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To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety.We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary.Highly advanced HBPS was performed in 121 518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (P .001). Ninety-day mortality rates were 2.1%, 1.82%, 1.62%, 1.28%, 1.46%, 1.22%, 1.19%, and 0.98%, respectively (P .001). Summary reports were submitted by 20 hospitals between 2015 and 2019. Mortality rates before and after the start of report submission and audit were 5.72% and 2.79%, respectively (odds ratio 0.690, 95% confidence interval 0.487-0.977; P = .037).Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS.

Although the number of minimally invasive liver resections (MILRs) has been steadily increasing in many institutions, minimally invasive anatomic liver resection (MIALR) remains a complicated procedure that has not been standardized. We present the results of a survey among expert liver surgeons as a benchmark for standardizing MIALR.We administered this survey to 34 expert liver surgeons who routinely perform MIALR. The survey contained questions on personal experience with liver resection, inflow/outflow control methods, and identification techniques of intersegmental/sectional planes (IPs).All 34 participants completed the survey; 24 experts (70%) had more than 11 years of experience with MILR, and over 80% of experts had performed over 100 open resections and MILRs each. Regarding the methods used for laparoscopic or robotic anatomic resection, the Glissonean approach (GA) was a more frequent procedure than the hilar approach (HA). Although hepatic veins were considered essential landmarks, the exposure methods varied. The top three techniques that the experts recommended for identifying IPs were creating a demarcation line, indocyanine green negative staining method, and intraoperative ultrasound.Minimally invasive anatomic liver resection remains a challenging procedure; however, a certain degree of consensus exists among expert liver surgeons.

Purpose In this systematic review, we aimed to clarify the useful anatomic structures and assess available surgical techniques and strategies required to safely perform minimally invasive anatomic liver resection (MIALR), with a particular focus on the hepatic veins (HVs). Methods A systematic review was conducted using MEDLINE/PubMed for English articles and Ichushi databases for Japanese articles through September 2020. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN). Results A total of 3,372 studies were obtained, and 59 were selected and reviewed. Due to the limited number of published comparative studies and case series, the degree of evidence from our review was low. Thirty-two articles examined the anatomic landmarks and crucial structures for approaching HVs. Regarding the direction of HV exposure, 32 articles focused on the techniques and advantages of exposing HVs from either the root or the periphery. Ten articles focused on the techniques to perform a segmentectomy 8 in particularly difficult cases of MIALR. In seven articles, bleeding control from HVs was also discussed. Conclusions This review may help experts reach a consensus regarding the best approach to the management of hepatic veins during MIALR.

Background In preparation for the upcoming consensus meeting in Tokyo in 2021, this systematic review aimed to analyze the current available evidence regarding surgical anatomy of the liver, focusing on useful landmarks, strategies and technical tools to perform precise anatomic liver resection (ALR). Methods A systematic review was conducted on MEDLINE/PubMed for English articles and on Ichushi database for Japanese articles until September 2020. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN). Results A total of 3169 manuscripts were obtained, 1993 in English and 1176 in Japanese literature. Subsequently, 63 English and 20 Japanese articles were selected and reviewed. The quality assessment of comparative series and case series was revealed to be usually low; only six articles were qualified as high quality. Forty-two articles focused on analyzing intersegmental/sectional planes and their relationship with specific hepatic landmark veins. In 12 articles, the authors aimed to investigate liver surface anatomic structures, while 36 articles aimed to study technological tools and contrast agents for surgical segmentation during ALR. Although Couinaud's classification has remained the cornerstone in daily diagnostic/surgical practices, it does not always portray the realistic liver segmentation and there has been no standardization on which a single strategy should be followed to perform precise ALR. Conclusions A global consensus should be pursued in order to establish clear guidelines and proper recommendations to perform ALR in the era of minimally invasive surgery.

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 (

Background/purpose Anatomical sectionectomy or larger resection is known to be effective in patients with hepatocellular carcinoma (HCC) with microvascular invasion. A non-smooth tumor margin on hepatobiliary-phase gadoxetic acid disodium-enhanced magnetic resonance imaging (EOB-MRI) can predict microvascular invasion of HCC. We evaluated the usefulness of EOB-MRI for operative planning. Methods We evaluated 224 patients with single HCC who underwent hepatectomy between 2010 and 2013. The tumor margin was determined preoperatively. The hepatic resection was determined based on tumor location, liver function, 3D CT simulation and functional liver reserve. To control for confounding variable distributions, propensity score match was applied to compare the outcomes. Multivariate analysis was conducted to identify independent predictors of 5-year recurrence-free survival (RFS) and overall survival (OS). Results Of 113 patients with a non-smooth tumor margin, 40 patients (35%) showed microscopic portal invasion. The 5-year RFS and OS rates were significantly higher after sectionectomy or larger hepatectomy (hemihepatectomy) than after segmentectomy or smaller hepatectomy (non-anatomical resection). Of 111 patients with a smooth tumor margin, eight patients (7%) showed microscopic portal invasion. The 5-year RFS and OS rates did not differ significantly between patients who underwent sectionectomy and those who underwent segmentectomy. Conclusions Our preliminary results appear to recommend that HCC with a non-smooth margin on HB-phase images is treated with anatomical sectionectomy or larger hepatectomy.

