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.
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Rebuilding the microenvironment of primary tumors in humans: a focus on stroma Siwon Mun, Hyun Jin Lee, Pilnam Kim Experimental & Molecular Medicine.2024;[Epub] CrossRef
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
Multiple primary malignancies (MPMs) are defined as the presence of two or more malignancies in different organs, without a subordinate relationship. Although rarely reported, hepatocellular carcinoma (HCC) occasionally presents with simultaneous or metachronous primary malignancies in other organs. In this report, we describe a patient with lung adenocarcinoma and lymph node and bone metastases, treated with five chemotherapeutic regimens for 24 months. Changing the chemotherapy regimen based on the suspicion of metastasis of a new liver mass did not lead to improvements. This prompted a liver biopsy and a revised diagnosis of HCC. Sixth-line treatment with the concurrent use of cisplatin-paclitaxel for lung cancer and sorafenib for HCC, stabilized the disease. The concurrent treatment was not tolerated and was discontinued owing to adverse events. Considering our findings, treatment with increased efficacy and lower toxicity for MPMs is warranted.
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.
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The Epidemiology of Hepatitis B Virus Infection in Korea: 15-Year Analysis Log Young Kim, Jeong-Ju Yoo, Young Chang, Hoongil Jo, Young Youn Cho, Sangheun Lee, Dong Hyeon Lee, Jae Young Jang Journal of Korean Medical Science.2024;[Epub] CrossRef
Long-Term HBsAg Titer Kinetics with Entecavir/Tenofovir: Implications for Predicting Functional Cure and Low Levels Soon Kyu Lee, Soon Woo Nam, Jeong Won Jang, Jung Hyun Kwon Diagnostics.2024; 14(5): 495. CrossRef
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
Recently, the superiority of atezolizumab plus bevacizumab (AteBeva) over sorafenib was proven in the IMbrave150 trial, and AteBeva became the first-line systemic treatment for untreated, unresectable hepatocellular carcinoma (HCC). While the results are encouraging, more than half of patients with advanced HCC are still being treated in a palliative setting. Radiotherapy (RT) is known to induce immunogenic effects that may enhance the therapeutic efficacy of immune checkpoint inhibitors. Herein, we report the case of a patient with advanced HCC with massive portal vein tumor thrombosis treated with a combination of RT and AteBeva, who showed near complete response in tumor thrombosis and favorable response to HCC. Although this is a rare case, it shows the importance of reducing the tumor burden via RT to combination immunotherapy in patients with advanced HCC.
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Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab Tae Hyun Kim, Bo Hyun Kim, Yu Ri Cho, Young-Hwan Koh, Joong-Won Park Journal of Liver Cancer.2023; 23(2): 330. CrossRef
Carbon Ion Radiotherapy in the Treatment of Hepatocellular Carcinoma Hwa Kyung Byun, Changhwan Kim, Jinsil Seong Clinical and Molecular Hepatology.2023; 29(4): 945. CrossRef
Hepatoblastoma is an exceptionally rare malignancy in adults with just over 70 non-pediatric cases reported in literature. Recounted is a case of a 49-year-old female who presented with acute right upper quadrant abdominal pain, elevated serum alpha fetoprotein and a large liver mass on imaging. Hepatectomy was performed under clinical suspicion of hepatocellular carcinoma. Immunomorphologic characteristics of the tumor proved consistent with hepatoblastoma of mixed epithelial and mesenchymal type. Hepatocellular carcinoma remains to be the primary differential diagnosis for adult hepatoblastoma, however, distinguishing between these two neoplasms requires close histomorphologic assessment and immunohistochemical profiling as clinical, radiologic and gross pathologic findings typically overlap. Making this distinction is highly crucial in the timely initiation of surgical and chemotherapeutic interventions for this inherently aggressive and rapidly fatal disease.
Recently, the efficacy of immuno-oncologic agents for advanced hepatocellular carcinoma (HCC) has been proven in several trials. In particular, atezolizumab with bevacizumab (AteBeva), as a first-line therapy for advanced HCC, has shown tremendous advances in the IMBrave150 study. However, second or third-line therapy after treatment failure with AteBeva has not been firmly established. Moreover, clinicians have continued their attempts at multidisciplinary treatment that includes other systemic therapy and radiotherapy (RT). Here, we report a case that showed a near complete response (CR) of lung metastasis to nivolumab with ipilimumab therapy after achieving a near CR of intrahepatic tumor using sorafenib and RT in a patient with advanced HCC who had experienced treatment failure of AteBeva.
