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Introduction: In recent years, single-cell RNA sequencing (scRNA-seq) and high-dimensional spatial transcriptomics (ST-seq) have contributed significantly to our understanding of the tumor microenvironment (TME) in many cancers. This is essential for understanding the tumor-stromal crosstalk. Thus, integrating scRNA-seq data with ST-seq data will facilitate understanding intercellular communication in TMEs. Material and Method: We performed and combined ST-seq in CRC with public scRNA-seq. And, immunohistochemistry (IHC) (HLA-G, CD68, and SPP1) was performed on 20 CRC surgical specimens collected in our hospital. To verify this, we knocked out H2-M3 (HLA-G in humans) in mouse CRC cell lines (MC-38 cells) using the CRISPR/Cas9 system and examined H2-M3 KO tumor volume in xenograft mouse models. Results: We identified co-localized cells with CRC cells at the invasive front and those in the center based on the spatial distribution estimated by an analytical pipeline, Cell2location. At the invasive front, CRC cells co-localized more frequently with SPP1+ macrophages than other cells. To dissect the molecular machinery and cell types inducing SPP1+ macrophages, we found ligand activity by another pipeline, NicheNet. The prominent signal to SPP1+ macrophages was mediated by several ligand-receptor pairs including HLA-G- immunoglobulin-like transcript (ILT)2/ILT4. Next, we disclosed the effect on CD8+ cells, and SPP1+ macrophages secrete IL-10 suppressing the immune activity of CD8+ T cells. And the ratio of HLA-G-positive cancer cells was predominantly higher in areas with more SPP1+ macrophages by IHC in CRC. In vivo analysis, H2-M3 KO reduced CRC tumor volume and tumor tissue from H2-M3 KO cells exhibited higher SPP1 and CD68 staining compared with wild type cells. Conclusion: SPP1+ macrophages and cancer cells secreting high levels of HLA-G may represent targets to improve the prognosis of patients with CRC. Further analysis is currently underway with a focus on early-stage cancer in carcinoma in adenoma. Citation Format: Masahiro Hashimoto, Yuki Ozato, Yusuke Nakano, Tadashi Abe, Yuichi Hisamastu, Takeo Toshima, Yusuke Yonemura, Mamoru Uemura, Takaaki Masuda, Hirofumi Yamamoto, Masaki Mori, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Spatial transcriptomics deciphers the cellular society of advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5855.

Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule‐associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence‐free survival (RFS). OPTN KO cells proliferated relatively slower versus wild‐type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta‐oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production., Optineurin (OPTN) is required for mitophagic activity as shown by the significant association of OPTN expression levels with mitochondrial beta‐oxidation. Moreover, elevated levels of OPTN were associated with worse prognosis of HCC. Our findings provide a foundation for determining the roles of other autophagy adaptor proteins in the pathogenesis and progression of HCC as well as in other cancers.

Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI 2, n = 48) and obesity groups (BMI ≥ 25.0 kg/m2, n = 26), respectively. Serum carbohydrate antigen 19–9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on 18F-FDG PET/CT (n = 46, r = 0.5152). Patients with high 18F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8 + tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3 + TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.

We evaluated the prognostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in hepatocellular carcinoma (HCC). Their association with programmed death ligand 1 (PD-L1) expression and vascular formation was further investigated. In this retrospective study, using a database of 418 patients who had undergone 18F-FDG PET/CT before hepatic resection for HCC, immunohistochemical staining of PD-L1, clusters of differentiation (CD) 8, CD68, and CD34 was performed. Patients with a high maximum standardized uptake value (SUVmax) on 18F-FDG PET/CT showed a significantly worse recurrence-free survival (RFS) (hazard ratio [HR]: 1.500; 95% confidence interval [CI]: 1.088-2.069; P = 0.0133) and overall survival (OS) (HR: 2.259; 95% CI: 1.276-4.000; P = 0.0052) than patients with a low SUVmax. Logistic regression analysis showed that a high SUVmax in HCC was significantly associated with PD-L1-positive expression (odds ratio: 4.407; 95% CI: 2.265-8.575; P < 0.0001). SUVmax values of HCC were associated with intratumoral CD8-positive T-cell counts (P = 0.0044) and CD68-positive macrophage counts (P = 0.0061). Stratification based on SUVmax, PD-L1 expression, and the vessels that encapsulate tumor clusters (VETC) status was also significantly associated with RFS and OS. SUVmax, VETC, and PDL1 expression were independently predictive of survival on multivariable analysis. Conclusion: Our large cohort study showed that a high SUVmax on 18F-FDG PET/CT is associated with a poor clinical outcome and PD-L1 expression in patients with HCC. Additionally, stratification of patients based on the combination of SUVmax, PD-L1 expression, and the VETC status predicts poor clinical outcome.

