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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., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Recurrence of hepatocellular carcinoma (HCC) after living donor liver transplant (LDLT) is an essential factor defining prognosis, and surgical resection is the only curative treatment. However, the factors that define whether surgical resection is possible remain unclear. Here, we compared resectable and unresectable HCC recurrence cases after LDLT and examined factors that determine whether surgical resection is possible. Resectable (n = 17) and unresectable (n = 14) groups among 264 patients who underwent LDLT for HCC from January 1999 to March 2020 were compared and examined for recurrence type, prognosis, and clinicopathologic factors. Overall survival after LDLT (median, 8.5 vs 1.7 years, P < .01) was significantly longer in the resectable group. In univariate analysis, female recipient rate, lymphocyte to monocyte ratio (LMR) ≥2.75, and tumor size ≤5.0 cm were significantly higher in the resectable group. Younger donors, lower Model for End-Stage Liver Disease scores, lower graft volume, and lower graft volume to standard liver volume ratio were evident in the resectable group. In multivariate analysis, female recipient rate (P = .0034) and LMR ≥2.75 (P = .0203) were independent predictive factors for resectable HCC recurrence after LDLT. Female recipient and LMR ≥2.75 before transplant could predict the surgically resectable type of HCC recurrence after LDLT., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The recipient muscle status is closely associated with postoperative poor survival in recipients of living donor liver transplantation (LDLT). However, it is uncertain whether LDLT donor muscle quality and quantity affect graft quality. Hence, we analyzed the correlation between donor muscle status and graft function. We measured the skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) of 380 LDLT donors. We examined the correlation between donor SMI or IMAC and graft mortality, the occurrence rates of small-for-size graft (SFSG) syndrome, and 6-month graft survival rates. The donor SMI had no effect on the occurrence of SFSG syndrome and graft survival, while a high IMAC in both male and female donors was significantly correlated with the rate of SFSG syndrome [high vs low: (male donors) 15.8% vs. 2.5%, p = 0.0003; (female donors) 12.8% vs. 3.1%, p = 0.0234] and 6-month graft survival rates [(male donors) 87.7% vs 95.9%, p = 0.02; (female donors) 83.0% vs. 99.0%, p < 0.0001]. Multivariate analysis revealed that a high donor IMAC (HR; 5.42, CI; 2.13-13.8, p = 0.0004) was an independent risk factor for 6-month graft survival, and the donor IMAC is useful for donor selection for high-risk recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tomiyama, Harada, Toshima, Nakayama, Toshida, Morinaga, Kosai-Fujimoto, Tomino, Kurihara, Takeishi, Nagao, Morita, Itoh and Yoshizumi.)

Background: Congenital portosystemic shunt is an infrequent abnormal connection between the portal vascular system and the systemic circulation. Portosystemic shunts are common findings in patients with cirrhosis, causing gastroesophageal varices, hepatic encephalopathy, and others. However, there is no consensus or literature describing how to manage asymptomatic patients with portosystemic shunts and normal liver., Case Presentation: The patient was a 39-year-old female who underwent donor right hepatectomy for living donor liver transplantation. The patient was healthy by nature, however, developed hepatic encephalopathy after the surgery due to a development of portosystemic shunt. Portosystemic shunt stole portal blood flow, and imaging modalities revealed narrowing of the portal trunk, representing prolonged depletion of portal blood flow. Balloon-occluded retrograde transvenous obliteration (B-RTO) was performed for occlusion of the portosystemic shunt. B-RTO increased portal blood flow, and hepatic encephalopathy with hyperammonemia was successfully resolved without the outbreak of any other symptom of portal hypertension., Conclusions: A congenital portosystemic shunt itself is not a contraindication for donor hepatectomy, but perioperative endovascular shunts occlusion or intraoperative ligature of these shunts should be considered., (© 2022. The Author(s).)

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., (© 2022 Japan Society of Hepatology.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 X c - (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., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

We examined phosphorylated nuclear factor erythroid 2-related factor 2 (P-NRF2) expression in surgically resected primary hepatocellular carcinoma (HCC) and investigated the association of P-NRF2 expression with clinicopathological features and patient outcome. We also evaluated the relationship among NRF2, cancer metabolism, and programmed death ligand 1 (PD-L1) expression. In this retrospective study, immunohistochemical staining of P-NRF2 was performed on the samples of 335 patients who underwent hepatic resection for HCC. Tomography/computed tomography using fluorine-18 fluorodeoxyglucose was performed, and HCC cell lines after NRF2 knockdown were analyzed by array. We also analyzed the expression of PD-L1 after hypoxia inducible factor 1α (HIF1A) knockdown in NRF2-overexpressing HCC cell lines. Samples from 121 patients (36.1%) were positive for P-NRF2. Positive P-NRF2 expression was significantly associated with high alpha-fetoprotein (AFP) expression, a high rate of poor differentiation, and microscopic intrahepatic metastasis. In addition, positive P-NRF2 expression was an independent predictor for recurrence-free survival and overall survival. NRF2 regulated glucose transporter 1, hexokinase 2, pyruvate kinase isoenzymes L/R, and phosphoglycerate kinase 1 expression and was related to the maximum standardized uptake value. PD-L1 protein expression levels were increased through hypoxia-inducible factor 1α after NRF2 overexpression in HCC cells. Conclusions: Our large cohort study revealed that P-NRF2 expression in cancer cells was associated with clinical outcome in HCC. Additionally, we found that NRF2 was located upstream of cancer metabolism and tumor immunity., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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., (© 2022 Japan Society of Hepatology.)

