Prognostic significance of MRI features in patients with solitary large hepatocellular carcinoma following surgical resection.

OBJECTIVE: To assess the prognostic impact of preoperative MRI features on outcomes for single large hepatocellular carcinoma (HCC) (≥ 8 cm) after surgical resection. MATERIAL AND METHODS: This retrospective study included 151 patients (mean age: 59.2 years; 126 men) with a single large HCC who underwent gadoxetic acid-enhanced MRI and surgical resection between 2008 and 2020. Clinical variables, including tumor markers and MRI features (tumor size, tumor margin, and the proportion of hypovascular component on hepatic arterial phase (AP) (≥ 50% vs. < 50% tumor volume) were evaluated. Cox proportional hazards model analyzed overall survival (OS), recurrence-free survival (RFS), and associated factors. RESULTS: Among 151 HCCs, 37.8% and 62.2% HCCs were classified as ≥ 50% and < 50% AP hypovascular groups, respectively. The 5- and 10-year OS and RFS rates in all patients were 62.0%, 52.6% and 41.4%, 38.5%, respectively. Multivariable analysis revealed that ≥ 50% AP hypovascular group (hazard ratio [HR] 1.7, p = 0.048), tumor size (HR 1.1, p = 0.006), and alpha-fetoprotein ≥ 400 ng/mL (HR 2.6, p = 0.001) correlated with poorer OS. ≥ 50% AP hypovascular group (HR 1.9, p = 0.003), tumor size (HR 1.1, p = 0.023), and non-smooth tumor margin (HR 2.1, p = 0.009) were linked to poorer RFS. One-year RFS rates were lower in the ≥ 50% AP hypovascular group than in the < 50% AP hypovascular group (47.4% vs 66.9%, p = 0.019). CONCLUSION: MRI with ≥ 50% AP hypovascular component and larger tumor size were significant factors associated with poorer OS and RFS after resection of single large HCC (≥ 8 cm). These patients require careful multidisciplinary management to determine optimal treatment strategies. CLINICAL RELEVANCE STATEMENT: Preoperative MRI showing a ≥ 50% arterial phase hypovascular component and larger tumor size can predict worse outcomes after resection of single large hepatocellular carcinomas (≥ 8 cm), underscoring the need for tailored, multidisciplinary treatment strategies. KEY POINTS: MRI features offer insights into the postoperative prognosis for large hepatocellular carcinoma. Hypovascular component on arterial phase ≥ 50% and tumor size predicted poorer overall survival and recurrence-free survival. These findings can assist in prioritizing aggressive and multidisciplinary approaches for patients at risk for poor outcomes.

Role of Lymphatic Embolization in Chylothorax Associated with Gorham-Stout Disease: A Case Report.

A 45-year-old male patient with spontaneous chylothorax and osteolysis in the right 1st and 2nd ribs was diagnosed with Gorham-Stout disease based on clinical manifestations and bone biopsy. The chylothorax temporarily decreased after a successful selective lymphatic embolization. The patient presented with recurrent chylothorax, mild chest discomfort, and progressive osteolysis (despite administering sirolimus) during the follow-up period of 15 months.

Refining MRI-based criteria for portal vein invasion in hepatocellular carcinoma: improving sensitivity beyond portal vein tumor thrombosis.

PURPOSE: To investigate the imaging features indicating portal vein invasion (PVI) of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI and to create more accurate diagnostic criteria than the presence of portal vein tumor thrombosis (PVTT) on MRI. METHODS: This retrospective study included patients with surgically resected HCC larger than 5 cm, and the presence of PVI was investigated. On MRI, we evaluated the image findings of portal vein occlusion, the parenchymal signal change caused by hemodynamic alterations of the portal vein, and their combination showing the highest odds ratio (OR) to define the diagnostic criteria for radiological PVI detection (rPVI criteria). The diagnostic performance and recurrence-free survival were compared between the rPVI criteria and the presence of PVTT using McNemar's test and Kaplan-Meier method, respectively. Interobserver agreement was evaluated using Cohen's weighted ĸ statistics. RESULTS: Of 189 enrolled patients, 25 (13.2%) had PVI on histology. To diagnose PVI on MRI, either peripheral wedge-shaped arterial peritumoral hyperemia with an abrupt cut-off of a portal vein or the presence of PVTT had the highest OR (41.67, p < 0.001). The sensitivity of PVI was significantly increased under this diagnostic criterion (64.0% to 88.0%; p = 0.031) with comparable accuracy (95.2% vs. 94.7%; p > 0.999). In terms of recurrence-free survival, the patient group with rPVI was significantly worse (p = 0.017) compared with the patients without rPVI. Interobserver agreement of radiologic findings was substantial (ĸ = 0.64). CONCLUSION: Diagnostic criteria for radiologically PVI detection increase the sensitivity more than the only presence of PVTT.