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). 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. 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). SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

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.

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.

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.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.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.STX17 contributes to mitophagy and maintenance of mitochondrial function in hepatocytes and may be a predictor of graft dysfunction in LDLT patients.

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.We collected data of 82 recipients who underwent LDLT for liver failure between 1997 and 2020 and reviewed it retrospectively.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%).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.

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

The transcription factor capicua (CIC) regulates mammalian development and homeostasis. Growing evidence shows that CIC suppresses various human cancers by directly repressing the downstream cancer-related target genes. This study investigated the clinical and biologic significance of CIC expression in pancreatic cancer (PC). The study reviewed 132 patients with PC who underwent curative resection. The patients were divided into two groups according to CIC immunoreactivity score by immunohistochemistry, and the associations between CIC expression, clinicopathologic characteristics, and postoperative prognosis were investigated. Moreover, the influence of CIC expression on the malignant potential of PC cells was assessed with cell proliferation, motility assays, and use of quantitative real time-polymerase chain reaction and Western blot on the downstream target genes of CIC in knockdown experiments. The low-CIC expression group showed a higher proportion of lymphatic invasion (72.9% vs. 53.1%; p = 0.024), intrapancreatic neural invasion (94.1% vs. 81.3%; p = 0.021), and extrapancreatic plexus invasion (30.9% vs. 7.8%; p = 0.0006) than the high-CIC expression group as well as significantly worse overall survival (p = 0.0002) and recurrence-free survival (p = 0.0041) rates. Low CIC expression was an independent risk factor for poor prognosis (p = 0.038). Pancreatic cancer cells with knockdown CIC significantly enhanced cell motilities and cell cycle progression, promoted expression levels of ETV4 and MMP-9, and induced EMT. The study elucidated the association of low CIC expression with a poor prognosis for patients with PC and suggested that the CIC–ETV4–MMP-9 axis might control PC progression.

Objective: The aim of this study was to clarify the predictive factors of recurrence-free time more than 10 years after primary hepatic resection for hepatocellular carcinoma (HCC). Summary of background data: Surgical resection is a curative treatment for HCC patients with hepatic functional reserve; however, the high recurrence rate must be addressed. Methods: The study included 595 patients who had undergone curative resection for HCC. Multivariate analysis was performed to identify factors associated with recurrence-free survival at more than 10 years. Results: Multivariate analysis revealed that tumor size ≤2 cm (P = 0.004), albumin-bilirubin (ALBI) grade 1 (P = 0.03), Fibrosis-4 (FIB-4) index ≤3.3 (P = 0.002), and histologic inflammation grade ≤1 (P = 0.03) were independent predictive factors for recurrence-free survival for more than 10 years. Predictive points were scored as follows: 2 points, tumor size ≤2 cm or FIB-4 index ≤3.3; and 1 point, ALBI grade 1 or histologic inflammation grade ≤1. Patients were divided into 3 groups according to their total points: group 1, 0 to 2 points (n = 317); group 2, 3 to 4 points (n = 239); and group 3, 5 to 6 points (n = 39). Recurrence-free survival rates among the 3 groups were significantly different (P < 0.0001). Conclusions: Tumor size, ALBI, FIB-4 index, and histologic inflammation grade were independent predictive factors for recurrence-free survival longer than 10 years after curative hepatic resection for HCC.

Background/Objectives: 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC). Methods Ninety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined. Results The low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19–9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC. Conclusions Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.

Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8-hydroxy-deoxyguanosine (8-OHdG) DNA glycosylase (OGG1) enhances the repair of 8-OHdG, which is the primary oxidative stress-induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress-induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8-OHdG expressions in 86 resected HCC specimens. High 8-OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8-OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8-OHdG expression than in those with low 8-OHdG expression. The 8-OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8-OHdG group and the other group. The patients with low OGG1/high 8-OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8-OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8-OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.

Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors.Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively.Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for post-LDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well.Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component.

