Impact of TP53-induced glycolysis and apoptosis regulator on malignant activity and resistance to ferroptosis in intrahepatic cholangiocarcinoma.

TP53-induced glycolysis and apoptosis regulator (TIGAR) is an important gene that encodes a regulatory enzyme of glycolysis and reactive oxygen species (ROS) detoxification and is associated with worse prognosis in various cancers. Ferroptosis is a recently identified type of programmed cell death that is triggered by iron-dependent lipid peroxidation. There are no reports on the prognostic impact of TIGAR on intrahepatic cholangiocarcinoma (ICC), and its role in ferroptosis is unclear. Ninety ICC patients who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. The regulation of malignant activity by TIGAR and the association between ferroptosis and TIGAR were investigated in vitro. Twenty-two (24.4%) patients were categorized into TIGAR-high and -low groups by immunohistochemical staining. There were no noticeable differences in background factors between the two groups, but TIGAR positivity was an independent prognostic factor in disease-free survival (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.04-3.85, p = 0.0378) and overall survival (HR, 2.10; 95% CI, 1.03-4.30, p = 0.00422) in a multivariate analysis. In vitro, TIGAR knockdown (KD) decreased cell motility (cell proliferation/migration/invasion/colony-forming capabilities) and elevated ROS and lipid peroxidation. This indicated that TIGAR KD induced ferroptosis. TIGAR KD-induced ferroptosis was suppressed using liproxstatin. TIGAR KD decreased the expression of glutathione peroxidase 4, known as factor-suppressing ferroptosis. The combination of TIGAR KD with cisplatin significantly induced more ferroptosis. In conclusion, TIGAR is associated with poor outcomes in ICC patients and resistance to ferroptosis.

Impact of ACSL4 on the prognosis of hepatocellular carcinoma: Association with cancer-associated fibroblasts and the tumour immune microenvironment.

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

Impact of albumin-lymphocyte-platelet-C-reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2-related factor 2.

AIM: To investigate the prognostic value of the preoperative albumin-lymphocyte-platelet-C-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated the relationship between the ALPC index and the phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels. METHODS: Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival and overall survival in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC. RESULTS: A high preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage, and low rate of microscopic intrahepatic metastasis in the training dataset. A high preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. A higher preoperative ALPC index was an independent predictor of longer recurrence-free survival and overall survival in the training and testing datasets. A high ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells. CONCLUSIONS: We showed that a high ALPC index was an independent prognostic factor for patients with HCC undergoing curative hepatic resection.

Impact of electrical muscle stimulation on serum myostatin level and maintenance of skeletal muscle mass in patients undergoing living-donor liver transplantation: Single-center controlled trial.

AIM: Sarcopenia is reportedly associated with a poor prognosis in patients who undergo living-donor liver transplantation (LDLT), most of whom are not able to tolerate muscle strengthening exercise training. Myostatin is one of the myokines and a negative regulator of skeletal muscle growth. The clinical feasibility of an electrical muscle stimulation (EMS) system, which exercises muscle automatically by direct electrical stimulation, has been reported. In this study, we aimed to determine the effect of perioperative application of SIXPAD, which is a type of EMS system, with reference to the serum myostatin and sarcopenia in LDLT patients. METHOD: Thirty patients scheduled for LDLT were divided into a SIXPAD group (n = 16) and a control group (n = 14). In the SIXPAD group, EMS was applied to the thighs twice daily. The serum myostatin was measured in samples obtained before use of SIXPAD and immediately before LDLT. The psoas muscle index (PMI) at the level of the third lumbar vertebra and the quadriceps muscle area were compared on computed tomography images before use of SIXPAD and 1 month after LDLT. RESULTS: The preoperative serum myostatin was found to be higher in LDLT patients than in healthy volunteers and EMS significantly reduced the serum myostatin. Electrical muscle stimulation prevented a postoperative reduction not only in the area of the quadriceps muscles but also in the PMI despite direct stimulation of the thigh muscles. CONCLUSION: Stimulation of muscles by EMS decreases the serum myostatin and helps to maintain skeletal muscle in patients who have undergone LDLT.

Pretreatment eosinophil count predicts response to atezolizumab plus bevacizumab therapy in patients with hepatocellular carcinoma.