Abrogation of greater graft failure risk of female-to-male liver transplantation with donors older than 40 years or graft macrosteatosis greater than 5.

Greater graft-failure-risk of female-to-male liver transplantation (LT) is thought to be due to acute decrease in hepatic-estrogen-signaling. Our previous research found evidence that female hepatic-estrogen-signaling decreases after 40 years or with macrosteatosis. Thus, we hypothesized that inferiority of female-to-male LT changes according to donor-age and macrosteatosis. We stratified 780 recipients of grafts from living-donors into four subgroups by donor-age and macrosteatosis and compared graft-failure-risk between female-to-male LT and other LTs within each subgroup using Cox model. In recipients with ≤ 40 years non-macrosteatotic donors, graft-failure-risk was significantly greater in female-to-male LT than others (HR 2.03 [1.18-3.49], P = 0.011). Within the subgroup of recipients without hepatocellular carcinoma, the inferiority of female-to-male LT became greater (HR 4.75 [2.02-11.21], P < 0.001). Despite good graft quality, 1y-graft-failure-probability was 37.9% (23.1%-57.9%) in female-to-male LT within this subgroup while such exceptionally high probability was not shown in any other subgroups even with worse graft quality. When donor was > 40 years or macrosteatotic, graft-failure-risk was not significantly different between female-to-male LT and others (P > 0.60). These results were in agreement with the estrogen receptor immunohistochemistry evaluation of donor liver. In conclusion, we found that the inferiority of female-to-male LT was only found when donor was ≤ 40 years and non-macrosteatotic. Abrogation of the inferiority when donor was > 40 years or macrosteatotic suggests the presence of dominant contributors for post-transplant graft-failure other than graft quality/quantity and supports the role of hepatic-estrogen-signaling mismatch on graft-failure after female-to-male LT.

Clinical Implication of HER2 Aberration in Patients With Metastatic Cancer Using Next-Generation Sequencing: A Pan-Tumor Analysis.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) protein expression or gene amplification is a significant predictive biomarker for identifying patients with cancer, who may benefit from HER2-targeted therapy. The aim of this study was to survey the proportion of patients who had HER2 aberration and to investigate the correlation between HER2 amplification and HER2 overexpression in immunohistochemistry (IHC) as a real-world data. METHODS: We surveyed the incidence of HER2 aberration including mutation (single-nucleotide variant [SNV]), amplification (copy-number variation), and fusion by next-generation sequencing (NGS) in 2,119 patients with cancer from Samsung Medical Center in South Korea. RESULTS: Of 2,119 patients with cancer, 189 patients (8.9%) had HER2 aberration in their tumor specimen. Of 189 patients, 113 (5.3%) patients had HER2 amplification, 82 (3.9%) patients had HER2 mutations, and 11 (0.5%) patients had HER2 fusion. Of note, 10 patients (0.5%) had concurrent HER2 amplification and HER2 fusion. In addition, we identified that HER2 protein overexpression was strongly related to HER2 amplification by NGS. Of 74 patients with HER2 amplification only by NGS test, 64 patients (86.5%) had HER2 overexpression by IHC. Of 10 patients with concurrent HER2 amplification and fusion, 80% patients were HER2 overexpression. Among 51 patients with only HER2 mutation (SNV), 9 patients (17.6%) were HER2 (+). Interestingly, almost all patients with colorectal cancer (11 of 12) with HER2 amplification had very strong HER2 overexpression (3+) in their tumor specimen. CONCLUSION: In conclusion, we showed that when patients with metastatic cancer receive NGS test, approximately 8.9% have HER2 aberrations in their tumor specimen. Most patients have HER2 amplification, and a small percentage of patients have HER2 fusion. A great majority of patients with HER2 amplification and/or HER2 fusion had HER2 (+) tumor by IHC.

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.