The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage‐independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β‐lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α‐fetoprotein, and des‐γ‐carboxy‐prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P = .0073) and was an independent risk factor for poor prognosis (P = .0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage‐independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy., Downregulation of NADPH quinone oxidoreductase 1 (Nqo1) in suspended culture promoted intracellular reactive oxygen species production and induced anoikis, resulting in attenuated spheroid formation. Activation of Nqo1 by β‐lapachone showed a similar effect on anoikis sensitivity and diminished spheroid formation. Overexpression of Nrf2/Nqo1 was associated with intrahepatic recurrence and was an independent risk factor for poor prognosis.

The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarcinoma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.

Osteopenia, loss of bone mineral density (BMD), was recently identified to be independently associated with early marker of deconditioning that precedes sarcopenia in patients with hepatocellular carcinoma (HCC). The aim of this study was to clarify the impact of osteopenia as the risk factor for mortality after living donor liver transplantation (LDLT) compared with already-reported biological markers. Data were collected retrospectively for all consecutive patients who underwent LDLT for HCC at our institution between January 1998 and December 2015. BMD was evaluated with computed tomographic measurement of pixel density in the midvertebral core of the 11th thoracic vertebra. Data related to clinicopathological parameters and prognosis were analyzed. The median value of BMD was 163.6 Hounsfield units and osteopenia was identified in 103 (53.4%) of the 193 recipients, according to the age-specific formula. In addition to the other tumor burdens, such as tumor numbers ≥5 (HR 2.521, P = 0.027), DCP levels >200 mAU/mL (HR 2.678, P = 0.006), and neutrophil-to-lymphocyte ratio ≥3.01 (HR 2.068, P = 0.025), osteopenia (HR 2.106, P = 0.024) was independent risk factor for mortality by multivariate analysis. Overall survival of the patients who met the two risk factors and more was significantly lower than the others (HR 5.382, P

Background Cancer-related inflammation has been correlated with cancer prognosis. This study evaluated inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), programmed death ligand (PD-L) 1 expression, and tumour microenvironment in relation to prognosis and clinicopathological features of patients with hepatocellular carcinoma (HCC) undergoing curative hepatic resection. Methods Patients who had liver resection for HCC in 2000-2011 were analysed. Univariable and multivariable analyses were conducted for overall (OS) and recurrence-free (RFS) survival. Immunohistochemical analyses of PD-L1, CD8 and CD68 expression were performed. HCC cell lines were evaluated for PD-L1 expression. A subgroup analysis was conducted to determine patient features, survival and the tumour microenvironment. Results were validated in a cohort of patients with HCC treated surgically in 2012-2016. Results Some 281 patients who underwent hepatic resection for HCC were included. Multivariable analysis showed that low LMR was an independent prognostic factor of OS (hazard ratio (HR) 1·59, 95 per cent c.i. 1·00 to 2·41; P = 0·045) and RFS (HR 1·47, 1·05 to 2·04; P = 0·022) after resection. Low preoperative LMR values were correlated with higher α-fetoprotein values (P

Background/aim The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. Materials and methods The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. Results Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. Conclusion Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression.

We would like to respond to the Letter to the Editor “‘GRWR’ or ‘GV/SLV’ in clinical practice in living donor liver transplantation” by Haruki et al, that is a comment on our original article “Which is better to use ‘body weight’ or ‘standard liver weight,’ for predicting small‐for‐size graft syndrome after living‐donor liver transplantation?” in Annals of Gastroenterological Surgery.

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.

Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.

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). 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. 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. Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.

The aim of this study was to investigate the clinical value of nutritional and immunological prognostic scores as predictors of outcomes and to identify the most promising scoring system for patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-institutional study.Data were retrospectively collected for 589 patients who underwent surgical resection for PDAC. Prognostic analyses were performed for overall (OS) and recurrence-free survival (RFS) using tumor and patient-related factors, namely neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), modified GPS, C-reactive protein-to-albumin ratio, Controlling Nutritional Status score, and the Geriatric Nutritional Risk Index.Compared with PDAC patients with high PNI values (≥46), low PNI (46) patients showed significantly worse overall survival (OS) (multivariate hazard ratio (HR), 1.432; 95% CI, 1.069-1.918; p = 0.0161) and RFS (multivariate HR, 1.339; 95% CI, 1.032-1.736; p = 0.0277). High carbohydrate antigen 19-9 (CA19-9) values (≥450) were significantly correlated with shorter OS (multivariate HR, 1.520; 95% CI, 1.261-2.080; p = 0.0002) and RFS (multivariate HR, 1.533; 95% CI, 1.199-1.961; p = 0.0007). Stratification according to PNI and CA19-9 was also significantly associated with OS and RFS (log rank, P 0.0001).Our large cohort study showed that PNI and CA19-9 were associated with poor clinical outcomes in PDAC patients following surgical resection. Additionally, combining PNI with CA19-9 enabled further classification of patients according to their clinical outcomes.

