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Introduction: TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited. Methods: A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro. Results: Patients were divided into TIGAR-positive (n = 80, 20.7%) and -negative (n = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ des-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (p < 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (p = 0.0450), larger number of CD68-positive macrophages (p = 0.0058), larger number of programmed death-ligand 1-positive cases (p = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (p = 0.0004). In vitro, TIGAR knockdown decreased cell motility and induced ferroptosis. TIGAR knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by TIGAR knockdown was inhibited by liproxstatin and baicalein treatment. The combination of TIGAR knockdown and lenvatinib further induced ferroptosis. Conclusion: High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.

Abstract Aim There is limited evidence regarding the feasibility of living‐donor liver transplantation (LDLT) for patients aged over 70. The aims of this study were to assess postoperative outcomes in elderly recipients and to ascertain the potential feasibility and acceptability of LDLT. Methods Data were collected from 762 recipients, including 26 in the elderly group (aged ≥70) and 736 in the younger group (aged

Abstract Background There is limited published information regarding the expression of mechanistic target of rapamycin (mTOR) in vessels that encapsulate tumor cluster (VETC)‐positive hepatocellular carcinoma (HCC). The mTOR inhibitor, everolimus, has been approved as an immunosuppressant for use in HCC patients after living donor liver transplantation (LDLT). Methods Using a database of 214 patients who underwent LDLT for HCC, we examined the mTOR protein and angiopoietin‐2 (Ang‐2) in VETC‐positive HCC by immunohistochemical staining. The presence of VETC and mTOR expression were evaluated in both primary and recurrent HCC lesions. Results Forty‐three of the 214 patients (20.1%) were VETC‐positive, and 29 of these 43 patients (67.4%) expressed mTOR. Relative Ang‐2 expression was significantly higher in the mTOR‐positive than in the mTOR‐negative group (p = 0.037). Thirty‐four of the 214 patients experienced HCC recurrence after LDLT; 20 of these were operable. The primary lesions of six of these 20 patients were VETC‐positive; five of these six patients also had VETC‐positive recurrent lesions (p

Abstract Background Liver transplantation is the definitive therapy for patients with decompensated cirrhosis. Marfan syndrome is a systemic inheritable connective tissue disease associated with fibrillin-1 gene mutations, which cause abnormalities in connective tissue. Vascular changes due to Marfan syndrome occur mostly in the main vessels due to the high amount of connective tissue within the vessel wall and the high pressure and blood flow to which they are exposed. The incidence of changes in visceral arteries is about 0.42% and usually presents with cystic medial necrosis. This report is the first deceased-donor liver transplantation with a donor with Marfan syndrome with a history of abdominal surgery. Case presentation A patient in his 50s underwent liver transplantation for decompensated alcoholic cirrhosis. The donor, a 50s male with Marfan syndrome, was diagnosed with brain-death due to a cerebral hemorrhage caused by a cerebral aneurysm. The donor’s clinical presentation as Marfan syndrome was aortic dissection, with multiple surgical procedures performed from the aortic root to the abdominal aorta. An intraoperative biopsy of the hepatic artery showed no abnormality, so this organ was considered appropriate. The surgery was completed without any problems of the arterial anastomosis. The patient’s postoperative course was uneventful, and he was transferred to a hospital for recuperation on the 18th postoperative day. One year after the surgery, the patient is still alive without any complications from the transplantation or arterial problems. Conclusions Even if the patient had a history of surgery for vascular anomalies extending to the abdominal aorta due to Marfan syndrome, the patient can be a donor for liver transplantation under appropriate judgment, including intraoperative biopsy.

Abstract Background and Aim Many recent studies have shown a relationship between various systemic diseases and the gut microbiota (GM), with the gut–liver axis receiving particular attention. In contrast, no report has comprehensively shown the effects of GM on the pathophysiology of patients undergoing living donor liver transplantation (LDLT). Method We enrolled 16 recipients who underwent LDLT for liver cirrhosis, and 17 donors constituted the reference group. We examined the differences in GM between recipients and donors. We also examined the relationships between GM, short‐chain fatty acids, and portal vein pressure (PVP) in recipients. Results There was no significant difference in alpha‐diversity between the recipients and donors, but there was variation in beta‐diversity among the recipients. The abundance of the phylum Bacteroidetes was significantly higher in recipients than in donors (P = 0.016), and it was positively correlated with PVP (r = 0.511, P = 0.043). Propionic acid, which is a component of short‐chain fatty acids, was positively correlated with PVP (r = 0.544, P = 0.0295), the phylum Bacteroidetes (r = 0.677, P = 0.004), and total bilirubin concentration (r = 0.501, P = 0.048). Propionic acid was negatively correlated with serum albumin concentration (r = −0.482, P = 0.043). Conclusion Our findings suggest relationships between fecal Bacteroidetes levels, propionic acid concentrations, and PVP in patients with liver cirrhosis undergoing LDLT.