AIM: Pretreatment peripheral blood markers have value in predicting the treatment outcome of various cancers. In particular, the eosinophil count has recently gained attention. However, no study has reported the influence of the pretreatment eosinophil count on the outcomes of atezolizumab plus bevacizumab (ATZ/BEV), which is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (u-HCC). METHODS: We enrolled 114 patients with u-HCC treated with ATZ/BEV (n = 48) or lenvatinib (n = 66). The patients receiving ATZ/BEV or lenvatinib were divided into two groups by calculating the cutoff value of the pretreatment eosinophil count. The groups were compared regarding the clinicopathological characteristics, outcomes, and incidence of adverse events (AEs). RESULTS: Twenty-three of 48 patients (47.9%) who received ATZ/BEV therapy were categorized as the ATZ/BEV-eosinophil-high group, which had better responses than the ATZ/BEV-eosinophil-low group (P = 0.0090). Kaplan-Meier curves revealed a trend toward significantly better progression-free survival (PFS) in the ATZ/BEV-eosinophil-high group than the ATZ/BEV-eosinophil-low group (the median PFS: 4.7 months in the ATZ/BEV-eosinophil-low group vs 12.6 months in the ATZ/BEV-eosinophil-high group; P = 0.0064). Multivariate analysis showed that a low eosinophil count was an independent risk factor for worse PFS after ATZ/BEV therapy (P = 0.0424, hazard ratio: 2.24, 95% confidence interval: 1.02-4.89). AEs (≥ grade 3) were significantly more likely to occur in the ATZ/BEV-eosinophil-high group (P = 0.0285). The outcomes did not significantly differ between the LEN-eosinophil-high group and the LEN-eosinophil-low group. CONCLUSION: A high pretreatment eosinophil count predicted a better response to ATZ/BEV therapy for u-HCC and was associated with the incidence of AEs (≥ grade 3).

Venous reconstruction using a round ligament-covered prosthetic vascular graft in right­lobe living­donor liver transplantation: a technical report.

PURPOSE: To evaluate the short term-outcomes of venous reconstruction using a round ligament-covered prosthetic vascular graft and assess its effectiveness in the prevention of prosthetic vascular graft migration in right­lobe living donor liver transplantation (LDLT). METHODS AND RESULTS: Thirty patients underwent reconstruction of the middle hepatic vein (MHV) tributaries during right lobe LDLT between January, 2021 and October, 2022. These patients were divided into the autologous vascular graft group (A group, n = 24) and the round ligament-covered prosthetic vascular graft group (RP group, n = 6). The computed tomography (CT) density ratio of the drainage area in the posterior segment of patent grafts was significantly higher in the RP group than in the A group (0.91 vs. 1.06, p = 0.0025). However, the patency rates of reconstructed MHV tributaries in the A and RP groups were 61% and 67%, respectively, with no significant difference between the groups (p = 0.72). Prosthetic vascular graft migration did not occur in the RP group. CONCLUSION: Venous reconstruction using round ligament-covered prosthetic vascular grafts is a feasible and simple method to prevent prosthetic vascular graft migration in right-lobe LDLT.

Treatment strategy for hepatocellular carcinoma recurrence in the transplant era: Focusing on the Japan criteria.

PURPOSE: To clarify the Japan criteria (JC), as proposed in 2019, in order to identify the most appropriate treatment methods for hepatocellular carcinoma (HCC) recurrence and assess the feasibility of pre-living donor liver transplantation (LDLT) downstaging within these criteria. METHODS: The subjects of this study were 169 LDLT patients with HCC recurrence. We performed univariate and multivariate analyses of the factors contributing to HCC recurrence after LDLT and clarified the post-transplant outcomes of pre-LDLT downstaging. RESULTS: Univariate and multivariate analysis identified beyond the JC (p = 0.0018) and a neutrophil-to-lymphocyte ratio > 2.01 (p = 0.029) as independent risk factors. Patients who met the JC had significantly higher recurrence-free and overall survival rates after LDLT (p < 0.0001) than those who did not (p = 0.0002). The post-transplant outcomes of patients within the JC after downstaging were significantly better than those of patients beyond the JC (p = 0.034) and equivalent to those within the JC without downstaging. CONCLUSION: Even for HCC recurrence, the JC could play an important role in deciding on the best treatment strategy, and downstaging within the JC had good post-transplant outcomes.

Prognostic significance for recurrence of fibroblast growth factor receptor 2 in intrahepatic cholangiocarcinoma patients undergoing curative hepatic resection.