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.

Intrahepatic recipient hepatic artery dissection caused by hepatic artery thrombosis is a lethal complication of living-liver donor liver transplantation (LDLT). We herein report a new surgical technique that avoids the ligation of the recipient hepatic arteries in LDLT. Patients undergoing LDLT between 2009 and 2019 were evaluated. In the second half of this period, a technique involving no ligation of the recipient hepatic artery was initiated and its impact on the incidence of intrahepatic recipient hepatic artery dissection was determined. The middle and left hepatic arteries were ligated in 195 cases (53.4%), and the no-ligation technique was used in 170 (46.6%). The incidence of intraoperative hepatic artery dissection was significantly lower in the no-ligation group (n = 0, 0.0%) than in the ligation group (n = 10, 5.1%) (p = 0.0021). After propensity score matching to evaluate the patient characteristics, the incidence of intraoperative hepatic artery dissection was also significantly lower in the no-ligation group (n = 0, 0.0%) than in the ligation group (n = 6, 4.5%) (p = 0.0295). As a result, this new surgical technique is highly recommended to avoid recipient hepatic artery ligation in LDLT.

Portal vein embolization before liver resection is considered the therapy of choice for patients with inadequate future liver remnants. The concept of radioembolization with Yttrium-90 to achieve the same goal has limited data.We retrospectively compared patients who underwent portal vein embolization and Yttrium-90 lobectomy before resection of hepatocellular carcinoma in patients with chronic liver disease.Seventy-three patients underwent portal vein embolization and 22 patients underwent Yttrium-90. Forty-seven percent of patients before portal vein embolization required additional procedures for tumor control, and 27% of patients after Yttrium-90 required additional procedure to mainly induce further hypertrophy. Both therapies achieved the goal of future liver remnants40%, but the degree of hypertrophy was significantly higher in Yttrium-90 patients (63% for Yttrium-90, 36% for portal vein embolization, P.01). Tumor response was significantly better with Yttrium-90, achieving complete response in 50% of patients. Resectability rate was higher after portal vein embolization (85% for portal vein embolization, 64% for Yttrium-90, P = .03). Tumor progression was the most common reason precluding surgery. Complete tumor control was the reason not to pursue surgery in 18% of patients after Yttrium-90.Both preoperative portal vein embolization and Yttrium-90, increases liver resectability rates by inducing hypertrophy of future liver remnants in patients with hepatocellular carcinoma and chronic liver disease. Yttrium-90 lobectomy achieved better tumor control and provided more time to assess therapy response, optimizing the indication for surgery.

To treat small-for-size syndrome (SFSS) after living donor liver transplantation (LDLT), many procedures were described for portal flow modulation before, during, or after transplantation. The selection of the procedure as well as the best timing remains controversial.A 43-year-old female with end-stage liver disease underwent LDLT with extended left with caudate lobe graft from her donor who was her 41-year-old brother (graft volume/standard liver volume (GV/SLV), 35.7%; graft to recipient weight ratio (GRWR), 0.67%). During the surgery, splenectomy could not be performed owing to severe peri-splenic adhesions to avoid the ruined bleedings. The splenic artery ligation was not also completely done because it was dorsal to the pancreas and difficult to be approached. Finally, adequate portal vein (PV) inflow was confirmed after portal venous thrombectomy. As having post-transplant optional procedures that are accessible for PV flow modulation, any other procedures for PV modulation during LDLT were not done until the postoperative assessment of the graft function and PV flow for possible postoperative modulation of the portal flow accordingly. Postoperative PV flow kept as high as 30 cm/s. By the end of the 1st week, there was a progressive deterioration of the total bilirubin profile (peak as 19.4 mg/dL) and ascitic fluid amount exceeded 1000 mL/day. Therefore, splenic artery embolization was done effectively and safely on the 10th postoperative day (POD) to reverse early allograft dysfunction as PV flow significantly decreased to keep within 20 cm/s and serum total bilirubin levels gradually declined with decreased amounts of ascites below 500 mL on POD 11 and thereafter. The patient was discharged on POD 28 with good condition.SFSS can be prevented or reversed by the portal inflow modulation, even by post-transplant procedure. This case emphasizes that keeping accessible angiographic treatment options for PV modulation, such as splenic artery embolization, after LDLT is quite feasible.

