Immunohistochemical expression of NRF2 is correlated with the magnitude of inflammation and fibrosis in chronic liver disease.

BACKGROUND: The nuclear factor E2-related factor 2-Kelch-like Ech-associated protein (NRF2-KEAP1) pathway is a major cellular defense mechanism against oxidative stress. However, the role of NRF2-KEAP1 signaling in the development of chronic liver disease remains unclear. METHODS: Clinical liver specimens from 50 hepatocellular carcinoma (HCC) developed from non-alcoholic steatohepatitis (NASH), 49 HCCs developed from chronic viral hepatitis C (CHc), and 48 liver metastases of colorectal cancer (CRC) from both tumorous and non-tumorous areas were collected during hepatic resection surgery. They were evaluated by immunohistochemical analyses of hematoxylin-eosin, Masson's trichrome, NRF2, and KEAP1, and compared with clinicopathological information. RESULTS: Hepatic inflammation and fibrosis were more severe in the low-intensity NRF2 group than in the high-intensity NRF2 group both between CRC and NASH (Low vs. High: inflammation; p = 0.003, fibrosis; p = 0.014), and between CRC and CHc (Low vs. High: inflammation; p = 0.031, fibrosis; p = 0.011), which could indicate that NRF2 expression in cytosol of hepatocytes was inversely correlated with liver inflammation and fibrosis in non-tumorous areas. The dense staining of NRF2 in the nuclei of non-tumor hepatocytes positively correlated with liver inflammation (CRC and NASH; R = 0.451, p < 0.001, CRC and CHc; R = 0.502, p < 0.001) and fibrosis (CRC and NASH; R = 0.566, p < 0.001, CRC and CHc; R = 0.548, p < 0.001) in both NASH and CHc, and was inversely correlated with hepatic spare ability features such as platelet count (R = -0.253, p = 0.002) and prothrombin time (R = -0.206, p = 0.012). However, KEAP1 expression was not correlated with NRF2 expression levels and nuclear staining intensity. CONCLUSIONS: Nuclear translocation of NRF2 was correlated with the magnitude of liver inflammation and fibrosis in chronic liver disease. These results suggest that NRF2 plays a protective role in the development of chronic liver diseases such as NASH and CHc.

Conversion surgery for hepatocellular carcinoma after tyrosine kinase inhibitor treatment.

Background and Aim: Conversion surgery (CS), which aims to cure after systematic therapy, is only scarcely reported in the field of hepatocellular carcinoma (HCC). However, advancements in systemic therapy for HCC are expected to increase the candidates eligible for CS because of the higher response rate. The aim of this study was to clarify the characteristics of patients who underwent CS after tyrosine kinase inhibitor (TKI) therapy. Methods: In all, 364 patients who were treated with first-line sorafenib (SOR; n = 292) and lenvatinib (LEN; n = 72) from July 2009 to October 2020 were retrospectively enrolled. The endpoint of this analysis was overall survival (OS), and factors associated with CS are revealed. Results: Six patients underwent CS after TKI therapy, and of these four (1.4%) and two (2.7%) patients received SOR and LEN, respectively. At baseline, patients who underwent CS were significantly younger (median 52 [range, 46-83] years of age, P = 0.019), and their etiology included viral hepatitis, especially hepatitis B virus (HBV) (P = 0.049). Improvements or maintenance of preoperative modified albumin-bilirubin grade from baseline were observed in five (83.3%) patients, and partial radiologic response was observed in four (66.7%) patients. The median OS and 3-year survival rate of patients treated with CS were "not reached" and 80.0%, respectively. Conclusion: The patients who underwent CS after TKI therapy for HCC experienced long survival, were relatively young, and exhibited radiologic response to TKIs, and their liver function was either maintained or improved. Therefore, CS may lead to a better prognosis in patients with advanced HCC.

Intrahepatic Cholangiocarcinoma With Neither Intrahepatic Metastasis Nor Lymph Node Metastasis Is the Optimal Indication for Hepatectomy With Adjuvant Therapy.

