 36.5 vs. 37.2 months), and in advanced-stage HCC, transarterial (median, 25.3 vs. 26.3 months) and systemic therapy (median, 25.3 vs. 26.3 months) yielded comparable OS between the elderly and non-elderly HCC patients (all P>0.05).
Conclusions Personalized treatments tailored to individual patients can improve the prognosis of elderly patients with HCC to a level comparable to that of non-elderly patients.
Background/Aim Patients with large (>5 cm) hepatocellular carcinoma (HCC) have limited treatment options, thus necessitating the identification of prognostic factors and the development of predictive tools. This study aimed to identify prognostic factors and to construct a nomogram to predict survival outcomes in patients with large HCC.
Methods A cohort of 438 patients, who were diagnosed with large HCC at a tertiary hospital between 2015 and 2018, was analyzed. Cox proportional hazards models were used to identify key prognosticators of overall survival (OS), and an independent set of prognostic factors was used to develop a nomogram. The discrimination and calibration abilities of the nomogram were assessed and internal validation was performed using cross-validation and bootstrapping methods.
Results During a median follow-up of 9.3 months, the median OS was 9.9 months, and the 1-year OS rate was 43.9%. Multivariable Cox regression analysis revealed that performance status, modified albumin-bilirubin grade, tumor size, extent of portal vein tumor thrombosis, and initial treatment significantly affected OS. The newly developed nomogram incorporating these variables demonstrated favorable accuracy (Harrell’s concordance index, 0.807).
Conclusions The newly developed nomogram facilitated the estimation of individual survival outcomes in patients with large HCC, providing an acceptable level of accuracy.
Background/Aim Cancer-associated fibroblasts (CAFs) play an immunosuppressive role in the tumor microenvironment (TME) of human cancers; however, their characteristics and role in hepatocellular carcinoma (HCC) remain to be elucidated.
Methods Nine tumor and surrounding liver tissue samples from patients with HCC who underwent surgery were used to isolate patient-derived CAFs. Cell morphology was observed using an optical microscope after culture, and cell phenotypes were evaluated using flow cytometry and immunoblotting. Cytokines secreted by CAFs into culture medium were quantified using a multiplex cytokine assay.
Results CAFs were abundant in the TME of HCC and were adjacent to immune cells. After culture, the CAFs and non-tumor fibroblasts exhibited spindle shapes. We observed a robust expression of alpha-smooth muscle actin and fibroblast activation protein in CAFs, whereas alpha-fetoprotein, epithelial cell adhesion molecule, platelet/endothelial cell adhesion molecule-1, and E-cadherin were not expressed in CAFs. Furthermore, CAFs showed high secretion of various cytokines, namely C-X-C motif chemokine ligand 12, interleukin (IL)-6, IL-8, and C-C motif chemokine ligand 2.
Conclusions CAFs are abundant in the TME of HCC and play a crucial role in tumor progression. These fibroblasts secrete cytokines that promote tumor growth and metastasis.
Background/Aim Radiotherapy (RT) is an effective local treatment for hepatocellular carcinoma (HCC). However, whether additional RT is safe and effective in patients with advanced HCC receiving atezolizumab plus bevacizumab remains unclear. This retrospective cohort study aimed to evaluate the feasibility of additional RT in these patients.
Methods Between March and October 2021, we retrospectively analyzed seven patients with advanced HCC who received RT during treatment with atezolizumab plus bevacizumab. The median prescribed RT dose was 35 Gy (range, 33–66). Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) after RT were analyzed.
Results The median follow-up duration after RT was 14.2 months (range, 10.0–18.6). Of the seven patients, disease progression was noted in six (85.7%), the sites of disease progression were local in two (28.6%), intrahepatic in four (57.1%), and extrahepatic in four (57.1%). The median time of FFLP was not reached, and PFS and OS times were 4.0 (95% confidence interval [CI], 3.6–4.5) and 14.8% (95% CI, 12.5–17.2) months, respectively. The 1-year FFLP, PFS, and OS rates were 60% (95% CI, 43.8–76.2), 0%, and 85.7% (95% CI, 75.9–95.5), respectively. Grade 3 or higher hematologic adverse events (AEs) were not observed, but grade 3 nonhematologic AEs unrelated to RT were observed in one patient.
Conclusions The addition of RT may be feasible in patients with advanced HCC treated with atezolizumab plus bevacizumab. However, further studies are required to validate these findings.