Background:To treat small-for-size syndrome (SFSS) after living donor liver transplantation (LDLT), many procedures were described for portal flow modulation before, during, or after transplantation. The selection of the procedure as well as the best timing remains controversial.\nCase presentation:A 43-year-old female with end-stage liver disease underwent LDLT with extended left with caudate lobe graft from her donor who was her 41-year-old brother (graft volume/standard liver volume (GV/SLV), 35.7%; graft to recipient weight ratio (GRWR), 0.67%). During the surgery, splenectomy could not be performed owing to severe peri-splenic adhesions to avoid the ruined bleedings. The splenic artery ligation was not also completely done because it was dorsal to the pancreas and difficult to be approached. Finally, adequate portal vein (PV) inflow was confirmed after portal venous thrombectomy. As having post-transplant optional procedures that are accessible for PV flow modulation, any other procedures for PV modulation during LDLT were not done until the postoperative assessment of the graft function and PV flow for possible postoperative modulation of the portal flow accordingly. Postoperative PV flow kept as high as 30 cm/s. By the end of the 1st week, there was a progressive deterioration of the total bilirubin profile (peak as 19.4 mg/dL) and ascitic fluid amount exceeded 1000 mL/day. Therefore, splenic artery embolization was done effectively and safely on the 10th postoperative day (POD) to reverse early allograft dysfunction as PV flow significantly decreased to keep within 20 cm/s and serum total bilirubin levels gradually declined with decreased amounts of ascites below 500 mL on POD 11 and thereafter. The patient was discharged on POD 28 with good condition.\nConclusions:SFSS can be prevented or reversed by the portal inflow modulation, even by post-transplant procedure. This case emphasizes that keeping accessible angiographic treatment options for PV modulation, such as splenic artery embolization, after LDLT is quite feasible., 論文

Fascioliasis is a parasitic infestation caused by the digenetic trematodes Fasciola hepatica and F. gigantica. It is not commonly seen in developed countries, so diagnosis there is always difficult as a result of confusion with other hepatic or biliary disorders. A 56-year-old man presented at our hospital with a hepatic mass that had been inadvertently discovered by ultrasonography. Abdominal computed tomography revealed a multi-cystic lesion distributed along the branch of the right bile duct. Endoscopic retrograde cholangiopancreatography showed serrated changes ranging from the upper level of the common bile duct to the right hepatic bile duct. Eosinophilia was not observed and tumor marker levels were within normal ranges. Following right lobectomy combined with bile duct reconstruction, a histological examination revealed cholangitis with inflammatory cell infiltration accompanied by parasite egg-like structures and Charcot-Leyden crystals. An additional serologic test was positive for F. hepatica antibodies. A diagnosis of fascioliasis was thus confirmed by histopathology and serology. Fascioliasis should be suspected if imaging findings such as multiple small hypodense lesions in the liver are observed, and serologic tests can be useful for differential diagnosis.

OBJECTIVES The aim of this study was to evaluate recipient safety, tolerability, and pharmacokinetics of mycophenolate mofetil suspension compared with mycophenolate mofetil capsules as part of induction therapy after living-donor liver transplant. MATERIALS AND METHODS Between July 2017 and April 2019, we retrospectively enrolled 20 adult primary living-donor liver transplant recipients. Recipients were divided into 3 groups: group 1 received mycophenolate mofetil suspension of 3000 mg (n = 6), group 2 received 3000 mg mycophenolate mofetil via opened capsules (n = 8), and group 3 received mycophenolate mofetil suspension of 2000 mg (n = 6). Administration was started on postoperative day 1, with tacrolimus administered on postoperative day 2 or day 3. RESULTS The values of area under the plasma concentration time curve for 0 to 12 hours were significantly higher in the 3000 mg/day mycophenolate mofetil suspension group than in the 2000 mg/day mycophenolate mofetil suspension group (P = .024) and in the 3000mg/day mycophenolate mofetil capsule group (P = .013). Significant positive correlations were shown between blood concentration at 8 hours after administration and the plasma concentration time curve for 0 to 12 hours (r2 = 0.96; P < .001) in patients in the suspension group. No patients required mycophenolate mofetil reduction because of leukopenia and diarrhea. Only 1 biopsy-proven acute cellular rejection was recognized in the mycophenolate mofetil suspension group (at 2000 mg/day). There were no significant differences in frequency of opportunistic infections among the 3 groups. CONCLUSIONS Mycophenolate mofetil suspension is useful as part of immunosuppressive induction therapy after living-donor liver transplant because its concentration increases greater than that of mycophenolate mofetil capsules and because of the low risk of rejection and adverse events.