Background/Aim: The optimal indication of hepatectomy with adjuvant therapy for intrahepatic cholangiocarcinoma (ICC) has not been evaluated in detail. Patients and Methods: We retrospectively studied 224 patients with ICC who underwent hepatectomy between 2000 and 2019. Prognostic factors for overall survival (OS) were evaluated by univariate and multivariate analysis. A total of 127 patients were treated with adjuvant therapy (62 patients with chemotherapy and 65 patients with immunotherapy) after hepatectomy, and 97 patients were treated with hepatectomy alone. Results: Intrahepatic metastasis (IM), lymph node metastasis (LNM) of ICC, adjuvant chemotherapy, and adjuvant immunotherapy were significant prognostic factors for OS on multivariate analysis. In 127 patients with neither IM nor LNM, the 5-year OS rate was significantly higher in 36 patients with adjuvant chemotherapy (81%) and in 34 patients with adjuvant immunotherapy (68%) than in 57 patients with hepatectomy alone (45%). Conclusion: The absence of IM or LNM is the optimal indication for hepatectomy with adjuvant therapy in patients with ICC.

Improved Mortality, Morbidity, and Long-Term Outcome After Anatomical Hepatectomy With the Glissonean Pedicle Approach in Patients With Hepatocellular Carcinoma: 30 Years' Experience at a Single Institute.

OBJECTIVE: We evaluated the morbidity and mortality after anatomical hepatectomy with the Glissonean pedicle approach, and long-term outcomes in relation to the morbidity in patients with hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: The mortality, morbidity, and long-term outcomes were evaluated retrospectively. METHODS: A total of 1953 patients with HCC underwent various anatomical hepatectomies with the Glissonean pedicle approach between 1985 and 2014. The mortality (30-day and 90-day) and morbidity (Clavien-Dindo class Ilia or higher) were evaluated among six 5-year eras (1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, 2010-2014). RESULTS: A total of 460 patients (24%) showed morbidity, and the overall 30-day and 90-day mortality rates were 1.8% and 3.3%, respectively. The 30-day (3.9%, 3.0%, 1.8%, 1.3%, 0.3%, 0.5%: P = 0.0074) and 90-day mortality (6.0%, 4.3%, 3.8%, 2.8%, 2.2%, 1.4%: P = 0.0445) significantly improved over the eras. Blood loss >2 L (odds ratio: 11.808, P = 0.0244) was an independent risk factor for 30-day mortality, and blood loss >2 L (odds ratio: 4.046, P = 0.0271) and bile leakage (odds ratio: 2.122, P = 0.0078) were independent risk factors for 90-day mortality on multivariate analysis. Morbidity was significant independent prognostic factors for overall survival (relative risk: 2.129, P < 0.0001) and recurrence-free survival (relative risk: 1.299, P < 0.0001) in patients with HCC. CONCLUSIONS: Anatomical hepatectomy with the Glissonean pedicle approach was achieved safely in patients with HCC. For more safety and longer survival, blood loss, bile leakage, and morbidity should be reduced. Longterm outcomes after anatomical hepatectomy with the Glissonean pedicle approach in patients with HCC have been improved over 30 years with gradually less mortality and morbidity due to decreases in blood loss >2 L and bile leakage.

Debulking of giant liver hemangiomas with severe symptoms: a case report.

BACKGROUND: There are no previous reports of debulking of giant liver hemangioma. This report describes our experience with debulking surgery for a patient with bilateral giant liver hemangiomas with severe symptoms. CASE PRESENTATION: We present a case of symptomatic giant liver hemangioma in a 41-year-old woman. She presented with abdominal pain and fullness at a local hospital and underwent trans-arterial embolization (TAE). TAE was not effective, and she was not able to walk a long distance. Giant liver hemangiomas, 30 cm and 15 cm in diameter, were located in the right liver and in the left lateral section, respectively, and normal liver parenchyma with tiny liver hemangiomas was present in segment 4. The liver function was normal. However, right hemi-hepatectomy with left lateral sectionectomy was considered to be risky according to the 3DCT volumetry. Therefore, we performed right hemi-hepatectomy in order to reduce her symptoms. The postoperative course was uneventful, and she was discharged on the 14th day after surgery. The abdominal fullness and abdominal pain disappeared immediately after surgery. The hemangiomas in the remnant liver, 15 cm in diameter, showed no change, and she is well without symptoms 7 years after surgery. CONCLUSIONS: Debulking surgery is one of the options for bilateral giant liver hemangiomas with severe symptoms.

