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Background & Aims: Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl‐CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood. Methods: We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC. Results: Patients were divided into ACSL4‐positive (n = 72, 20.1%) and ACSL4‐negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α‐fetoprotein (p =.0180) and more histological liver fibrosis (p =.0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p <.0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer‐associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC. Conclusion: ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer‐associated fibroblasts and anti‐tumour immunity. [ABSTRACT FROM AUTHOR]

Aim: We aimed to evaluate the association between the intraoperative indocyanine green (ICG) fluorescence imaging (FI) pattern, preoperative magnetic resonance imaging (MRI) findings using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd‐EOB‐DTPA), preoperative diffusion‐weighted imaging (DWI) of MRI, and histological differentiation of hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed the data for 80 tumors of 64 patients. Intraoperative ICG FI patterns were classified into cancerous or rim‐positive type. We evaluated the signal intensity ratio of the tumor and the surrounding liver tissue in the portal phase (SIRPP) and intensity in the hepatobiliary phase (HBP) of Gd‐EOB‐DTPA‐enhanced MRI, the apparent diffusion coefficient (ADC) in the DWI of MRI, and clinicopathologic factors. Results: In the rim‐positive group, the rate of poorly differentiated HCC and hypointensity type in HBP were significantly higher, and SIRPP and ADC were significantly lower than the rim‐negative group. In the cancerous group, the rate of well or moderately differentiated HCC and hyperintensity type in HBP, SIRPP, and ADC were significantly higher than the noncancerous group. Multivariate analysis identified low SIRPP, low ADC, and hypointensity type in HBP as the significant predictive factors for rim‐positive HCC and high SIRPP, high ADC, and hyperintensity type in HBP as the significant predictive factors for cancerous HCC. The positive rate of programmed cell death 1‐ligand 1 and vessels that encapsulate tumor clusters status of the rim‐positive HCC and HCC with low SIRPP were significantly higher than the control group. Conclusions: The intraoperative ICG FI pattern of HCC closely correlated with histological differentiation, preoperative SIRPP and intensity type in the Gd‐EOB‐DTPA MRI, and preoperative ADC in the DWI of MRI. [ABSTRACT FROM AUTHOR]

The association between tumor microenvironment (TME) and cancer‐associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC) progression is poorly understood. This study aimed to reveal whether specific microRNAs (miRNAs) in extracellular vesicles (EVs) derived from CAFs were involved in ICC progression. Conditioned medium (CM) and EVs in the CM of CAFs and normal fibroblasts (NFs) derived from ICC specimens were used to investigate the effects on tumor cell lines. miRNA microarray assay was used to examine the miRNAs of EVs derived from CAFs and NFs in ICC, and the effects of miR‐493‐5p on tumor cell lines were examined. Additionally, databases were used to identify miR‐493‐5p targets, and the relationship between prognosis of ICC patients and cocaine‐ and amphetamine‐regulated transcript propeptide (CARTPT), one of the targets of miR‐493‐5p, expression in ICC tissues was retrospectively analyzed. Compared with NF‐derived CM and EVs, CAF‐derived CM and EVs promoted cell lines in proliferation, scratch, migration, and invasion assays. miRNA microarray analysis revealed that miR‐493‐5p was significantly increased in CAF‐derived EVs compared to NF‐derived EVs. Tumor cell lines transfected with miR‐493‐5p were promoted in proliferation and scratch assays. Immunohistochemical staining was performed on 76 ICC specimens; both overall and recurrence‐free survival rates were significantly worse in the CARTPT‐negative group. Univariate and multivariate analyses showed that low CARTPT expression was an independent poor prognostic factor for overall and recurrence‐free survival. Overall, our data suggest that CAFs in the ICC TME suppress CARTPT in tumor cells and promote tumor cells via miR‐493‐5p in EVs. [ABSTRACT FROM AUTHOR]

Aim: Although the survival rate after living‐donor liver transplantation (LDLT) is improving, sepsis still limits the prognosis. Immune dysfunction and sarcopenia are often observed in LDLT patients, and increase susceptibility to infection. Brain‐derived neurotrophic factor (BDNF) is a myokine produced by immune cells and skeletal muscle. We aimed to determine whether serum BDNF could be a feasible biomarker for sepsis of LDLT patients. Methods: We measured serum samples from 124 patients who underwent LDLT and 9 healthy volunteers for BDNF. We examined its correlation with incidence rate of sepsis. To clarify the source of BDNF, we examined its expression in lymphocytes, skeletal muscle cells, and hepatocytes. Results: Patients who experienced sepsis showed worse short‐term survival. Preoperative serum BDNF was lower in LDLT patients compared with healthy volunteers, and was also lower in Child–Pugh C compared with Child–Pugh A or B. Serum BDNF was inversely correlated with Model for End‐Stage Liver Disease and controlling nutritional status (CONUT) scores, but had a weak positive correlation with skeletal muscle mass index (SMI). Multivariate analysis revealed that serum BDNF was independently associated with sepsis. Preoperative serum BDNF was a better predictor of sepsis in LDLT patients than CONUT score or SMI. Serum BDNF was positively correlated with lymphocyte counts, especially T cells. In vitro, T cells and skeletal muscle cells produced BDNF. Conclusions: Preoperative serum BDNF could be a predictive biomarker for sepsis after LDLT, by reflecting the systemic condition including hepatic function, nutritional status, and immune status. [ABSTRACT FROM AUTHOR]