Introduction The aim of this study was to clarify the impact of middle hepatic artery reconstruction on the outcomes of duct-to-duct biliary anastomosis after living donor liver transplantation (LDLT) using the left lobe. Materials and methods Among 258 patients who underwent LDLT using the left lobe, 216 patients who underwent hepatic artery reconstruction and one hepatic duct reconstruction with duct-to-duct interrupted anastomosis were divided into three groups: Group A (n = 123), one arterial stump with left hepatic artery reconstruction; Group B (n = 32), two arterial stumps with only left hepatic artery reconstruction; and Group C (n = 61), two arterial stumps with reconstruction of the left and middle hepatic arteries. The outcomes after LDLT were compared among the three groups. Results No hepatic artery complications occurred. Group B had a significantly greater incidence of anastomotic biliary stricture than Group C. A multivariate analysis with Cox regression revealed that being in Group B was the only significant independent risk factor for postoperative anastomotic biliary stricture after LDLT. Conclusions Middle and left hepatic artery reconstruction is safe in LDLT and may prevent biliary stricture caused by dual hepatic artery reconstruction when the graft has left and middle hepatic artery stumps.

Background The Japan criteria (JC, maximum tumor size within 5 cm, within five tumor nodules, AFP within 500 ng/mL or within Milan criteria) have been applied to cadaveric liver transplantation (LT) for hepatocellular carcinoma (HCC) and will be used for living donor LT (LDLT) in Japan. The aim of this study was to verify the JC in LDLT and to clarify the risk factor of HCC recurrence and mortality after LDLT beyond the JC. Patients and methods Adult patients who underwent LDLT for end‐stage liver disease with HCC until October 2019 were reviewed retrospectively (n = 246). Patients were divided into two groups according to whether they were within JC (n = 203) or beyond JC (n = 43). Recurrence‐free or overall survival rates after LDLT were compared. Univariate and multivariate analyses were performed to identify risk factors of HCC recurrence and HCC‐related mortality after LDLT for patients beyond the JC. Results Patients beyond the JC had significantly poorer 5‐year recurrence‐free (50.3% vs 95.9%, P, The aim of this study was to clarify the risk factor of HCC recurrence and mortality after LDLT beyond the Japan criteria (JC). We revealed that des‐gamma‐carboxy prothrombin (DCP) ≥300 mAU/ml was an independent risk factor for tumor recurrence and recipient HCC‐related mortality after LDLT in patients beyond the JC.

BACKGROUND/AIM Computed tomography (CT) has recently been applied to measure bone mineral density (BMD). However, the definition of osteopenia, which means depletion of BMD, using CT remains controversial. The aim of this study was to establish formulae to calculate standard BMD. PATIENTS AND METHODS Fifty healthy donors for liver transplantation underwent CT. BMD was measured as cross-sectional average pixel density (Hounsfield units) only in trabecular-bone at Th11 bottom. Validation was performed on another 50 healthy donors to check the accuracy of formulae for standard BMD. RESULTS Measured BMD was significantly correlated with age in both males and females (p