Clinical and anthropometric characteristics of non-obese non-alcoholic fatty liver disease subjects in Japan.

AIM: The underlying mechanism of non-obese non-alcoholic fatty liver disease (NAFLD) has not been fully elucidated. We classified patients with NAFLD by sex and body mass index and compared their clinical features to clarify the background pathophysiology of non-obese NAFLD. METHODS: A total of 404 patients with NAFLD were divided according to their body mass index (<25 [non-obese], 25 to <30 [obese], and ≥30 [severe obese]), and were further compared with 253 patients without obesity and NAFLD (non-NAFLD). RESULTS: The proportion of the individuals with non-obese NAFLD was 25.7% in men and 27.6% in women. The male and female non-obese NAFLD groups had lower skeletal muscle mass and muscle strength than the obese NAFLD groups. The visceral fat area, although low, was ≥100 cm2 in 59.3% of men and 43.8% of women. An increase in liver fat accumulation, hepatic fibrosis, homeostasis model assessment of insulin resistance, and leptin levels was modest in the non-obese NAFLD group compared with a marked increase in the obese NAFLD groups. The muscle mass of the non-obese NAFLD group was similar to that of the non-NAFLD group, but muscle steatosis was particularly common among women. Multivariate analysis revealed that the factors contributing to increased liver fat accumulation in the non-obese NAFLD group were visceral fat area, HbA1c, myostatin, and leptin. CONCLUSIONS: In patients with non-obese NAFLD, a sex difference was observed in the clinical features. In addition to increased visceral fat, decreased muscle mass and muscle strength, muscle atrophy (presarcopenia), and impaired glucose tolerance were considered to be important pathophysiological factors.

Gender difference in development of steatohepatitis in p62/Sqstm1 and Nrf2 double-knockout mice.

Gender and menopause influence the severity and development manner of nonalcoholic steatohepatitis (NASH). Male p62/Sqstm1 and nuclear factor E2-related factor-2 (p62 and Nrf2) double-knockout (DKO) mice exhibit severe steatohepatitis caused by hyperphagia-induced obesity, overload of lipopolysaccharide (LPS) into the liver, and potentiation of the inflammatory response in Kupffer cells. However, the pathogenetic phenotype of steatohepatitis in female DKO mice remains unknown. Phenotypic changes of steatohepatitis in DKO mice were compared in terms of gender differences. Compared with DKO male mice, DKO female mice exhibited later onset of steatohepatitis with obesity after 30 weeks of age, as well as milder severity of hepatic inflammation and fibrosis. Serum estradiol was higher in female than male mice, with levels increasing up to 30 weeks of age before decreasing until 50 weeks of age (corresponding to the post-menopausal period). Fecal and serum LPS were lower in female mice than male mice, and inflammatory signaling in the liver was attenuated in female compared with male mice. Correlating with LPS levels, the composition of intestinal microbiota in female mice was different from male mice. Gender differences were observed for the development of steatohepatitis in DKO mice. Low-grade inflammatory hit in the liver under in vivo conditions of high estradiol may be attributable to the milder pathological features of steatohepatitis in female mice.

A patient with post-Fontan operation underwent left hepatectomy and caudate lobectomy for hepatocellular carcinoma: a case report.

BACKGROUND: The Fontan procedure has been widely accepted for children with single ventricle physiology and guarantees survival rates of approximately 80% at age 20 years. However, there have been cases of Fontan-associated liver disease (FALD) caused due to congestion, along with recent reports of the development of hepatocellular carcinoma (HCC) in younger patients with FALD. The literature consists of only five previous case reports of patients who underwent hepatectomy for HCC due to poorer cardiac function and liver cirrhosis caused due to congestion. CASE PRESENTATION: The patient was a 37-year-old woman who presented with epigastralgia. Computed tomography (CT) revealed a liver tumor, 8 cm in diameter, in the caudate lobe. Liver damage was A, with an indocyanine green retention rate of 6% at 15 min. The levels of alpha-fetoprotein (AFP) and protein induced by vitamin K antagonists-II (PIVKA-II) were elevated to 81,663 ng/ml (normal < 10 ng/ml) and 238 mAU/ml (normal < 40 mAU/ml), respectively. Left ventricular ejection fraction was 56%, and central venous pressure (CVP) was 12 mmHg. Left hepatectomy and caudate lobe resection were successfully performed in the reverse Trendelenburg position which reduced the CVP. The total operation duration was 450 min, with a total blood loss of 3200 ml. The patient's postoperative course was uneventful, and she is still alive 16 months after surgery. CONCLUSIONS: First left hepatectomy with caudate lobectomy during reverse Trendelenburg position which reduced the CVP was performed in a patient with HCC and FALD.