Considering the initial treatment of hepatocellular carcinoma (HCC), the best prognostic index for Child–Pugh classes B and C (CP-BC) patients has not been yet established. This study aimed to elucidate the risk factors for disease-free survival (DFS) and overall survival (OS) in multicenter patients with a poor liver functional reserve after curative treatment. Between April 2000 and April 2014, 212 CP-BC patients who received treatment in five high-volume centers in Japan were included in this study. CP-B and C patients were 206 and 6, respectively. Cox proportional hazard regression analyses for DFS and OS were performed to estimate the risk factors. The mean observation time was 1132 days. Mean Child–Pugh score and indocyanine green retention rate at 15 min were 7.5 and 31.5%, respectively. Histological chronic hepatitis and liver cirrhosis were observed in 20% and 74% patients, respectively. In the multivariate analysis, the risk factors for DFS were des-gamma-carboxy prothrombin (DCP) [hazard ratio (HR), 1.6; P = 0.012] and treatment without liver transplantation. Moreover, DCP was identified as an independent risk factor for OS (HR, 1.7; P = 0.01). Tumor size, number, tumor thrombus, Milan criteria, liver cirrhosis, and treatment without liver transplantation were not identified as risk factors for OS. The 5-year OS in patients with high serum DCP levels (

The Brisbane 2000 Terminology for Liver Anatomy and Resections, based on Couinaud's segments, did not address how to identify segmental borders and anatomic territories of less than one segment. Smaller anatomic resections including segmentectomies and subsegmentectomies, have not been well defined. The advent of minimally invasive liver resection has enhanced the possibilities of more precise resection due to a magnified view and reduced bleeding, and minimally invasive anatomic liver resection (MIALR) is becoming popular gradually. Therefore, there is a need for updating the Brisbane 2000 system, including anatomic segmentectomy or less. An online "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was hosted on February 23, 2021.The Steering Committee invited 34 international experts from around the world. The Expert Committee (EC) selected 12 questions and two future research topics in the terminology session. The EC created seven tentative definitions and five recommendations based on the experts' opinions and the literature review performed by the Research Committee. Two Delphi Rounds finalized those definitions and recommendations.This paper presents seven definitions and five recommendations regarding anatomic segmentectomy or less. In addition, two future research topics are discussed.The PAM-HBP Surgery Consensus has presented the Tokyo 2020 Terminology for Liver Anatomy and Resections. The terminology has added definitions of liver anatomy and resections that were not defined in the Brisbane 2000 system.

Background The concept of Minimally invasive anatomic liver resection (MIALR) is gaining popularity. However, specific technical skills need to be acquired to safely perform MIALR. The "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was developed as a special program during the 32nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS). Methods Thirty-four international experts gathered online for the consensus. A Research Committee performed a comprehensive literature review, classifying studies according to the Scottish Intercollegiate Guidelines Network (SIGN) method. Based on the literature review and experts' opinions, tentative recommendations were drafted and circulated among experts using online Delphi Rounds. Finally, formulated recommendations were presented online in the Expert Consensus Meeting of the JSHBPS on February 23rd, 2021. The final recommendations were validated and finalized by the 2nd Delphi Round in May 2021. Results Seven Clinical Questions (CQs) were selected, and 22 recommendations were formulated. All recommendations reached more than 85% consensus among experts at the final Delphi Round. Conclusions The Expert Consensus Meeting for safely performing MIALR has presented a set of clinical guidelines based on available literature and experts' opinions. We expect these guidelines to have a favorable effect on the safe implementation and development of MIALR.

BACKGROUND/AIM The aim of the study was to compare the outcomes of anatomical resection (AR) versus non-anatomical resection (NAR) for Japanese and Taiwanese patients with single, resectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS A propensity score matched (PSM) analysis was performed to compare the outcomes of the AR group to those of the NAR group. Tumor size

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.

We examined a 22-year-old woman who was admitted to our hospital with abdominal distention. At 19 years of age, the patient presented with hepatosplenomegaly. She was examined several times in another hospital; however, the cause was unidentified. Our evaluation showed severe pancytopenia and a spleen 13×24 cm in size. The serum levels of angiotensin-converting enzyme and lysozyme were elevated. She was diagnosed with liver sarcoidosis based on non-caseating epithelioid granuloma in liver biopsy tissue. To improve the symptoms, splenectomy was performed, and her pancytopenia and symptoms improved. Sarcoidosis should be considered in cases of massive splenomegaly.

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.

Highlights • Obstructive jaundice due to tumor thrombus in the common bile duct with HCC is classified as icteric-type HCC. • Biliary drainage for patients with icteric-type HCC is sometimes difficult. • A staged approach with initial tumor thrombectomy followed by hepatectomy should be considered as one of the options for icteric-type HCC., 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.