The aims of this study were to clarify the relationship of gait speed, hand grip strength, and skeletal muscle mass with complications after hepatic resection and to identify risk factors for complications in patients who underwent hepatic resection. We evaluated the risk factors for complications after hepatic resection in 154 consecutive patients. Preoperative factors included gait speed, hand grip strength, and skeletal muscle mass. The gait speed and hand grip strength of patients were measured by physical therapists, and skeletal muscle mass was measured by computed tomography. Multivariate logistic regression analyses using preoperative factors were performed to assess predictors of the development of complications after hepatic resection. Thirty-three patients (21.4%) developed complications after hepatic resection. These patients had a significantly lower serum albumin level (p = 0.015), slower gait speed (p = 0.007), higher rate of hepatic resection ≥ 2 Couinaud segments (p = 0.014), and lower rate of laparoscopic hepatic resection (p = 0.017) than patients without complications. Multivariate analysis revealed that a gait speed ≤ 1.10 m/s and a serum albumin level of ≤ 4.0 g/dl were independent risk factors for complications after hepatic resection. Slow gait speed and low serum albumin level are significant risk factors for complications after hepatic resection. These data will be helpful for perioperative patient management.

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.

Autophagy is a homeostatic process regulating turnover of impaired proteins and organelles, and p62 (sequestosome-1, SQSTM1) functions as the autophagic receptor in this process. p62 also functions as a hub for intracellular signaling such as that in the mammalian target of rapamycin (mTOR) pathway. Liver stem/progenitor cells have the potential to differentiate to form hepatocytes or cholangiocytes. In this study, we examined effects of autophagy, p62, and associated signaling on hepatic differentiation. Adult stem/progenitor cells were isolated from the liver of mice with chemically induced liver injury. Effects of autophagy, p62, and related signaling pathways on hepatic differentiation were investigated by silencing the genes for autophagy protein 5 (ATG5) and/or SQSTM1/p62 using small interfering RNAs. Hepatic differentiation was assessed based on increased albumin and hepatocyte nuclear factor 4α, as hepatocyte markers, and decreased cytokeratin 19 and SOX9, as stem/progenitor cell markers. These markers were measured using quantitative RT-PCR, immunofluorescence, and Western blotting. ATG5 silencing decreased active LC3 and increased p62, indicating inhibition of autophagy. Inhibition of autophagy promoted hepatic differentiation in the stem/progenitor cells. Conversely, SQSTM1/p62 silencing impaired hepatic differentiation. A suggested mechanism for p62-dependent hepatic differentiation in our study was activation of the mTOR pathway by amino acids. Amino acid activation of mTOR signaling was enhanced by ATG5 silencing and suppressed by SQSTM1/p62 silencing. Our findings indicated that promoting amino acid sensitivity of the mTOR pathway is dependent on p62 accumulated by inhibition of autophagy and that this process plays an important role in the hepatic differentiation of stem/progenitor cells. J. Cell. Physiol. 232: 2112-2124, 2017. © 2016 Wiley Periodicals, Inc.

Thrombectomy is a routine or common practice for treating organized portal vein thrombosis (PVT) during liver transplantation. However, this procedure is often performed in a blinded fashion and can result in insufficient thrombectomy or devastating consequences such as injury to the retropancreatic portal vein where prompt repair is very difficult. To overcome these drawbacks for blind thrombectomy, we herein describe a new technique that makes complex thrombectomy safe and easy under direct ultrasound vision. This procedure is readily available and highly reproducible and can be used as the standard procedure for treating extensive PVT.

The surgical indication for non-hypervascular hypointense nodules (NHVN) detected incidentally on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) for classical hepatocellular carcinoma (HCC) is unknown. Our aim is to clarify the long-term outcomes in patients with this finding. We reviewed the cases of 290 HCC patients, including 66 patients with NHVN, who underwent Gd-EOB-MRI prior to hepatectomy, between October 2008 and December 2017 at our center. We divided the patients into three groups: a no-NHVN group, a treated NHVN group, and an untreated NHVN group. There was no significant difference in (RFS) or overall survival (OS) between the no-NHVN and untreated NHVN groups (p = 0.103 and 0.103, respectively). There was no significant difference between these two groups after propensity score matching. Multivariate analyses showed that microscopic intrahepatic metastases and the size of the main classical HCC, the target tumor, were independent prognostic factors of overall survival, but the presence of non-hypervascular hypointense nodules was not. There was no significant difference in RFS or OS between the treated NHVN and untreated NHVN groups (p = 0.158 and 0.109, respectively). Non-hypervascular hypointense nodules detected incidentally on Gd-EOB-MRI associated with targeted hypervascular HCC did not reflect prognosis of HCC after hepatectomy. Surgical procedures for classical enhancing HCC may be performed even if non-hypervascular hypointense nodules adjacent to the targeted HCC cannot be removed completely.