AIMS: The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor-infiltrating lymphocytes (TILs). METHODS AND RESULTS: We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n = 18) and negative (n = 74) FGFR2 groups. The FGFR2-positive group contained more men (p < 0.0001) and had lower serum albumin (p = 0.0355) and higher carcinoembryonic antigen (p = 0.0099). Furthermore, multivariable analyses revealed that the FGFR2-positive group had worse disease-free survival (DFS) (p = 0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5 cm) (p = 0.0011), tumor localization (perihilar type) (p = 0.0180), and FGFR2 positivity (p = 0.0029). There was no significant difference in TILs count between the two groups. CONCLUSION: We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC.

The hemoglobin, albumin, lymphocyte, and platelet score is a prognostic factor for Child-Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.

AIM: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score reflects the immune system and the nutritional status of patients, and prognosis in various cancers. However, the HALP score in hepatocellular carcinoma has not been reported. METHODS: Data were analyzed retrospectively from Child-Pugh A patients undergoing hepatic resection for single hepatocellular carcinoma ≤5 cm. For cross-validation, patients were divided into the training (332 patients) and validation cohort (210 patients). In the training cohort, we divided patients into two groups by appropriate cut-off value of the HALP score, and univariable and multivariable analyses were conducted for disease-free and overall survival (OS) between two groups. In the validation cohort, we examined OS by Kaplan-Meier analysis in the same cut-off value of the HALP score in the training cohort. RESULTS: The HALP-low group was significantly older (p = 0.0003), had fewer hepatitis B surface antigen-positive patients (p = 0.0369), higher prothrombin time (p = 0.0141), lower fibrosis-4 index (p = 0.0206), bigger maximum tumor size (p = 0.0196), and less histological liver fibrosis (p = 0.0077). Multivariate analysis showed that the independent prognostic factors for disease-free survival were fibrosis-4 index ≥2.67 (p = 0.0008), simple nodular type with extranodular growth or confluent multinodular type (p = 0.0221), and intrahepatic metastasis (p = 0.0233), and that for OS were fibrosis-4 index ≥2.67 (p = 0.0020), HALP ≤45.6 (p = 0.0228), and poor differentiation (p = 0.0305). In the validation cohort, Kaplan-Meier analysis revealed the trend toward significantly impaired OS (p = 0.0220) in the HALP-low group. CONCLUSION: We showed that a low HALP score is the independent prognostic factor for Child-Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.

Preoperative HALP score is a prognostic factor for intrahepatic cholangiocarcinoma patients undergoing curative hepatic resection: association with sarcopenia and immune microenvironment.

BACKGROUND: The hemoglobin-albumin-lymphocyte-platelet (HALP) score is a combination index that assesses nutritional status and systemic inflammatory response and is reported to predict prognosis in several cancer types. However, researches about the usefulness of the HALP score in intrahepatic cholangiocarcinoma (ICC) are limited. METHODS: This was a single-center, retrospective study of 95 patients who underwent surgical resection for ICC between 1998 and 2018. We divided patients into two groups by calculating the cutoff value of the HALP score and examined clinicopathological characteristics, prognosis, and sarcopenia. Tumor-infiltrating lymphocytes (TILs), CD8 + TILs, and FOXP3 + TILs were evaluated by immunohistochemical staining of resected tumors. RESULTS: Of 95 patients, 22 were HALP-low. The HALP-low group had significantly lower hemoglobin (p = 0.0007), lower albumin (p = 0.0013), higher platelet counts (p < 0.0001), fewer lymphocytes (p < 0.0001), higher CA19-9 levels (p = 0.0431), and more lymph node metastasis (p = 0.0013). Multivariate analysis revealed that the independent prognostic factors for disease-free survival were maximum tumor size (≥ 5.0 cm) (p = 0.0033), microvascular invasion (p = 0.0108), and HALP score (≤ 25.2) (p = 0.0349), and that factors for overall survival were lymph node metastasis (p = 0.0020) and HALP score (≤ 25.2) (p = 0.0014). The HALP-low group contained significantly more patients with sarcopenia (p = 0.0015). Immunohistochemistry showed that counts of CD8 + TILs were significantly lower in the HALP-low group (p = 0.0075). CONCLUSIONS: We demonstrated that low HALP score is an independent prognostic factor for ICC patients undergoing curative hepatic resection and is associated with sarcopenia and the immune microenvironment.

Hand-assisted laparoscopic splenectomy and gastropancreatic fold division: a less-invasive simplified technique of Hassab's procedure for refractory esophagogastric varices.