Abstract 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.

Abstract The quality and size of liver grafts are critical factors that influence living‐donor liver transplantation (LDLT) function and safety. However, the biomarkers used for predicting graft quality are lacking. In this study, we sought to identify unique graft quality markers, aside from donor age, by using the livers of non‐human primates. Hepatic gene microarray expression data from young and elderly cynomolgus macaques revealed a total of 271 genes with significantly increased expression in the elderly. These candidate genes were then narrowed down to six through bioinformatics analyses. The expression patterns of these candidate genes in human donor liver tissues were subsequently examined. Importantly, we found that grafts exhibiting up‐regulated expression of these six candidate genes were associated with an increased incidence of liver graft failure. Multivariable analysis further revealed that up‐regulated expression of LRRN2 (encoding leucine‐rich repeat protein, neuronal 2) in donor liver tissue served as an independent risk factor for graft failure (odds ratio 4.50, confidence interval 2.08–9.72). Stratification based on graft expression of LRRN2 and donor age was also significantly associated with 6‐month graft survival rates. Conclusion: Up‐regulated LRRN2 expression of liver graft is significantly correlated with graft failure in LDLT. In addition, combination of graft LRRN2 expression and donor age may represent a promising marker for predicting LDLT graft quality.

Abstract 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.

IntroductionWe examined the neutralizing antibody production efficiency of the second and third severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine doses (2nd- and 3rd-dose) and neutralizing activity on mutant strains, including, the Ancestral, Beta and Omicron strains using green fluorescent protein-carrying recombinant SARS-CoV-2, in living-donor liver transplantation (LDLT) recipients.MethodsThe patients who were administered vaccines other than Pfizer- BioNTechBNT162b2 and who had coronavirus disease 2019 in this study period were excluded. We enrolled 154 LDLT recipients and 50 healthy controls.ResultThe median time were 21 days (between 1st and 2nd vaccination) and 244 days (between 2nd and 3rd vaccination). The median neutralizing antibody titer after 2nd-dose was lower in LDLT recipients than in controls (0.46 vs 1.00, P

Abstract 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.

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.

Abstract We examined the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incident cases, over 24 years. Data of 20,547 HCC patients (1996–2019) were analyzed in this prospective study. We divided the study period into four 6-yearly quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV + hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). The incident cases of HCC per quarter of the study period were 4311 (21.0%), 5505 (26.8%), 5776 (28.1%), and 4955 (24.1%), sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients

Abstract 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.

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

Abstract 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.

Abstract Aim Little evidence about whether to apply graft‐to‐recipient body weight ratio (GRWR) or graft weight to standard liver weight (GW/SLW) for graft selection has been published. The aim of the present study was to clarify the importance of the correct use of GRWR and GW/SLW for selecting graft according to the recipients’ physique in living donor liver transplantation (LDLT). Methods Data were collected for 694 recipients who underwent LDLT between 1997 and 2020. Results One of the marginal grafts meeting GW/SLW ≥ 35% but GRWR 30 kg/m2, the recipients with GRWR

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.

Abstract 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.

Abstract 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

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

Abstract 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

Abstract Background Neuroendocrine tumor (NET) is a relatively rare tumor and can develop in almost any organ, but primary mesenteric NETs are extremely rare. In addition, liver metastases from synchronous double cancer of neuroendocrine tumor graded as G1 and second primary malignancies (SPMs) have never been reported before. We herein report a case of multiple liver metastases from synchronous double cancer of NET (G1) at the ileal mesentery and rectal cancer. Case presentation A 66-year-old man was identified as having tumors in the rectum and the ileal mesentery by computed tomography (CT). He underwent laparoscopic low anterior resection for rectal cancer and biopsy of the ileal mesentery lymph node and was diagnosed with rectal cancer as pT3 pN1 cM0 (stage IIIB) and NET (G1) of the ileal mesentery. He received oxaliplatin and capecitabine (XELOX) for 3 months as adjuvant chemotherapy for rectal cancer. The NET (G1) of the ileal mesentery was low grade and had not expanded at follow-up. A CT scan performed 4 years after the surgery indicated multiple liver metastases. All the metastases had the same findings on CT and magnetic resonance imaging (MRI). Thus, the patient underwent the first stage of modified associating liver partition and portal vein ligation for staged hepatectomy (modified ALPPS), comprising partial hepatectomies of segments 3 and 4, ligation of the right branch of portal vein, and hepatic partition on the demarcation line, followed by the second stage of modified ALPPS (right lobectomy). Histopathological findings revealed that the 14 nodules were metastatic liver tumors of rectal cancer and the 2 nodules were liver metastases of the NET (G1). Conclusions Our findings suggest that synchronous double cancer of NET and gastrointestinal cancer may be indistinguishable in preoperative images. However, curative resection, precise pathological diagnosis, and adequately adjusted treatment may result in a better prognosis.