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Letter regarding “Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab” Sun Hyun Bae, Hee Chul Park Journal of Liver Cancer.2023; 23(2): 402. CrossRef
Sun Hong Yoo, Soon Sun Kim, Sang Gyune Kim, Jung Hyun Kwon, Han-Ah Lee, Yeon Seok Seo, Young Kul Jung, Hyung Joon Yim, Do Seon Song, Seong Hee Kang, Moon Young Kim, Young-Hwan Ahn, Jieun Han, Young Seok Kim, Young Chang, Soung Won Jeong, Jae Young Jang, Jeong-Ju Yoo
J Liver Cancer. 2023;23(1):189-201. Published online March 24, 2023
Background/Aim Abdominal ultrasonography (USG) is recommended as a surveillance test for high-risk groups for hepatocellular carcinoma (HCC). This study aimed to analyze the current status of the national cancer surveillance program for HCC in South Korea and investigate the effects of patient-, physician-, and machine-related factors on HCC detection sensitivity.
Methods This multicenter retrospective cohort study collected surveillance USG data from the high-risk group for HCC (liver cirrhosis or chronic hepatitis B or C >40 years of age) at eight South Korean tertiary hospitals in 2017.
Results In 2017, 45 experienced hepatologists or radiologists performed 8,512 USG examinations. The physicians had a mean 15.0±8.3 years of experience; more hepatologists (61.4%) than radiologists (38.6%) participated. Each USG scan took a mean 12.2±3.4 minutes. The HCC detection rate by surveillance USG was 0.3% (n=23). Over 27 months of follow-up, an additional 135 patients (0.7%) developed new HCC. The patients were classified into three groups based on timing of HCC diagnosis since the 1st surveillance USG, and no significant intergroup difference in HCC characteristics was noted. HCC detection was significantly associated with patient-related factors, such as old age and advanced fibrosis, but not with physician- or machine-related factors.
Conclusions This is the first study of the current status of USG as a surveillance method for HCC at tertiary hospitals in South Korea. It is necessary to develop quality indicators and quality assessment procedures for USG to improve the detection rate of HCC.
Background/Aim The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend systemic therapy as the only first-line treatment for patients with BCLC stage C hepatocellular carcinoma (HCC) despite its heterogeneity of disease extent. We aimed to identify patients who might benefit from combined transarterial chemoembolization (TACE) and radiation therapy (RT) by subclassifying BCLC stage C.
Methods A total of 1,419 treatment-naïve BCLC stage C patients with macrovascular invasion (MVI) who were treated with combined TACE and RT (n=1,115) or systemic treatment (n=304) were analyzed. The primary outcome was overall survival (OS). Factors associated with OS were identified and assigned points by the Cox model. The patients were subclassified into three groups based on these points.
Results The mean age was 55.4 years, and 87.8% were male. The median OS was 8.3 months. Multivariate analysis revealed a significant association of Child-Pugh B, infiltrative-type tumor or tumor size ≥10 cm, main or bilateral portal vein invasion, and extrahepatic metastasis with poor OS. The sub-classification was categorized into low (point ≤1), intermediate (point=2), and high (point ≥3) risks based on the sum of points (range, 0–4). The OS in the low, intermediate, and high-risk groups was 22.6, 8.2, and 3.8 months, respectively. In the low and intermediate-risk groups, patients treated with combined TACE and RT exhibited significantly longer OS (24.2 and 9.5 months, respectively) than those who received systemic treatment (6.4 and 5.1 months, respectively; P<0.0001).
Conclusions Combined TACE and RT may be considered as a first-line treatment option for HCC patients with MVI when classified into low- and intermediate-risk groups.
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How to optimize the treatment strategy for advanced-stage hepatocellular carcinoma with macrovascular invasion Beom Kyung Kim Journal of Liver Cancer.2023; 23(1): 121. CrossRef
Background/Aim To evaluate the applicability of transarterial chemoembolization (TACE) treatment with doxorubicin drug-eluting beads (DEBs) in advanced hepatocellular carcinoma (HCC) patients with portal vein invasion (PVI).
Methods This prospective study was approved by the institutional review board and informed consent was obtained from all participants. A total of 30 HCC patients with PVI received DEB-TACE between 2015 and 2018. The following parameters were evaluated: complications during DEB-TACE, abdominal pain, fever, and laboratory outcomes, including liver function change. Overall survival (OS), time to progression (TTP), and adverse events were also analyzed and assessed.