Some patients with refractory esophagogastric varices require surgery, such as gastric devascularization and splenectomy (Hassab's procedure). However, these patients are at risk of perioperative morbidities when undergoing devascularization to develop collateral vessels. We performed a more simplified procedure, splenectomy, and en bloc gastropancreatic fold division (GPFD) with hand-assisted laparoscopic surgery. Four patients with refractory esophagogastric varices and portal hypertension underwent splenectomy and GPFD. We reviewed patients' perioperative laboratory and morphological data, operative variables, and postoperative outcomes. Esophagogastric varices improved in 3 (75%) of the 4 patients. In one patient, esophageal varices (F1RC0) were observed 3 years after surgery, but they required no treatment and only received follow-up. Treatment with splenectomy and GPFD is not only less invasive than Hassab's procedure but also provides effective outcomes for refractory esophagogastric varices.

Simultaneous splenectomy improves outcomes after adult living donor liver transplantation.

BACKGROUND & AIMS: Small-for-size graft (SFSG) syndrome is a major cause of graft loss after living donor liver transplantation (LDLT). Splenectomy (Spx) is an option to prevent this catastrophic complication, but its effect remains controversial. Herein, we aimed to elucidate the effect of simultaneous Spx on graft function and long-term outcomes after LDLT. METHODS: Three hundred and twenty patients were divided into 2 groups: those undergoing (n = 258) and those not undergoing (n = 62) simultaneous Spx. To overcome selection bias, propensity score matching (PSM) was performed (n = 50 in each group). RESULTS: Before PSM, recipients undergoing simultaneous Spx showed better graft function on post-operative day (POD) 7 and 14, as well as lower sepsis frequency within 6 months after LDLT and better graft survival rates compared to those not undergoing Spx. After PSM, compared to patients not undergoing Spx, those undergoing Spx had a lower frequency of early graft dysfunction on POD 7 (p = 0.04); a lower frequency of SFSG syndrome (p = 0.01), lower serum total bilirubin levels (p = 0.001), and lower international normalized ratio (p = 0.004) on POD 14; lower sepsis frequency within 6 months after LDLT (p = 0.02), and better graft survival rates (p = 0.04). Univariate analysis revealed that not undergoing Spx (hazard ratio 3.06; 95% CI 1.07-11.0; p = 0.037) was the only risk factor for graft loss after LDLT. CONCLUSIONS: Simultaneous Spx may prevent SFSG syndrome and is a predictive factor for graft survival after LDLT. Simultaneous Spx is recommended when a small graft (≤35% of standard liver weight) is predicted preoperatively, or for patients with portal hypertension or high portal pressure (above 20 mmHg) after reperfusion in LDLT. LAY SUMMARY: Living donor liver transplantation (LDLT) for patients with acute or chronic liver failure is an alternative to overcome the deceased donor shortage. The potential mismatch between graft and body size is a problem that needs to be solved for LDLT recipients. Herein, we evaluated the impact of simultaneous splenectomy and showed that it was associated with favorable outcomes in patients undergoing LDLT.

Impact of Immune Response on Outcomes in Hepatocellular Carcinoma: Association With Vascular Formation.

BACKGROUND AND AIMS: We investigated the prognostic value of programmed death ligand 1 (PD-L1) expression, tumor-infiltrating CD8-positive T-cell status, and their combination in hepatocellular carcinoma (HCC). Their association with PD-L1 expression and vascular formation was further explored. APPROACH AND RESULTS: Using a database of 387 patients who underwent hepatic resection for HCC, immunohistochemical staining of PD-L1, CD8, and CD34 was performed. Additionally, we undertook an enzyme-linked immunosorbent assay for soluble PD-L1. Compared with patients with HCC and PD-L1-negative expression (n = 311), patients with HCC and PD-L1-positive expression (n = 76) showed significantly worse overall survival (OS; multivariate hazard ratio, 2.502; 95% confidence interval [CI], 1.716-3.649; P < 0.0001). The presence of tumor-infiltrating CD8-positive T cells was significantly correlated with longer OS (multivariate hazard ratio, 0.383; 95% CI, 0.274-0.537; P < 0.0001). Stratification based on PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status was also significantly associated with OS (log-rank, P < 0.0001). HCC with PD-L1-positive expression was significantly correlated with positivity for vessels that encapsulated tumor clusters. Serum PD-L1 levels were significantly higher in the group of patients who had PD-L1-positive expression than in the group of patients who had PD-L1-negative expression (P = 0.0158). CONCLUSIONS: PD-L1 expression in cancer cells was associated with a poor clinical outcome and vascular formation in patients with HCC. Additionally, the combination of PD-L1 expression with tumor-infiltrating CD8-positive T-cell status enabled further classification of patients based on their clinical outcome. Thus, PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status might serve as predictive tissue biomarkers.