Aim: Liver transplantation (LT) is the only curative therapy for decompensated liver cirrhosis. For recipients of living donor LT (LDLT), restoration of liver function after transplantation is highly dependent on liver regenerative capacity, which requires large amounts of intracellular energy. Mitochondrial metabolism provides a stable supply of adenosine 5′‐triphosphate (ATP) for liver regeneration. Mitophagy is a selective process in which damaged, non‐functional mitochondria are degraded and replaced with new functional mitochondria. We investigated the relationship between expression of Syntaxin17 (STX17), a key protein in mitophagy regulation, in donor livers and graft survival. Methods: We examined STX17 expression in grafts from 143 LDLT donors who underwent right lobe resection and investigated the relationship between STX17 expression and graft function. We investigated the correlations among STX17 expression, mitochondrial membrane potential and cell proliferation, using a STX17‐knockdown hepatocyte cell line. Results: Recipients transplanted with low STX17‐expression grafts had significantly lower graft survival rates than recipients transplanted with high STX17‐expression grafts (88.9% vs. 100%, p < 0.01). Multivariate analysis showed that low STX17 expression (HR: 10.7, CI: 1.29–88.0, p < 0.05) and the absence of splenectomy (HR: 6.27, CI: 1.59–24.8, p < 0.01) were independent predictive factors for small‐for‐size graft syndrome, which is the severe complication in LDLT. In the vitro experiments, the percentage of depolarized damaged mitochondria was increased in the STX17‐knockdown hepatocyte cell line, suggesting decreased mitophagy and ATP synthesis. Cell proliferation was significantly decreased in the STX17‐knockdown hepatocyte cell line. Conclusion: STX17 contributes to mitophagy and maintenance of mitochondrial function in hepatocytes and may be a predictor of graft dysfunction in LDLT patients. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to clarify the clinical effects of the indocyanine green (ICG)‐fluorescence imaging (FI) technique for determination of liver transection lines during laparoscopic partial liver resection for liver tumors. Methods: This was a retrospective study including 112 patients who underwent laparoscopic partial liver resection for liver tumors. These enrolled patients were divided into an ICG‐FI group (n = 55) and a non‐ICG‐FI group (n = 57) according to the availability of the ICG‐FI. The clinicopathological characteristics of patients between two groups were compared before and after propensity score matching. Results: The ICG‐FI and non‐ICG‐FI groups differed at baseline in terms of ICG retention rate at 15 min. After propensity score matching, two comparable groups of 32 patients each were obtained. The negativity rated of the pathological surgical margins were comparable between the two groups before and after propensity score matching. However, the surgical margins were significantly wider in the ICG‐FI group before and after propensity score matching (P =.039 and P =.047, respectively). Conclusion: The ICG‐fluorescence imaging technique may offer clinical benefits in terms of a secure surgical margin in laparoscopic partial liver resection. [ABSTRACT FROM AUTHOR]

Aim: Recently, new diagnostic criteria for acute‐on‐chronic liver failure (ACLF) were established in Japan. However, there is little evidence regarding the feasibility of classifying patients undergoing living‐donor liver transplantation (LDLT). The aim was to re‐evaluate the impact of these new diagnostic criteria on ACLF and the severity classification of patients undergoing LDLT. Methods: We collected data of 82 recipients who underwent LDLT for liver failure between 1997 and 2020 and reviewed it retrospectively. Results: Of the 82 patients with liver failure, 31 (37.8%) were diagnosed with ACLF; Grade 0 (n = 6), Grade 1 (n = 7), Grade 2 (n = 9), and Grade 3 (n = 9). There was no substantial difference in overall survival (OS) and the occurrence of postoperative complications between liver failure patients with and without ACLF. The OS after LDLT was significantly different among the four groups of ACLF patients (P =.036). Interestingly, ACLF Grade 3 patients had substantially lower OS compared to other ACLF groups even after LDLT (P =.006; 5‐year OS rates, 33.3% vs. 85.9%). Conclusion: Proper use of the new diagnostic criteria for ACLF in Japan demonstrated that the presence and severity of ACLF, especially the presence of multiple organ failures, leads to morbidity and mortality even in an LDLT setting. Considering that the patients with ACLF Grade 3 do not have the favorable outcomes of LDLT, deceased‐donor liver transplantation usage, or LDLT before reaching the severity of Grade 3 may be suitable for further research. [ABSTRACT FROM AUTHOR]