Loss of F-Box and Leucine Rich Repeat Protein 5 (FBXL5) Expression Is Associated With Poor Survival in Patients With Hepatocellular Carcinoma After Curative Resection: A Two-institute Study.

BACKGROUND/AIM: Alteration of F-box and leucine-rich repeat protein 5 (FBXL5), an iron-sensing ubiquitin ligase, might be related with carcinogenesis of hepatocellular carcinoma (HCC), by disturbing cellular iron homeostasis. However, the clinical implications of FBXL5 expression using patient samples need to be elucidated. PATIENTS AND METHODS: We collected HCC tissue samples from two institutes: Samsung Medical Center (n=259) and Hallym University Sacred Heart Hospital (n=115) and evaluated FBXL5 expression using immunohistochemistry. Using cut-off values determined by X-tile software, association between FBXL5 expression and several clinicopathological parameters was investigated. For external validation, the Cancer Genome Atlas (TCGA) cohort was used. RESULTS: The best cutoff value for FBXL5 IHC expression associated with recurrence-free survival (RFS) was 5%. Low FBXL5 expression was found in 18.7% of the total 374 HCCs and was associated with non-viral etiology (p=0.019). Low FBXL5 expression was related with inferior disease-specific survival (DSS, p=0.002) and RFS (p=0.001) and also was an independent prognostic factor for DSS and RFS. In addition, cases with low FBLX5 mRNA levels showed inferior DSS and RFS (p<0.001 and p=0.002, respectively) compared to high FBLX5 mRNA levels in the TCGA cohort. CONCLUSION: Down-regulation of FBXL5 expression in HCCs might be associated with poor prognosis. FBXL5 might be a prognostic biomarker of HCCs and a potential therapeutic target in conjunction with iron homeostasis.

Histologic Activity and Steroid Use History Are Risk Factors of Clinical Relapse in Ulcerative Colitis With Mayo Endoscopic Subscore of 0 or 1.

BACKGROUND: The treatment goal of ulcerative colitis (UC) has changed from the control of symptoms to mucosal healing, previously evaluated mainly by endoscopy. Recently, the importance of histologic activity has emerged. Therefore, this study aimed to investigate the risk of clinical relapse according to histologic activity in UC with a Mayo endoscopic subsccore (MES) of 0 or 1. METHODS: In a retrospective cohort after our center's biopsy guideline for UC was instituted, 492 UC patients with an MES of 0 or 1 were enrolled and analyzed. The primary outcome was the development of a clinical relapse including changes in medication, hospitalization, colectomy, and the development of colorectal cancer during the follow-up period. RESULTS: During the median 549 days of follow-up, 92 (18.7%) patients had a clinical relapse. All the patients changed their medication, including 4 hospitalized patients. Histologic activity defined by a Geboes score of ≧3.1 (hazard ratio [HR], 1.732; P = .035) and steroid use history (HR, 1.762; P = .008) were independent factors associated with clinical relapse. When stratified, the 1- and 2-year incidence rates of clinical relapse were 4.1% and 10.6%, respectively, for patients with histologic improvement and no steroid use history, whereas the rates were 23.9% and 39.4% for patients with histologic activity and steroid use history. CONCLUSIONS: In UC with an MES of 0 or 1, histologic activity and steroid use history can be used to stratify the risk of clinical relapse.

Histologic activity defined by Geboes score of ≥3.1 and steroid use history are independent risk factors associated with clinical relapse in UC patients with Mayo endoscopic subscore of 0 or 1.

Dual Oxidase 2 (DUOX2) as a Proteomic Biomarker for Predicting Treatment Response to Chemoradiation Therapy for Locally Advanced Rectal Cancer: Using High-Throughput Proteomic Analysis and Machine Learning Algorithm.

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins-DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.

Expression of PD-L1 as a predictive marker of sensitivity to immune checkpoint inhibitors in patients with advanced biliary tract cancer.