Right anatomical hepatectomy: pioneers, evolution, and the future.

To identify the pioneers of right anatomical hepatectomy (RAH), and clarify the development of associated operative procedures, concepts, and the future, we reviewed the "hidden" literature published in Eastern and Western countries since the 1940s. We searched the English and non-English literature on RAH through web search engines, text books and documents, and also referred to experts' comments. Non-English literature, other than in Japanese, was translated. Changes in the anatomical concept, anatomical identification, vascular control technique, approaches, pre-operative management, and other aspects of RAH were analyzed. Honjo and Lortat-Jacob, in 1949 and 1951, respectively, reported the first cases of successful RAH; since then, RAH has been used in the treatment of liver malignancies worldwide. Vascular in-flow control is divided into intrafascial, extrafascial or transfissual access. The anatomical border along the main hepatic veins was proposed for transection, and anterior approaches have been suggested as alternative options in the hazardous situation of right liver rotation. In the laparoscopic era, several procedures and positions have been devised for RAH. In summary, RAH and related anatomical hepatectomy have been established as treatment methods for 70 years, and the future of RAH includes new concepts, approaches, and techniques to optimize patient safety and disease curability.

Urinary Levels of Titin-N Fragment, a Skeletal Muscle Damage Marker, are Increased in Subjects with Nonalcoholic Fatty Liver Disease.

Sarcopenia is a pathological condition affecting the development and progression of NAFLD. Urinary levels of titin-N fragment, a biomarker reflecting muscle damage, were measured in NAFLD subjects, and analyzed in a retrospective manner for possible correlations with NAFLD pathophysiology to assess their clinical relevance. This study enrolled 153 NAFLD subjects and 100 subjects without NAFLD, obesity or diabetes mellitus (non-NAFLD). NAFLD subjects had more decreased knee extension strength. NAFLD subjects had greater subcutaneous fat thickness and echo intensity (brightness) of the rectus femoris muscle on ultrasound images; higher levels of the intra- and extra-myocellular lipids (IMCL, EMCL) using 1H-MRS. Urinary titin-N fragment levels were increased with increasing age but not different between males and females. NAFLD subjects had higher titin-N fragment levels than non-NAFLD subjects. The levels were negatively correlated with skeletal muscle mass and knee extension strength and positively correlated with muscle echo intensity, EMCL, and liver fibrosis scores (NAFLD fibrosis score, FIB-4 index). Multivariate analysis revealed that factors affecting the levels were skeletal mass index, leg skeletal muscle mass, liver stiffness, and NAFLD fibrosis score. Urinary levels of titin-N fragment reflected skeletal muscle deterioration and functional decline, and was closely associated with hepatic pathological conditions in NAFLD subjects.

A staged approach with initial tumor thrombectomy followed by hepatectomy for icteric-type hepatocellular carcinoma: A case report.

INTRODUCTION: Biliary drainage for patients with icteric-type hepatocellular carcinoma (HCC) is sometimes difficult, because the drainage tube makes contact with the tumor thrombus (TT) and effective drainage cannot be achieved due to hemobilia. PRESENTATION OF CASE: We performed endoscopic naso-biliary drainage for an icteric-type HCC patient; however, the serum bilirubin level was not decreased due to bleeding from the TT. Therefore, we performed tumor thrombectomy in the bile duct and transection of the right hepatic bile duct prior to right hepatectomy. After the first operation, the bilirubin level was decreased, and liver function was recovered so that the patient could undergo right hepatectomy 4 months after the first operation. The postoperative course was uneventful after the second operation and the patient was discharged from the hospital on the 30th postoperative day. The patient is well without recurrence 10 years after surgery. CONCLUSION: Biliary drainage is one of the key points for successful treatment of icteric-type HCC patients. A staged approach with initial tumor thrombectomy followed by hepatectomy should be considered as one of the options for icteric-type HCC.