Abstract Background Mac‐2 binding protein glycosylation isomer (M2BPGi) is a novel serum glycomarker used to assess liver fibrosis. However, it has been reported that M2BPGi is likely to reflect other factors not limited to liver fibrosis. Methods We retrospectively analyzed 79 patients with liver tumors who underwent liver resection. M2BPGi was measured within 1 week before operation and almost 1 month after operation. We introduced a value termed the “ΔM2BPGi ratio” (=M2BPGiafter operation/M2BPGibefore operation), and analyzed factors that influenced the ΔM2BPGi ratio. Results The median value of the ΔM2BPGi ratio was 1.28 (range, 0.36‐5.68). In 64 patients (81.0%), the cutoff index values of M2BPGi were elevated approximately 1 month after operation, especially in patients who experienced post‐hepatectomy liver failure (PHLF). Multiple linear regression showed total Pringle time, PHLF grade ≥B, and preoperative value of creatinine were significant predictors of the ΔM2BPGi ratio. The mean values of the ΔM2BPGi ratio were 1.37 ± 0.07, 1.52 ± 0.22, and 2.94 ± 0.30 for PHLF grade 0, grade A, and grade B, respectively, resulting in statistically significant differences by the Kruskal‐Wallis test (P = 0.022). Conclusions Total Pringle time, PHLF grade ≥B, and preoperative creatinine significantly influenced the elevation of M2BPGi almost 1 month after liver resection. This study strongly affirms the previous suggestion that M2BPGi is likely to reflect other factors not limited to liver fibrosis.

Abstract Background Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that present most commonly at intrathoracic sites. SFTs of the liver are rare, with only a few having been reported in the English-language literature. We report a rare case of a hepatic SFT and literature review. Case presentation A 49-year-old woman underwent surgery for a cranial hemangiopericytoma two decades previously. She currently presented with malaise. Abdominal computed tomography (CT) showed a huge, sharply demarcated mass in the anterior segment of the liver. Tumor marker levels were within the normal range. Following central bisegmentectomy of the liver, histological examination of the specimen revealed that the tumor was composed of spindle and fibroblast-like cells with collagenous stroma. Immunohistochemically, the spindle cells were negative for CD34 but positive for STAT6. The NAB2–STAT6 fusion gene was detected by the reverse transcription polymerase chain reaction. A diagnosis of SFT was thus confirmed histopathologically and genetically. Conclusions The SFT of the liver is an uncommon finding. Because there are no specific imaging features, it is difficult to diagnose the hepatic SFT preoperatively. We consider that careful surgical resection and postoperative follow-up are necessary for hepatic SFTs.

Abstract Background Hepatic carcinosarcomas, which include both carcinomatous and sarcomatous elements, are uncommon in adults. Although carcinosarcoma in hepatocellular carcinoma is occasionally reported, carcinosarcoma in intrahepatic cholangiocarcinoma (ICC) is an extremely rare ICC variant. Few such cases have been reported in English and no large study of its clinicopathological features exists. Case presentation Here, we report a 60-year-old man with an asymptomatic hepatic B infection who developed hepatic carcinosarcoma from an otherwise normal liver. The 6.0-cm tumor was accidentally discovered by PET-CT in a cancer examination. Serum examinations showed no elevation of tumor markers. He underwent left and caudate lobectomy of the liver. The diagnosis of intrahepatic cholangiocarcinoma with sarcomatous stroma was based on thorough pathologic examination and immunohistochemical staining. The tumor exhibited adenocarcinomatous and sarcomatous components; the adenocarcinomatous element was positive for epithelial markers, the sarcomatous element was positive for mesenchymal markers, but negative for epithelial markers. The patient made an uneventful recovery after surgery. At present, 14 months after surgery, he remains well with no evidence of tumor recurrence. Conclusions We report an unusual case of hepatic carcinosarcoma (intrahepatic cholangiocarcinoma with sarcomatous stroma) and discuss the etiology and prognosis of this rare disease.