Background: Expression of programmed death-ligand 1 (PD-L1) has been reported to correlate with response to immune checkpoint inhibitors (ICIs) in various tumor types. However, there are few data on the role of PD-L1 expression as a predictive and prognostic biomarker of sensitivity to ICIs in patients with advanced biliary tract cancer (BTC). Objectives: We evaluated the role of PD-L1 expression as a predictive and prognostic biomarker of response to ICIs in patients with advanced BTC. Design: We retrospectively analyzed data from 83 advanced BTC patients who received ICIs as second- or third-line treatment between February 2018 and April 2021. Methods: All patient data analysis included evaluation of PD-L1 expression by the combined positive score (CPS). Results: Among 83 patients, 56 (67.5%) had PD-L1 positivity (CPS ⩾ 1). The objective response rate (ORR) to ICIs was significantly higher in advanced BTC patients with PD-L1 expression compared to those without PD-L1 expression (17.8% versus 0%, p = 0.026). However, there were no significant differences in median progression-free survival (PFS; 2.9 versus 2.6 months, p = 0.330) and median overall survival (OS; 8.1 versus 6.3 months, p = 0.289) as a response to ICIs between patients with and without PD-L1 expression. Also, there were no significant differences in ORR, PFS, and OS as a response to ICIs in conjunction with a response to a prior gemcitabine plus cisplatin regimen (p = 0.654, p = 0.278, and p = 0.302, respectively). Conclusions: The present study suggests that the expression of PD-L1 alone was not sufficient as a novel marker to select advanced BTC patients who might benefit from ICIs. Additional comprehensive studies of biomarkers that can assist in predicting BTC patient responses to pembrolizumab and/or nivolumab therapy are required.

Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers.

Checkpoint inhibitor approval for microsatellite instability-high (MSI-H) tumours has made MSI as a therapeutically important biomarker. Next-generation sequencing (NGS)-based MSI detection is being widely used for assessing MSI. However, MSI tumours detected using NGS and their relevance to MSI-polymerase chain reaction (PCR) and mismatch repair deficiency (dMMR) are unclear. In 1942 solid cancer cases tested using NGS-based comprehensive cancer panel with 523 genes (1.94 mb), the MSI score, tumour mutation burden (TMB; ≥ 10 mutations/mb), and frameshift mutations were analysed. GeneScan analyses of five mononucleotide markers (MSI-PCR) and MMR protein immunohistochemistry (IHC) were compared with the NGS-MSI results. With a ≥ 12% MSI score as a cut-off for MSI-H, two MSS cases were classified as MSI-H. With a ≥ 20% cut-off, 10 cases categorised as MSS by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. To avoid discrepant cases, we adopted a high MSI cut-off and a borderline MSI category. Finally, MSI-H (≥ 20%), borderline MSI (≥ 7% and < 20%), and MSS (< 7%) were found in 35 (1.8%), 24 (1.2%), and 1883 (97%) cases, respectively. All MSI-H cases by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. Of the 24 borderline MSI cases by NGS, MSI-H/dMMR was 9 (37.5%) cases, MSS/dMMR was 1 (4.2%) case, and 11 (45.8%) of them had high TMB. All MSS cases by NGS were MSS/pMMR by MSI-PCR/IHC, and 257 (13.6%) had high TMB. With those arbitrary cut-off points, 10 (0.5%) MSS cases using NGS were discrepant with MSI-PCR or MMR IHC, and all were borderline MSI cases. The mean number of frameshift mutations was significantly higher in the MSI-H group (28.3) than in the borderline MSI (7.7) or MSS (1.3) groups (p < 0.001). In conclusion, to facilitate therapeutic decision-making for NGS, cut-off points for MSI can be defined based on MSI-PCR/dMMR confirmation.

HER2 Aberrations as a Novel Marker in Advanced Biliary Tract Cancer.

HER2 aberrations have been reported as a novel biomarker in HER2-directed therapy or as a prognostic marker in various tumor types. However, in advanced biliary tract cancer (BTC), there have been few studies regarding HER2 aberrations as a biomarker. We analyzed 121 advanced BTC patients who had been treated with Gemcitabine/Cisplatin (GP) as a 1st line therapy between November 2019 and April 2021. Next-generation sequencing (NGS), namely, HER2 aberrations was performed in all patients. The TruSight™ Oncology 500 assay from Illumina was used for the NGS panel. Among 121 patients with advanced BTC, HER2 aberrations were observed in 18 patients (14.9%). For subtypes of HER2 aberrations, point mutation was observed in 5 patients (27.8%), gene amplification in 11 patients (61.1%), and both point mutation and gene amplification in 2 patients (11.1%). The frequency of HER2 aberrations was significantly different according to the primary tumor (p = 0.009). In gallbladder cancer, HER2 aberrations were observed at a relatively high frequency (36.4%). The tumor response to GP did not differ between patients with and without HER2 aberrations (33.3%, vs. 26.2%, respectively, p = 0.571). The median progression-free survival (PFS) to GP was 4.7 months (95% CI, 4.0 to 5.5 months) in patients with HER2 aberrations and 7.0 months (95% CI, 5.2 to 8.8 months) without HER2 aberrations (p = 0.776). The median overall survival (OS) was not reached and not reached in patients with and without HER2 aberrations (p = 0.739), respectively. The univariate analysis for PFS to GP and OS showed that HER2 aberrations were not an independent factor for survival. This study showed that the HER2 aberrations were observed in 14.9% of advanced BTC and were not an independent biomarker for survival.