Diabetes Mellitus and/or Nonalcoholic Steatohepatitis-related Hepatocellular Carcinoma Showed Favorable Surgical Outcomes After Hepatectomy.

BACKGROUND/AIM: Diabetes mellitus (DM) is known as an important risk factor for hepatocellular carcinoma (HCC). However, surgical outcomes in patients with DM and HCC have not been evaluated in detail. PATIENTS AND METHODS: We retrospectively studied 177 patients with type 2 DM who underwent curative hepatectomy for HCC. Surgical outcomes after curative hepatectomy and prognostic factors were evaluated among 75 patients with DM and/or nonalcoholic steatohepatitis (NASH)-related HCC and 102 patients with DM and viral or alcoholic hepatitis (VAH)-related HCC. RESULTS: The 5-year survival rate and 5-year recurrence-free survival rate were significantly higher in the DM and/or NASH-related HCC group (87% and 51%) than in the DM and VAH-related HCC group (68%: p=0.0001 and 26%: p=0.0002). Multivariate analysis showed DM and/or NASH-related HCC to be significant independent prognostic factors for overall survival and recurrence-free survival. CONCLUSION: Patients with DM and/or NASH-related HCC showed more favorable surgical outcomes after hepatectomy in patients with DM and HCC.

High-signal-intensity MR Image in the Hepatobiliary Phase Predicts Long-term Survival in Patients With Hepatocellular Carcinoma.

BACKGROUND/AIM: The aim of the study was to evaluate surgical outcomes of patients with high-signal intensity (SI) image hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Between 2008 and 2013, 257 HCC patients were retrospectively evaluated. A total of 21 patients were diagnosed as high-SI image HCC, 215 as low-SI image HCC, and 21 patients as mixed (high and low)-SI image HCC in the hepatobiliary (HB) phase of MRI. Five-year overall survival (OS) and recurrence-free survival (RFS) were compared among patient groups. RESULTS: The 5-year OS and RFS rates were significantly higher in patients with high-SI image HCC (100% and 56%) than in patients with low-SI image HCC (71%; p=0.097 and 38%; p=0.0209) and in patients with mixed-SI image HCC (73%; p=0.0329 and 9%; p=0.0021). High-SI image was an independent prognostic factor for OS (relative risk 0.167, p=0.0178) and RFS (relative risk 0.471, p=0.0322) on multivariate analysis. CONCLUSION: Patients with high-SI image HCC showed favorable long-term survival after curative surgery.

Cavo-atrial thrombectomy prior to hepatectomy for hepatocellular carcinoma with tumor thrombus in the right atrium: a case report.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumor thrombus (TT) in the right atrium is a critical condition. The general consensus is to perform hepatectomy prior to cavo-atrial thrombectomy because of the risk of uncontrollable bleeding during the liver transection after heparinization. However, sudden cardiac arrest due to the ball-valve effect and pulmonary embolism have been reported in cases of TT. Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium was successfully performed to prevent sudden cardiac arrest and pulmonary embolism. CASE PRESENTATION: Tumor thrombectomy under cardiopulmonary bypass with heparin and electrical ventricular fibrillation prior to hepatectomy was successfully performed to prevent sudden cardiac arrest or pulmonary embolism in a 75-year-old woman with a huge HCC and TT in the right atrium. After the neutralization of heparin, right hepatectomy with tumor thrombectomy in the inferior vena cava was performed. The total operation time was 9 h, and the total blood loss was 8200 mL. The patient's postoperative course was uneventful, and she was discharged 14 days after surgery. One year after surgery, she is alive with HCC recurrence in the lung. CONCLUSIONS: Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium can be performed safely to prevent sudden cardiac arrest and pulmonary embolism by collaboration of cardiovascular surgeons and gastroenterological surgeons.