Results DEBs measuring 100–300 μm in diameter were loaded with doxorubicin (150 mg per procedure). There were no complications during DEB-TACE and no significant differences in the levels of prothrombin time, serum albumin, or total bilirubin at follow-up compared to baseline. The median TTP was 102 days (95% confidence interval [CI], 42–207 days) and the median OS was 216 days (95% CI, 160–336 days). Three patients (10%) had severe adverse reactions, including transient acute cholangitis (n=1), cerebellar infarction (n=1), and pulmonary embolism (n=1), but no treatment-related death occurred.
Conclusions DEB-TACE may be a therapeutic option for advanced HCC patients with PVI.
Background/Aim This study aimed to determine the diagnostic performance of 2022 Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) imaging criteria compared with the 2018 KLCA-NCC for hepatocellular carcinoma (HCC) in high-risk patients using magnetic resonance imaging (MRI).
Methods This retrospective study included 415 treatment-naïve patients (152 patients who underwent extracellular contrast agent [ECA]-MRI and 263 who underwent hepatobiliary agent [HBA]-MRI; 535 lesions, including 412 HCCs) with a high risk of HCC who underwent contrast-enhanced MRI. Two readers evaluated all lesions according to the 2018 and 2022 KLCA-NCC imaging diagnostic criteria, and the per-lesion diagnostic performances were compared.
Results In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI showed a significantly higher sensitivity for the diagnosis of HCC than ECA-MRI (77.0% vs. 64.3%, P=0.006) without a significant difference in specificity (94.7% vs. 95.7%, P=0.801). On ECAMRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC had significantly higher sensitivity than those of the 2018 KLCA-NCC (85.3% vs. 78.3%, P=0.002) with identical specificity (93.6%). On HBA-MRI, the sensitivity and specificity of “definite” or “probable” HCC categories of both 2018 and 2022 KLCA-NCC were not significantly different (83.3% vs. 83.6%, P>0.999 and 92.1% vs. 90.8%, P>0.999, respectively).
Conclusions In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI provides better sensitivity than ECA-MRI without compromising specificity. On ECA-MRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC may improve sensitivity in the diagnosis of HCC compared with the 2018 KLCA-NCC.
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Young Chang, Soung Won Jeong, Jae Young Jang, Hyuksoo Eun, Young‑Sun Lee, Do Seon Song, Su Jong Yu, Sae Hwan Lee, Won Kim, Hyun Woong Lee, Sang Gyune Kim, Seongho Ryu, Suyeon Park
J Liver Cancer. 2022;22(2):167-177. Published online September 29, 2022
Background/Aim New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC.
Methods We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed.
Results Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098- 5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911).
Conclusions Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers.
Background/Aim The profile of patients with hepatocellular carcinoma (HCC) has changed globally; the role of etiology in predicting prognosis of HCC patients remains unclear. We aimed to analyze the characteristics and prognosis of Korean patients with HCC according to disease etiology.
Methods This retrospective observational study included patients diagnosed with HCC between 2010 and 2014 in a single center in Korea. Patients with HCC aged <19 years old, had coinfection with other viral hepatitis, had missing follow-up data, were Barcelona Clinic Liver Cancer stage D, or died before 1 month were excluded.
Results A total of 1,595 patients with HCC were analyzed; they were classified into the hepatitis B virus (HBV) group (1,183 [74.2%]), hepatitis C virus (HCV) group (146 [9.2%]), and non-B non-C (NBNC) group (266 [16.7%]). The median overall survival of all patients was 74 months. The survival rates at 1, 3, and 5 years were 78.8%, 62.0% and 54.9% in the HBV group; 86.0%, 64.0%, and 48.6% in the HCV group; and 78.4%, 56.5%, and 45.9% in the NBNC group, respectively. NBNC-HCC has a poorer prognosis than other causes of HCC. Survival was significantly longer in the HBV group with early-stage HCC than in the NBNC group. Furthermore, survival was shorter in patients with early-stage HCC and diabetes mellitus (DM) than in those without DM.
Conclusions The etiology of HCC affected clinical characteristics and prognosis to some extent. NBNC-HCC patients showed shorter overall survival than viral-related HCC patients. Additionally, the presence of DM is an additional important prognostic factor in patients with early-stage HCC.