LI-RADS Version 2018 Targetoid Appearances on Gadoxetic Acid-Enhanced MRI: Interobserver Agreement and Diagnostic Performance for the Differentiation of HCC and Non-HCC Malignancy.

BACKGROUND. In LI-RADS version 2018, observations showing at least one of five targetoid appearances in different sequences or postcontrast phases are categorized LR-M, indicating likely non-hepatocellular carcinoma (HCC) malignancy. OBJECTIVE. The purpose of this study was to evaluate interobserver agreement for LI-RADS targetoid appearances among a large number of radiologists of varying experience and the diagnostic performance of targetoid appearances for differentiating HCC from non-HCC malignancy. METHODS. This retrospective study included 100 patients (76 men, 24 women; mean age, 58 ± 9 [SD] years) at high risk of HCC who underwent gadoxetic acid-enhanced MRI within 30 days before hepatic tumor resection (25 randomly included patients with non-HCC malignancy [13, intrahepatic cholangiocarcinoma; 12, combined HCC-cholangiocarcinoma]; 75 matched patients with HCC). Eight radiologists (four more experienced [8-15 years]; four less experienced [1-5 years]) from seven institutions independently assessed observations for the five targetoid appearances and LI-RADS categorization. Interobserver agreement and diagnostic performance for non-HCC malignancy were evaluated. RESULTS. Interobserver agreement was poor for peripheral washout (κ = 0.20); moderate for targetoid transitional phase or hepatobiliary phase appearance (κ = 0.33), delayed central enhancement (κ = 0.37), and targetoid restriction (κ = 0.43); and substantial for rim arterial phase hyperenhancement (κ = 0.61). Agreement was fair for at least one targetoid appearance (κ = 0.36) and moderate for at least two, three, or four targetoid appearances (κ = 0.43-0.51). Agreement for individual targetoid appearances was not significantly different between more experienced and less experienced readers other than for targetoid restriction (κ = 0.63 vs 0.43; p = .001). Agreement for at least one targetoid appearance was fair among more experienced (κ = 0.29) and less experienced (κ = 0.37) reviewers. Agreement for at least two, three, or four targetoid appearances was moderate to substantial among more experienced reviewers (κ = 0.45-0.63) and moderate among less experienced reviewers (κ = 0.42-0.56). Existing LR-M criteria of at least one targetoid appearance had median accuracy for non-HCC malignancy of 62%, sensitivity of 84%, and specificity of 54%. For all reviewers, accuracy was highest when at least three (median accuracy, 79%; sensitivity, 68%; specificity, 82%) or four (median accuracy, 80%; sensitivity, 54%; specificity, 88%) targetoid appearances were required. CONCLUSION. Targetoid appearances and LR-M categorization exhibited considerable interobserver variation among both more and less experienced reviewers. CLINICAL IMPACT. Requiring multiple targetoid appearances for LR-M categorization improved interobserver agreement and diagnostic accuracy for non-HCC malignancy.

Direct comparison of the next-generation sequencing and iTERT PCR methods for the diagnosis of TERT hotspot mutations in advanced solid cancers.