Impact of Capicua on Pancreatic Cancer Progression.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Surgical Indications for Hepatocellular Carcinoma with Non-hypervascular Hypointense Nodules Detected by Gd-EOB-DTPA-Enhanced MRI.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Mitochondrial expression of the DNA repair enzyme OGG1 improves the prognosis of pancreatic ductal adenocarcinoma.

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.

Impact of middle hepatic artery reconstruction after living donor liver transplantation using the left lobe.

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.

Prognostic nutritional index is superior as a predictor of prognosis among various inflammation-based prognostic scores in patients with hepatocellular carcinoma after curative resection.

AIM: There is increasing evidence that inflammation-based prognostic scores are stage-independent predictors of poor outcome in patients with hepatocellular carcinoma (HCC). However, these findings were observed in a small-sized study comparing the prognostic value of these scores for patients after curative resection for HCC. METHODS: We retrospectively analyzed 717 consecutive patients with HCC who underwent curative liver resection at Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital. Clinicopathological variables including preoperative inflammation-based prognostic scores, such as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, Controlling Nutritional Status score, prognostic nutritional index (PNI), and Glasgow Prognostic Score were analyzed. The prognostic value of these scores was compared by the time-dependent receiver operating characteristic curve analyses. RESULTS: The integrate area under the curve of PNI, Controlling Nutritional Status score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and Glasgow Prognostic Score were 0.6751, 0.6435, 0.5845, 0.5276, and 0.5351 for overall survival (OS), respectively, and 0.5955, 0.5694, 0.4692, 0.4873, and 0.5272 for disease-free survival, respectively. Multivariate analyses for prognosis factor in HCC patients showed that PNI was an independent predictor of both OS (HR 0.91, P < 0.001) and disease-free survival (HR 0.94, P < 0.001). When the patients were divided into high and low PNI groups, the patients in the low PNI group had significant poorer OS (P < 0.001) and disease-free survival (P < 0.001), even after background factors were matched between these two groups. CONCLUSIONS: PNI is superior to Controlling Nutritional Status score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, or Glasgow Prognostic Score as a predictor of OS and recurrence-free survival in patients with HCC who underwent curative hepatic resection.

The Effect of Prone Positioning as Postoperative Physiotherapy to Prevent Atelectasis After Hepatectomy.

BACKGROUND: The incidences of postoperative pulmonary complications (PPCs) such as atelectasis, pneumonia and pleural effusion after major surgery range from <1 to 23%. Atelectasis after abdominal surgery increases the duration of hospitalization and short-term mortality rate, but there are few reports about atelectasis after hepatectomy. The effectiveness of prone position drainage as physiotherapy has been reported, but it remains unclarified whether prone positioning prevents atelectasis after hepatectomy. This study aimed to evaluate the effect of the prone position on the incidence of atelectasis after hepatectomy. METHODS: We retrospectively analyzed the incidence of PPCs after hepatectomy at a single center. Patients were divided into two cohorts. The earlier cohort (n = 165) underwent hepatectomy between January 2016 and March 2018 and was analyzed to identify the risk factors for atelectasis and short-term outcomes; the later cohort (n = 51) underwent hepatectomy between April 2018 and March 2019 and underwent prone position drainage in addition to regular mobilization postoperatively. The incidences of PPCs were compared between the two cohorts. RESULTS: Independent risk factors for atelectasis were anesthetic duration (P = 0.016), operation time (P = 0.046) and open surgery (P = 0.011). The incidence of atelectasis was significantly lower in the later cohort (9.8%) than the earlier cohort (34.5%, P < 0.001). Moreover, the later cohort had a significantly shorter duration of oxygen support (P < 0.001) and postoperative hospitalization (P < 0.001). After propensity score-matching, the incidence of atelectasis remained significantly lower in the later cohort (P = 0.027). CONCLUSION: Prone position drainage may decrease the incidence of atelectasis after hepatectomy and improve the short-term outcomes.

Prognostic Impact of Osteopenia in Patients Who Underwent Living Donor Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.001). Besides, the calibration plot for the 5-year overall survival using nomogram was predicted very well (C-index 0.746). CONCLUSIONS: Preoperative osteopenia was independently associated with post-LDLT mortality among patients with HCC. Moreover, risk score and nomogram with calibration curve were developed to confirm the clinical usefulness of osteopenia for post-LDLT patients.