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Background/Aim We aimed to investigate the efficacy and safety of stereotactic body radiation therapy (SBRT) in elderly patients with small hepatocellular carcinomas (HCC).
Methods Eighty-three patients (89 lesions) with HCC who underwent SBRT between January 2012 and December 2018 were reviewed in this retrospective observational study. The key inclusion criteria were as follows: 1) age ≥75 years, 2) contraindications for hepatic resection or percutaneous ablative therapies, 3) no macroscopic vascular invasion, and 4) no extrahepatic metastasis.
Results The patients were 75-90 years of age, and 49 (59.0%) of them were male. Most patients (94.0%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Seventy-four patients (89.2%) had Child-Pugh class A hepatic function before SBRT. The median tumor size was 1.6 cm (range, 0.7-3.5). The overall median follow-up period was 34.8 months (range, 7.3-99.3). The 5-year local tumor control rate was 90.1%. The 3-year and 5-year overall survival rate was 57.1% and 40.7%, respectively. Acute toxicity grade ≥3 was observed in three patients (3.6%) with elevated serum hepatic enzymes; however, no patient experienced a worsening of the Child-Pugh score to ≥2 after SBRT. None of the patients developed late toxicity (grade ≥3).
Conclusions SBRT is a safe treatment option with a high local control rate in elderly patients with small HCC who are not eligible for other curative treatments.
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Background/Aim Since the introduction of laparoscopy for liver resection in the 1990s, the performance of laparoscopic liver resection (LLR) has been steadily increasing. However, there is currently no data on the extent to which laparoscopy is used for liver resection. Herein, we investigated the extent to which laparoscopy is performed in liver resection and sought to determine whether surgeons prefer laparoscopy or laparotomy in the posterosuperior (PS) segment.
Methods For this retrospective observational study, we enrolled patients who had undergone liver resection at the Samsung Medical Center between January 2020 and December 2021. The proportion of LLR in liver resection was calculated, and the incidence and causes of open conversion were investigated.
Results A total of 1,095 patients were included in this study. LLR accounted for 79% of the total liver resections. The percentage of previous hepatectomy (16.2% vs. 5.9%, P<0.001) and maximum tumor size (median 4.8 vs. 2.8, P<0.001) were higher in the open liver resection (OLR) group. Subgroup analysis revealed that tumor size (median 6.3 vs. 2.9, P<0.001) and surgical extent (P<0.001) in the OLR group were larger than those in the LLR group. The most common cause of open conversion (OC) was adhesion (57%), and all OC patients had tumors in the PS.
Conclusions We investigated the recent preference of practical surgeons in liver resection, and found that surgeons preferred OLR to LLR when treating a large tumor located in the PS.
Background/Aim There has been a long-standing debate about the association of directacting antiviral (DAA) therapy and hepatocellular carcinoma (HCC) recurrence. This study aimed to investigate the association between DAA therapy and HCC recurrence after curative therapy.
Methods We retrospectively enrolled 1,021 patients with HCV-related (hepatitis C virus) HCC who underwent radiofrequency ablation (RFA), liver resection, or both as the first treatment modality from January 2007 to December 2016 and without a history of HCV therapy before HCC treatment from a nationwide database. The effect of HCV treatment on HCC recurrence and all-cause mortality was also investigated.
Results Among the 1,021 patients, 77 (7.5%) were treated with DAA, 14 (1.4%) were treated with interferon-based therapy, and 930 (91.1%) did not receive HCV therapy. DAA therapy was an independent prognostic factor for lower HCC recurrence rate (hazard ratio [HR], 0.04; 95% confidence interval [CI], 0.006-0.289; P=0.001 for landmarks at 6 months after HCC treatment and HR, 0.05; 95% CI, 0.007-0.354; P=0.003 for landmarks at 1 year). Furthermore, DAA therapy was associated with lower all-cause mortality (HR, 0.049; 95% CI, 0.007-0.349; P=0.003 for landmarks at 6 months and HR, 0.063; 95% CI, 0.009-0.451; P=0.006 for landmarks at 1 year).
Conclusions DAA therapy after curative HCC treatment can decrease HCC recurrence and all-cause mortality compared to interferon-based therapy or no antiviral therapy. Therefore, clinicians should consider administering DAA therapy after curative HCC treatment in patients with HCV-related HCC.
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Background/Aim Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis.
Methods The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry.
Results The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers.
Conclusions The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.