BACKGROUND: Mutations in the telomerase reverse transcriptase (TERT) promoter region have been proposed as novel mechanisms for the transcriptional activation of telomerase. Two recurrent mutations in the TERT promoter, C228T and C250T, are prognostic biomarkers. Herein, we directly compared the commercially available iTERT PCR kit with NGS-based deep sequencing to validate the NGS results and determine the analytical sensitivity of the PCR kit. METHODS: Of the 2032 advanced solid tumors diagnosed using the TruSight Oncology 500 NGS test, mutations in the TERT promoter region were detected in 103 cases, with 79 cases of C228T, 22 cases of C250T, and 2 cases of C228A hotspot mutations. TERT promoter mutations were detected from 31 urinary bladder, 19 pancreato-biliary, 22 hepatic, 12 malignant melanoma, and 12 other tumor samples. RESULTS: In all 103 TERT-mutated cases detected using NGS, the same DNA samples were also tested with the iTERT PCR/Sanger sequencing. PCR successfully verified the presence of the same mutations in all cases with 100% agreement. The average read depth of the TERT promoter region was 320.4, which was significantly lower than that of the other genes (mean, 743.5). Interestingly, NGS read depth was significantly higher at C250 compared to C228 (p < 0.001). CONCLUSIONS: The NGS test results were validated by a PCR test and iTERT PCR/Sanger sequencing is sensitive for the identification of the TERT promoter mutations.

Down-regulation of TRPV6 Is Associated With Adverse Prognosis in Hepatocellular Carcinoma Treated With Curative Resection.

BACKGROUND/AIM: Transient receptor potential vanilloid 6 (TRPV6), an endothelial Ca2+-selective entry channel, is expressed in various cancer types, and a selective TRPV6 inhibitor is currently being investigated in a clinical trial. However, TRPV6 expression in hepatocellular carcinoma (HCC) has not been reported. MATERIALS AND METHODS: We evaluated TRPV6 expression in 219 cases of HCC and analyzed its association with clinicopathological parameters and prognostic significance. TRPV6 mRNA expression was compared between HCC and non-tumor liver tissues using various public datasets, and its prognostic effect was examined in The Cancer Genome Atlas (TCGA) cohort. RESULTS: Low TRPV6 expression was found in 37.4% of patients, which was significantly associated with adverse histologic features, and patients with low TRPV6 expression had shorter recurrence-free and disease-free survival. TRPV6 mRNA expression was consistently lower in HCC compared to non-tumor liver samples in public datasets, at the whole tissue level as well as single-cell level. Patients with low TRPV6 expression in the TCGA cohort had shorter progression-free survival. CONCLUSION: TRPV6 expression is down-regulated in HCCs and associated with a poor prognosis. TRPV6 may be a prognostic biomarker in HCC.

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

BACKGROUND: A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. METHODS: Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. RESULTS: The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. CONCLUSIONS: Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. TRIAL REGISTRATION: NCT#03163992 (first posted: May 23, 2017).

Hepatectomy outcomes in patients with hepatitis C virus-related hepatocellular carcinoma with or without cirrhosis.

PURPOSE: Hepatocellular carcinoma (HCC) is rare in HCV patients without cirrhosis, and little is known about the postoperative results of these patients. The present study compares the outcomes of cirrhotic and non-cirrhotic groups after liver resection (LR) in solitary HCV-related HCC patients and identifies risk factors for prognosis according to the presence or absence of cirrhosis in these patients. METHODS: Two hundred and 7 adult hepatectomy patients with treatment-naïve solitary HCV-related HCC were identified prospectively at our institution between July 2005 and May 2019. RESULTS: The non-cirrhotic group had better liver function than the cirrhotic group based on platelet count, liver function tests, liver stiffness measurement, and indocyanine green retention rate at 15 minutes but were older than the cirrhotic group. Consistently, noninvasive markers in the cirrhotic group were significantly higher than in the non-cirrhotic group. The cumulative disease-free survival and overall survival in the non-cirrhotic group were significantly higher than in the cirrhotic group. HCC recurrence was related to major LR and α-FP of >40 ng/mL and death was related to long hospitalization and α-FP of >40 ng/mL in multivariate analysis. Noninvasive markers and the presence of cirrhosis were not related to HCC recurrence or death in multivariate analyses. CONCLUSION: The cirrhotic group showed poor prognosis due to poor liver function after LR compared to the non-cirrhotic group, but this was not sustained in multivariate analysis. The factors influencing HCC recurrence and death were different in the cirrhotic and non-cirrhotic groups.

Sex Difference in the Tolerance of Hepatic Ischemia-reperfusion Injury and Hepatic Estrogen Receptor Expression According to Age and Macrosteatosis in Healthy Living Liver Donors.