Objective. Metabolic alteration is widely considered as one of the hallmarks of cancer. Hepatocellular carcinoma (HCC) presents a unique pathological feature in which lipid accumulation is common in well-differentiated HCC and rare in poorly differentiated HCC; however, the underlying mechanism remains unclear. Methods. Tissue samples were obtained from 103 HCC patients who had undergone hepatic resection and 12 living donors of liver transplantation. We evaluated metabolic gene expressions in cancer tissues as well as background noncancer tissues and compared the expressions by the degree of cancer differentiation and by liver disease states. Besides, the metabolomics was evaluated and integrated to gene expressions in nonalcoholic steatohepatitis (NASH)-HCC model mice. Results. In cancer tissues, the expression levels of enzymes related to glycolysis, pentose phosphate pathway (PPP), and fatty acid (FA) synthesis were increased and that of tricarboxylic acid (TCA) cycle and β-oxidation were suppressed. Same metabolic alterations were observed in noncancer tissue as the liver disease progresses from healthy liver to chronic hepatitis, cirrhosis, and HCC. Similar alterations of metabolic genes were detected in NASH-HCC mice, which were consistent with the results of metabolomics. As the degree of cancer differentiation decreased, glycolysis and PPP were accelerated; however, FA synthesis and uptake were diminished. Conclusions. The metabolic alterations including glycolysis, PPP, TCA cycle, and β-oxidation became more prominent as liver disease progresses from normal, chronic hepatitis, cirrhosis, well-, moderately, and poorly differentiated HCC. FA synthesis and uptake were highest in well-differentiated HCC, which could explain the lipid accumulation.

Abstract 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.

Abstract Background Hepatic sclerosing hemangioma, a very rare benign tumor, is characterized by fibrosis and hyalinization occurring in association with degeneration of a hepatic cavernous hemangioma. Such atypical hemangiomas can be diagnosed incorrectly as primary or metastatic malignancies based on imaging characteristics. We present herein a rare case of giant and multiple hepatic sclerosing hemangiomas that are difficult to differentiate from hepatic malignancies and review the relevant literature. Case presentation The patient was a 48-year-old male who was found to have multiple hepatic tumors and a giant tumor (67 × 53 mm) superior to the inferior vena cave by an abdominal ultrasonography during a routine medical examination. The patient was referred to our hospital for further evaluations and diagnosis of the multiple hepatic tumors. Dynamic CT showed low-density tumors in the delayed phase suggestive of membrane-covered lesions. EOB-MRI demonstrated a mass with low-signal intensity mass on T1-weighted images and areas of high-signal intensity on T2-weighted images and a hypointense mass in the hepatobiliary phase, which showed high intensity on DWI-based ADC map. FDG-PET showed no accumulation of [18F]-FDG. A provisional diagnosis of multiple scirrhous hepatocellular carcinomas was made on the basis of these imaging studies, and caudate lobectomy of the liver and partial hepatectomy of S2 and S6 were performed. Histopathological examination showed that the tumors were composed of various sized irregularly dilated vessels with some blood thrombi, inflammatory cell infiltration, fibrous and hyalinized sclerotic or myxomatous stroma, resulting in a diagnosis of multiple hepatic sclerosing hemangiomas. Conclusions Differentiation of multiple sclerosing hemangiomas from other hepatic malignant tumors, such as intrahepatic cholangiocarcinoma, metastatic liver cancer, and scirrhous hepatocellular carcinoma characterized by abundant fibrous stroma, is difficult because the radiological findings are very similar. Inclusion of hepatic sclerosing hemangioma in the differential diagnosis of multiple liver tumors could enable optimal management; this possibility is important to consider before planning invasive therapies.

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.

Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.