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Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update John D. Gordan, Erin B. Kennedy, Ghassan K. Abou-Alfa, Eliza Beal, Richard S. Finn, Terence P. Gade, Laura Goff, Shilpi Gupta, Jennifer Guy, Hang T. Hoang, Renuka Iyer, Ishmael Jaiyesimi, Minaxi Jhawer, Asha Karippot, Ahmed O. Kaseb, R. Kate Kelley, Jerem Journal of Clinical Oncology.2024;[Epub] CrossRef
The cross-sectional imaging findings play a crucial role in the diagnosis of hepatocellular carcinoma (HCC). Recent studies have shown that imaging findings of HCC are not only relevant for the diagnosis of HCC, but also for identifying genetic and pathologic characteristics and determining prognosis. Imaging findings such as rim arterial phase hyperenhancement, arterial phase peritumoral hyperenhancement, hepatobiliary phase peritumoral hypointensity, non-smooth tumor margin, low apparent diffusion coefficient, and the LR-M category of the Liver Imaging-Reporting and Data System have been reported to be associated with poor prognosis. In contrast, imaging findings such as enhancing capsule appearance, hepatobiliary phase hyperintensity, and fat in mass have been reported to be associated with a favorable prognosis. Most of these imaging findings were examined in retrospective, single-center studies that were not adequately validated. However, the imaging findings can be applied for deciding the treatment strategy for HCC, if their significance can be confirmed by a large multicenter study. In this literature, we would like to review imaging findings related to the prognosis of HCC as well as their associated clinicopathological characteristics.
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Radiomics and machine learning based on preoperative MRI for predicting extrahepatic metastasis in hepatocellular carcinoma patients treated with transarterial chemoembolization Gang Peng, Xiaojing Cao, Xiaoyu Huang, Xiang Zhou European Journal of Radiology Open.2024; 12: 100551. CrossRef
Imaging prognostication and tumor biology in hepatocellular carcinoma Diana Kadi, Marilyn F. Yamamoto, Emily C. Lerner, Hanyu Jiang, Kathryn J. Fowler, Mustafa R. Bashir Journal of Liver Cancer.2023; 23(2): 284. 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.
Peritoneal seeding of hepatocellular carcinoma (HCC) is incurable and has poor prognosis. A 68-year-old man underwent surgical resection for a 3.5 cm single nodular HCC at the tip of segment 3 and transarterial chemoembolization for a 1.5 cm-sized recurrent HCC at the tip of segment 6. 3 months later, an increasing 1 cm pelvic nodule on the rectovesical pouch warranted radiotherapy. Although it stabilized, a new 2.7 cm-sized peritoneal nodule in the right upper quadrant (RUQ) omentum appeared 3.5 years after radiotherapy. Hence, omental mass and small bowel mesentery mass excision were performed. 3 years later, recurrent peritoneal metastases in the RUQ omentum and rectovesical pouch progressed. 33 cycles of atezolizumab and bevacizumab treatment elicited stable disease response. Finally, laparoscopic left pelvic peritonectomy was performed without tumor recurrence. Herein, we present a case of HCC with peritoneal seeding that was successfully treated with surgery after radiotherapy and systemic therapy, leading to complete remission.
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Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab Tae Hyun Kim, Bo Hyun Kim, Yu Ri Cho, Young-Hwan Koh, Joong-Won Park Journal of Liver Cancer.2023; 23(2): 330. CrossRef
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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Impact of the updated KLCA-NCC criteria for diagnosis of “probable HCC” in liver MRI: comparisons between KLCA v2022 and v2018 Jeong Hee Yoon Journal of Liver Cancer.2023; 23(1): 124. CrossRef
Parenchymal-sparing hepatectomy (PSH), though technically challenging, is emerging as a choice of treatment for colorectal liver metastases (CRLM). PSH in Jehovah’s witness (JW) patients, for whom transfusion is not an option, involves complex surgical and medicolegal issues. A 52-year-old JW male with synchronous, multiple, bilobar liver metastases from a rectal adenocarcinoma was referred following neoadjuvant chemotherapy. At surgery, 10 metastatic deposits were observed and confirmed by intraoperative ultrasonography. Parenchymal-sparing non-anatomical resections were performed using a cavitron ultrasonic aspirator with the application of intermittent Pringle maneuvres. Histology confirmed multiple CRLMs with tumor-free resection margins. PSH is increasingly employed for CRLMs to preserve residual liver volume and minimize morbidity without compromising oncological outcomes. It is technically challenging, especially in the presence of bilobar, multi-segmental disease. This case illustrates the feasibility of performing complex hepatic surgery in special patient groups by meticulous planning and preparation involving multiple specialties and the patient.