Background and Aim: Sarcopenia has received much attention as a poor prognostic factor in various fields, and has also been reported to worsen prognosis in patients with hepatocellular carcinoma (HCC) treated with sorafenib or lenvatinib (LEN). Atezolizumab/bevacizumab (ATZ/BEV) is recommended as first‐line drug therapy for unresectable‐HCC, but the effect of sarcopenia on patients treated with ATZ/BEV is unknown. Methods: We enrolled 98 patients treated with ATZ/BEV or LEN. Computed tomography performed before the initiation of drug therapy was used to diagnose sarcopenia in accordance with the criteria proposed by the Japanese Society of Hepatology. Patients were divided into two groups based on the presence or absence of sarcopenia in each regimen, and patient characteristics, adverse events, and prognosis were compared. Results: In ATZ/BEV therapy, 57.1% of patients had sarcopenia. The sarcopenia group had significantly more women (P = 0.0125) and more macroscopic vascular invasion (P = 0.0270). Sarcopenia had no significant effect on progression‐free survival (PFS) and overall survival (OS). In LEN therapy, 63.4% of patients had sarcopenia. The sarcopenia group was significantly older (P = 0.0064) and had a higher number of women (P = 0.0003), a higher neutrophil–lymphocyte ratio (P = 0.0222), worse albumin–bilirubin grade (P = 0.0087), and worse best response (P = 0.0255). PFS (P = 0.0091) and OS (P = 0.0006) were worse in the sarcopenia group. In multivariate analysis, age (P = 0.0362), lymphocyte–monocyte ratio (P = 0.0365), and sarcopenia (P = 0.0268) were independent prognostic factors for OS. Conclusion: In ATZ/BEV therapy, sarcopenia does not determine prognosis, and therapeutic efficacy can be expected even in cases of sarcopenia. [ABSTRACT FROM AUTHOR]

The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron‐dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid‐derived 2‐like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib‐induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib‐induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor‐4 (FGFR4) or Nrf2 and overexpressing‐Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system Xc− (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing‐FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2‐silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2‐overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low‐FGFR4 expression than in those with high‐FGFR4 expression. Patients with FGFR4‐positive HCC displayed significantly longer progression‐free survival than those with FGFR4‐negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib. [ABSTRACT FROM AUTHOR]

Background: Early recurrence (ER) of hepatocellular carcinoma (HCC) (within 1 year after resection) is known to be a poor prognostic factor. The aim was to identify the risk factors associated with ER after HCC resection. Methods: Data were analyzed retrospectively from patients who underwent primary resection for HCC from two hospitals. For cross‐validation, HCC resection cases were divided into the training and testing cohort. The clinicopathological factors between the ER and non‐ER groups and factors for predicting ER and prognosis after HCC resection were compared. Results: Out of 173 patients in the training dataset, 33 patients had ER and the ER group showed larger tumor size, more intrahepatic metastasis (IM), and a higher ratio of serum des‐gamma‐carboxy prothrombin (DCP) to tumor volume (TV) (DCP/TV) than the non‐ER group. Out of 203 patients in the testing dataset, 30 patients had ER and the ER group demonstrated larger tumor size, more IM, and higher serum alpha‐fetoprotein, AFP/TV, DCP/TV, AFP/tumor maximum diameter (TMD), and DCP/TMD than the non‐ER group. The patients were divided into high and low DCP/TV groups and high serum DCP/TV was associated with unfavorable overall survival in the training and testing dataset. Multivariate analysis confirmed that high serum DCP/TV and IM were independently associated with ER. Conclusion: Preoperative high serum DCP/TV may be useful for stratifying patients at risk of early HCC recurrence after curative resection. [ABSTRACT FROM AUTHOR]

Background and Aim: The aims of this study were to determine whether a postoperative decrease in skeletal muscle mass (SMM) after hepatic resection can predict long‐term outcomes in patients with hepatocellular carcinoma (HCC) and identify risk factors for SMM loss in patients who undergo hepatic resection. Methods: This was a large retrospective study of 400 patients who underwent hepatic resection for HCC and pre‐ and postoperative computed tomography (CT) scans. SMM was measured at the third lumbar vertebrae, and the postoperative change in SMM compared with preoperative values was calculated as Δ SMM. The cutoff value for the post‐/preoperative ratio was set at 0.9. Results: Sixty patients (15.0%) developed SMM loss. These patients had a significantly prolonged prothrombin time (P = 0.0092), longer duration of surgery (P = 0.0021), more blood loss (P = 0.0040), and higher rate of postoperative complications (P = 0.0037) than those without SMM loss. Multivariate analysis revealed that prolonged prothrombin time and postoperative complications were independent risk factors for SMM loss after hepatic resection. Patients with SMM loss had significantly shorter overall survival (P = 0.0018) than the other patients had. SMM loss was an independent prognostic factor for overall survival (hazard ratio 1.551, 95% confidential interval 1.028–2.340, P = 0.0363). Conclusions: We demonstrated an association of SMM loss with postoperative complications and long‐term prognosis in patients with HCC. Patients with prolonged prothrombin time, or postoperative complications, may need to maintain their SMM. Further prospective studies are needed to investigate whether nutritional support can improve SMM loss. [ABSTRACT FROM AUTHOR]