BACKGROUND: Hepatic estrogen signaling, which is important in liver injury/recovery, is determined by the level of systemic estrogen and hepatic estrogen receptor. We aimed to evaluate whether females' advantage in the tolerance of hepatic ischemia-reperfusion injury decreases according to the age of 40 y (systemic estrogen decrease) and macrosteatosis (hepatic estrogen receptor decrease). METHODS: We included 358 living liver donors (128 female and 230 male individuals). The tolerance of hepatic ischemia-reperfusion injury was determined by the slope of the linear regression line modeling the relationship between the duration of intraoperative hepatic ischemia and the peak postoperative transaminase level. Estrogen receptor content was measured in the biopsied liver samples using immunohistochemistry. RESULTS: In the whole cohort, the regression slope for aspartate transaminase was comparable between female and male individuals (P = 0.940). Within the subgroup of donors aged ≤40 y, the regression slope was significantly smaller in female individuals (P = 0.031), whereas it was comparable within donors aged >40 y (P = 0.867). Within the subgroup of nonmacrosteatotic donors aged ≤40 y, the regression slope was significantly smaller in female individuals in univariable (P = 0.002) and multivariable analysis (P = 0.006), whereas the sex difference was not found within macrosteatotic donors aged ≤40 y (P = 0.685). Estrogen receptor content was significantly greater in female individuals within nonmacrosteatotic donors aged ≤40 y (P = 0.021), whereas it was not different in others of age >40 y or with macrosteatosis (P = 0.450). CONCLUSIONS: The tolerance of hepatic ischemia-reperfusion injury was greater in female individuals than in male individuals only when they were <40 y and without macrosteatosis. The results were in agreement with the hepatic estrogen receptor immunohistochemistry study.

HOXD10 expression as a prognostic factor for hepatocellular carcinoma treated with curative resection.

PURPOSE: HOXD10 downregulation resulting from epigenetic changesas well as its role as a tumor suppressor have been reported in several cancers including hepatocellular carcinomas (HCCs). However, the prognostic role of HOXD10 expression in HCC tissue samples has not been evaluated. METHODS: HOXD10 expression was investigated in 278 curatively resected HCC samples using immunohistochemistry and its effectiveness in predicting patient outcome was analyzed. RESULTS: Low expression of HOXD10 was observed in 82.7% of HCC samples, and this was associated with increased age, large tumor size and advanced stage.HOXD10 was an independent predictive factor for early tumor recurrence at less than 2 years. Patients with low HOXD10 expression showed shorter recurrence-free survival (RFS) (p=0.024) and disease-specific survival (DSS) (p=0.016) than those with high expression. Multivariate analysis confirmed that low HOXD10 expression was an independent predictor of shorter RFS (hazard ratio 1.873, p=0.006) and DSS (hazard ratio2.504, p=0.012) than high HOXD10 expression. CONCLUSIONS: The present study provides clinical evidence supporting the use of HOXD10 as a prognostic biomarker in curatively resected HCCs, and suggests that HOXD10 could also be a potential therapeutic target in HCC.

Realization of improved outcomes following liver resection in hepatocellular carcinoma patients aged 75 years and older.

PURPOSE: Little is known about liver resection (LR) in hepatocellular carcinoma (HCC) patients older than 75 years of age. This study aimed to compare the postoperative and long-term outcomes of hepatectomy in this patient population according to operation period. METHODS: This study included 130 elderly patients who underwent LR for solitary treatment-naïve HCC between November 1998 and March 2020. Group 1 included patients who underwent LR before 2016 (n = 68) and group 2 included those who underwent LR during or after 2016 (n = 62). RESULTS: The proportion of major LR, anatomical LR, and laparoscopic LR (LLR) in group 1 was significantly lower than those in group 2. Also, the median operation time, amount of blood loss, hospitalization length, rates of intraoperative blood transfusion, and complications in group 2 were less than those in group 1. In the subgroup analysis of group 1, high proteins induced by vitamin K absence or antagonist-II, long hospitalization, and LLR were closely associated with mortality. In the subgroup analysis of group 2, however, none of the factors increased mortality. Nevertheless, the presence of tumor grade 3 or 4 and the incidence of microvascular invasion were higher in group 1 than in group 2, and the disease-free survival and overall survival were better in group 2 than in group 1 because of minimized blood loss and quicker recovery period by increased surgical techniques and anatomical approach, and LLR. CONCLUSION: LR in elderly HCC patients has been frequently performed recently, and the outcomes have improved significantly compared to the past.