AIM:The clinical impact of pathological classification based on architectural pattern in hepatocellular carcinoma (HCC) remains elusive in spite of its well-known and common feature. METHODS:The prognostic impact of pathological classification was examined with prospective database. Three hundred and eighty HCC patients who underwent curative hepatectomy as an initial treatment in Kumamoto University were enrolled as a test cohort. The outcome was confirmed with a validation cohort in Kyushu University. RESULTS:Macrotrabecular (macro-T) subtype (n = 38) and compact subtype (n = 43) showed similar biological and prognostic features. Both showed higher AFP level and worse overall survival than microrabecular (micro-T) subtype (n = 266). Multivariate analysis for overall survival revealed that DCP ≥ 40, multiple tumor and macro-T/compact subtype were associated with poor overall survival (risk ratio = 2.2, 1.6 and 1.6; p = 0.002, 0.020, and 0.047, respectively). Of note, 32% of macro-T/compact subtype showed early recurrence within 1 year, which showed substantially low (5%) 5 year overall survival, whereas 16% of micro-T/PG subtype did. Twenty-one percent of macro-T/compact subtype showed multiple intrahepatic metastases (≥ 4) or distant metastases, which resulted in non-curative treatment, whereas 5% of micro-T/PG subtype did. In validation cohort, macro-T/compact subtype was an independent predictor of worse overall survival. CONCLUSION:Macro-T/compact subtype is biologically discriminated from micro-T and PG subtypes due to its aggressive features and poor prognosis after curative treatment. Additional treatment with curative hepatectomy on Macro-T/compact subtype should be discussed because of high possibility of systemic residual cancer cell.

There are no reports of cystic liver infection after liver transplantation. Herein, we report a rare case of cystic liver graft infection after living donor liver transplantation (LDLT). The patient was a 24-year-old man with primary sclerosing cholangitis who underwent right lobe graft LDLT. Preoperative abdominal computed tomography (CT) revealed a liver cyst at segment 8 of the donor liver. Biliary reconstruction was performed with hepaticojejunostomy. The postoperative course was uneventful until the patient developed a high fever and abdominal pain 15 months after LDLT. Abdominal contrast CT revealed abscess formation. Percutaneous drainage of the cyst was performed and purulent liquid was drained. The fever gradually subsided after treatment. On follow-up CT, the size of the infected liver cyst was decreased. Clinicians should be aware of the potential for cystic liver infection when using grafts with liver cysts, particularly when biliary reconstruction is performed with hepaticojejunostomy.

We herein present the case of a 77-year-old man who had fever and right hypochondriac pain. He visited his doctor and underwent contrast computed tomography (CT), and he was suspected to have a liver abscess. He received an antibiotic treatment and his symptoms soon disappeared, but the tumor did not get smaller and its density on contrast CT image got stronger. He underwent biopsy and moderately differentiated hepatocellular carcinoma (HCC) was found. Extended left hepatic and caudate lobectomy was performed. Histological examination showed moderately differentiated HCC with narrowing and occlusion both in the arteries and portal veins associated with mild chronic inflammation. The mechanisms of spontaneous regression of HCC, such as immunological reactions and tumor hypoxia, have been proposed. In our case, histological examination showed the same findings. However, the mechanism is complex, and therefore further investigations are essential to elucidate it.

β-catenin signaling is a major oncogenic pathway in hepatocellular carcinoma (HCC). Since β-catenin phosphorylation by glycogen synthase kinase 3β (GSK3β) and casein kinase 1ε (CK1ε) results in its degradation, mutations affecting these phosphorylation sites cause β-catenin stabilization. However, the relevance of missense mutations in non-phosphorylation sites in exon 3 remains unclear. The current study explores significance of such mutations in addition to addressing the clinical and biological implications of β-catenin activation in human HCC.Gene alteration in exon3 of CTNNB1, gene expression of β-catenin targets such as glutamate synthetase (GS), axin2, lect2 and regucalcin (RGN), and protein expression of β-catenin were examined in 125 human HCC tissues.Sixteen patients (12.8%) showed conventional missense mutations affecting codons 33, 37, 41, and 45. Fifteen additional patients (12.0%) had other missense mutations in codon 32, 34, and 35. Induction of exon3 mutation caused described β-catenin target gene upregulation in HCC cell line. Interestingly, conventional and non-phosphorylation site mutations were equally associated with upregulation of β-catenin target genes. Nuclear localization of β-catenin was associated with poor overall survival (p = 0.0461). Of these patients with nuclear β-catenin localization, loss of described β-catenin target gene upregulation showed significant poorer overall survival than others (p = 0.0001).This study suggests that both conventional and other missense mutations in exon 3 of CTNNB1 lead to β-catenin activation in human HCC. Additionally, the mechanism of nuclear β-catenin localization without upregulation of described β-catenin target genes might be of clinical importance depending on distinct mechanism.