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., (© 2022 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8 + T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8 + T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8 + T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8 + T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8 + T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSC high CD8 + T-cell Low , 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSC high CD8 + T-cell Low , 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8 + T-cell status enabled further classification of patients based on their outcomes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tomiyama et al.)

Background: Changes in immune cell and inflammation-associated protein levels, either independently or in combination, are commonly used as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of LCR and its relationship to various aspects of the tumor immune microenvironment in patients with intrahepatic cholangiocarcinoma (ICC)., Methods: This was a single-center, retrospective study of patients who underwent surgical resection for ICC between 1998 and 2018. Patients were dichotomized into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. Tumor-infiltrating CD8+ and FOXP3s+ lymphocytes and tumor expression of CD34 and programmed death-ligand 1 were evaluated by immunohistochemical staining of resected tumors., Results: A total of 78 ICC patients were enrolled and assigned to the high (n = 44)- and low (n = 34)-LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly higher serum CA19-9 level (median 20.6 vs. 77.3 U/mL, P = 0.0017) and larger tumor size (median 3.5 vs. 5.5 cm, P = 0.0018). LCR correlated significantly with tumor microvessel density (r = 0.369, P = 0.0009) and CD8+ T lymphocyte infiltration (r = 0.377, P = 0.0007) but not with FOXP3+ T lymphocyte infiltration or tumor PD-L1 expression. Low-LCR status was significantly associated with worse overall survival by multivariate analysis (P = 0.0348)., Conclusions: Low-LCR status may reflect a poor anti-tumor immune response and predict worse outcomes in ICC patients., (© 2021. Japan Society of Clinical Oncology.)

Background: Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent resections for hepatocellular carcinoma (HCC)., Methods: We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation., Results: LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8 + T-cell counts than low LCR patients., Conclusions: Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status., (© 2021. Japan Society of Clinical Oncology.)

Although viruses infect various organs and are associated with diseases, there may be many unidentified pathogenic viruses. The recent development of next-generation sequencing technologies has facilitated the establishment of an environmental viral metagenomic approach targeting the intracellular viral genome. However, an efficient method for the detection of a viral genome derived from an RNA virus in animal or human samples has not been established. Here, we established a method for the efficient detection of RNA viruses in human clinical samples. We then tested the efficiency of the method compared to other conventional methods by using tissue samples collected from 57 recipients of living donor liver transplantations performed between June 2017 and February 2019 at Kyushu University Hospital. The viral read ratio in human clinical samples was higher by the new method than by the other conventional methods. In addition, the new method correctly identified viral RNA from liver tissues infected with hepatitis C virus. This new technique will be an effective tool for intracellular RNA virus surveillance in human clinical samples and may be useful for the detection of new RNA viruses associated with diseases.

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., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Invasive aspergillosis (IA) is one of the most serious causes of death after liver transplantation (LT). IA is the second most common fungal infection, and its mortality rate exceeds 80%., Case Presentation: A 67-year-old man presented to our hospital because of fulminant hepatitis caused by hepatitis B virus. Candidiasis was detected in his sputum, and micafungin had already been administered. Living-donor LT was performed using a right lobe graft donated from his daughter with no intraoperative complications. Although he appeared to have good graft function, his oxygenation was inadequate, and a chest radiograph showed many invasive shadows on postoperative day 1. A computed tomography scan also showed many invasive shadows with the halo sign. A blood examination revealed positivity for Aspergillus antigen, and Aspergillus species were detected in his sputum. IA was diagnosed. The antifungal therapy was soon modified to amphotericin B combined with caspofungin. Despite good graft blood flow through the portal vein and hepatic artery and good graft function, the patient died of IA on postoperative day 3. The median time from LT to IA among reports published to date ranges from 18 to 25 days., Conclusions: The present report describes the first case of very early onset of IA after LT.