Inflammatory hepatocellular adenoma in a patient with Turner's syndrome: A case report.

INTRODUCTION: Hepatocellular adenoma (HCA) is a rare benign tumor and is related to the use of an oral contraceptive pill. Turner's syndrome requires various hormone replacement therapies, including the pill which is used as a female hormone replacement therapy. Herein we report a case of Turner's syndrome with HCA treated by liver segmentectomy. PRESENTATION OF CASE: A 36-year-old woman with Turner's syndrome was treated with oral contraceptive pills as a female hormone replacement therapy for 20 years. She presented with fatigue and liver tumor. Liver tumors in the posterior lobe measuring 60 mm and 10 mm in diameter were detected on CT; hence, she was referred to our department. Both the tumors showed high intensity in the arterial phase, iso-intensity in the portal and late phases, and low intensity in the hepatobiliary phase on Gb-EOB-MRI. She was diagnosed with multiple HCAs and underwent segmentectomy Section 7. Pathologically, both the tumors were diagnosed as HCAs, and inflammatory markers were detected by immunohistochemistry. Thirteen months postoperatively, she was doing well and there was no evidence of recurrence of HCA without the pill. DISCUSSION: There is only one report of HCA in patients with TS (Espat et al., 2000). We reported a case of multiple HCAs in a patient with TS underwent hepatectomy. CONCLUSION: With the use of the contraceptive pill as a long-term female hormone replacement therapy for Turner's syndrome, careful attention is required for HCA.

Correction: Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers.

[This corrects the article DOI: 10.18632/oncotarget.25308.].

Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers.

Integration of Hepatitis B virus (HBV) into the human genome can cause genetic instability, leading to selective advantages for HBV-induced liver cancer. Despite the large number of studies for HBV integration into liver cancer, little is known about the mechanism of initial HBV integration events owing to the limitations of materials and detection methods. We conducted an HBV sequence capture, followed by ultra-deep sequencing, to screen for HBV integrations in 111 liver samples from human-hepatocyte chimeric mice with HBV infection and human clinical samples containing 42 paired samples from non-tumorous and tumorous liver tissues. The HBV infection model using chimeric mice verified the efficiency of our HBV-capture analysis and demonstrated that HBV integration could occur 23 to 49 days after HBV infection via microhomology-mediated end joining and predominantly in mitochondrial DNA. Overall HBV integration sites in clinical samples were significantly enriched in regions annotated as exhibiting open chromatin, a high level of gene expression, and early replication timing in liver cells. These data indicate that HBV integration in liver tissue was biased according to chromatin accessibility, with additional selection pressures in the gene promoters of tumor samples. Moreover, an integrative analysis using paired non-tumorous and tumorous samples and HBV-related transcriptional change revealed the involvement of TERT and MLL4 in clonal selection. We also found frequent and non-tumorous liver-specific HBV integrations in FN1 and HBV-FN1 fusion transcript. Extensive survey of HBV integrations facilitates and improves the understanding of the timing and biology of HBV integration during infection and HBV-related hepatocarcinogenesis.

Glissonean pedicle approach in liver surgery.

Glisson's capsule was discovered by Johannis Walaeus in 1640 and described by Francis Glisson in 1654. The capsule wraps the hepatic artery, the portal vein and the bile duct in the liver and forms bundles at the hepatic hilus and in the liver as the Glissonean pedicle tree. Glisson's capsule does not connect to the proper membrane of the liver, which was discovered by Laennec; therefore, the Glissonean pedicles can be detached from the liver parenchyma without liver dissection. Couinaud described three main approaches to control the inflow system at the hepatic hilus in liver surgery; the intrafascial approach, the extrafascial and transfissural approach, and the extrafascial approach. The intrafascial approach is the so-called control method. The extrafascial and transfissural approach, and the extrafascial approach are recognized as the Glissonean pedicle approach. When the Glissonean pedicles are ligated before liver transection, various types of anatomical hepatectomy can be carried out. The Glissonean pedicle approach is, therefore, considered to be one of the most important procedures in liver surgery. We herein describe the historical aspects and procedures of the Glissonean pedicle approach in liver surgery.