Purpose: Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC)., Methods: We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time., Results: Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053)., Conclusion: SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Conclusion: Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a regulator of programmed death ligand 1 (PD-L1), which induces antitumor immunity in several cancers. This study aimed to clarify the relationship between CMTM6 and PD-L1 expression and clinical outcomes in patients with hepatocellular carcinoma (HCC). In total, 259 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for CMTM6 and PD-L1 was performed. The relationships between CMTM6 expression and the clinicopathological characteristics and outcomes were analyzed. Additionally, the stabilization of PD-L1 expression and regulation of malignant activities by CMTM6 were examined in vitro . Our patients were divided into high (n = 65, 25.1%) and low (n = 194, 74.9%) CMTM6 expression groups. High CMTM6 expression was significantly associated with malignant aggregates, including poor differentiation ( P  < 0.0001), microscopic intrahepatic metastasis ( P  = 0.0369), and multiple intrahepatic recurrences ( P  = 0.0211). CMTM6 expression was significantly correlated with PD-L1 expression in HCC tissues ( P  < 0.0001). The patients were classified into three groups: high CMTM6/PD-L1 positive (n = 21), high CMTM6/ PD-L1 negative (n = 44), and low CMTM6 (n = 194) expression pattern groups. Overall survival was significantly different among the three groups ( P  < 0.0001). Additionally, immunohistochemical double staining revealed that CMTM6 and PD-L1 were co-expressed on HCC cells. In vitro , PD-L1 expression was enhanced at late time points in the presence of CMTM6 expression. CMTM6 also regulated epithelial-to-mesenchymal transition and stemness phenotypes in HCC cells. Conclusion: Our large cohort study found that CMTM6 co-expressed with PD-L1 was strongly associated with the clinical outcome in patients with HCC. The evaluation of CMTM6 combined with PD-L1 in HCC might be useful for patient selection in immune checkpoint therapy., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Recently, immune checkpoint inhibitors(ICI)has been developed considerably. ICI has already been approved for malignant melanoma, lung cancer and renal cancer. We expected ICI to be taken for many cancers in the future. Therefore, the development of biomarker for them are needed. The recent large phase Ⅲ study IMbrave 150 evaluated atezolizumab plus bevacizumab vs sorafenib as the first treatment for patients with unresectable hepatocellular carcinoma(HCC). IMbrave 150 demonstrated statistically significant and clinically meaningful improvements in both OS and RFS for atezolizumab plus bevacizumab compared with sorafenib in HCC patients. A paradigm shift in the treatment of unresectable HCC is about to occur. In this article, we discussed the significance and biomarkers of tumor immunity in HCC microenvironment.

Extrahepatic malignancy is a relative contraindication for liver transplant in many countries. Nevertheless, the indications for living-donor liver transplantation (LDLT) for such patients vary by institution. Our aim was to reevaluate the indications for LDLT in patients with extrahepatic malignancy. We retrospectively reviewed data for 609 patients who underwent adult LDLT from May 1997 to January 2018 and analyzed patients with a history of extrahepatic malignancies or concurrent malignancies. Fourteen patients had extrahepatic malignancies concurrent with or before LDLT. Malignancies in 9 patients were detected during their systematic screening for LDLT. The mean duration between surgeries was 70 days (range, 20-209 days). Five patients had a history of extrahepatic malignancies before considering LDLT. The estimated 5-year survival rate was 100%. Although the risk and long-term prognosis of patients with extrahepatic malignancy are not well known, such patients can be candidates for LDLT if they undergo curative surgery for the malignancy, and if the prognosis of the malignancy is the same or superior to that of LDLT., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hemophagocytic syndrome (HPS) is a rare and potentially fatal complication following liver transplantation., Case Presentation: A 63-year-old woman with decompensated liver cirrhosis secondary to hepatitis B virus infection underwent living donor liver transplantation using the right posterior section of her husband's liver (graft volume, 581 g; 56.8% of the recipient's standard liver volume). She developed small-for-size syndrome on postoperative day (POD) 7, and HPS was diagnosed on POD 12 by bone marrow aspiration (white blood cells, 300/μL; neutrophils, 30/μL). Given that she tested negative for viral (hepatitis B virus and cytomegalovirus) and bacterial infections, it was considered likely to be secondary HPS. Steroid pulse therapy was initiated, and her white blood cell count increased to 4290/μL on POD 15, indicating that her peripheral blood leukocytes had improved. There were no surgical complications, but the patient died of prolonged graft dysfunction with bacterial sepsis on POD 14., Conclusions: We report a rare case of HPS occurring 2 weeks after living donor liver transplantation with a right posterior section graft, diagnosed early via bone marrow aspiration. This clinical course implies an association between HPS and graft dysfunction such as small-for-size syndrome. Further studies of the mechanism of hypercytokinemia-induced HPS are required to confirm the optimal treatment for HPS.