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).The mortality, morbidity, and long-term outcomes were evaluated retrospectively.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).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 loss2 L (odds ratio: 11.808, P = 0.0244) was an independent risk factor for 30-day mortality, and blood loss2 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, P0.0001) and recurrence-free survival (relative risk: 1.299, P0.0001) in patients with HCC.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 loss2 L and bile leakage.

Hepatocellular carcinoma (HCC) with extrahepatic metastasis is rare, and its prognosis is extremely poor. There is no standard treatment for HCC with extrahepatic metastasis. We report a case of abscopal effect in HCC with multiple pleural metastases in a patient who was treated with focal radiotherapy to extrahepatic metastasis, and achieved long-term survival. We performed radiotherapy only to the tumor in inferior vena cava and the proximal pleural tumor. The regimen comprised a total dose of 30 Gy administered in ten fractions to these tumors, followed by 12 Gy administered in four fractions (a total of 42 Gy in 14 fractions) as boost irradiation to the remaining tumor, and a complete regression was achieved. There have been some case reports on abscopal effects in HCC, but no reports on patients with multiple pleural metastases. To our knowledge, this is the first case report on the abscopal effect of focal radiotherapy resulting in complete regression of distant multiple pleural metastases.

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.

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.

Background/Aim: The aim of the study was to compare the outcomes of anatomical resection (AR) versus non-anatomical resection (NAR) for Japanese and Taiwanese patients with single, resectable hepatocellular carcinoma (HCC). Patients and Methods: A propensity score matched (PSM) analysis was performed to compare the outcomes of the AR group to those of the NAR group. Tumor size

Background Ring calcification in hepatocellular carcinoma is extremely rare. Untreated hepatocellular carcinoma occasionally includes calcified lesions. Here, we report a case of ring-calcified hepatocellular carcinoma. Case presentation A 60-year-old man with a hepatic tumor was referred to Tokyo Women’s Medical University Hospital. He had a history of chronic hepatitis C. Computed tomography showed a liver tumor 20 mm in diameter in segment 6 of the Couinaud classification, with ring calcification. Based on this uncommon imaging presentation and the patient’s past exposure to the definitive hosts of Echinococcus multilocularis, he was preoperatively diagnosed with echinococcosis. Partial hepatectomy was performed as a radical treatment for echinococcosis. A final diagnosis of hepatocellular carcinoma was confirmed based on pathological findings. The patient was discharged uneventfully. Conclusion The presentation of an extremely rare hepatocellular carcinoma with ring calcification may be disguised as hydatid disease.

Highlights • Contraceptive pill induced hepatocellular adenoma with Turner’s syndrome patient is extremely rare. • However Turner’s syndrome patient requires a lifetime hormone replacement therapy. • Proper diagnosis and treatment plan is necessary for hepatocellular adenoma., 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.

Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both p62/Sqstm1 and Nrf2 genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in p62:Nrf2 double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. In vitro experiments showed that the inflammatory response was accelerated in the p62:Nrf2 double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH.

We previously reported that hepatocellular carcinoma (HCC) changes to a phenotype producing des-γ-carboxy prothrombin (DCP) during epithelial mesenchymal transition (EMT) in vitro. To confirm this change in vivo, we evaluated the association between DCP production and HCC hemodynamics in patients undergoing resection as EMT and hemodynamic changes are closely associated with each other. We evaluated HCC hemodynamics by employing Sonazoid-enhanced ultrasound (SEUS) before surgical resection, and sought associations with histological grade and immunohistochemical staining of DCP in 19 areas from 11 patients. In 10 HCC areas showing early washout (3 min ≥) using SEUS, three areas corresponded to poorly differentiated HCC and the remaining seven areas corresponded to moderately differentiated HCC, and positive DCP staining was observed in only two of the seven moderately differentiated HCC areas, whereas no staining was observed in poorly differentiated HCC areas. Six HCC areas showing intermediate washout (3–10 min) using SEUS were moderately differentiated, of which five demonstrated positive DCP staining (83.3%, 5/6). However, all HCC areas without enhancement in the arterial phase were well-differentiated and did not show DCP staining. Our preliminary findings suggest that HCC hemodynamics evaluated by SEUS are associated with histological grade and/or DCP production.

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.

Background We compared survival after resection by systematic segmentectomy (SS) versus non-anatomic resection (NAR) in patients with small, solitary hepatocellular carcinomas (HCCs). Methods To control for variables, we used 1-to-1 propensity score matching to compare outcomes after surgery among 615 patients in Japan between 2003 and 2007 with primary solitary HCCs ≤3 cm in diameter who received SS (n = 114) or NAR (n = 114) of one Couinaud segment with complete removal of the portal territory containing the tumor. Results We successfully matched SS and NAR patients with primary HCC tumors ≤3.0 cm and similar liver function and tumor characteristics. The SS group had significantly longer recurrence-free survival (RFS; hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.10-2.21, P = .013) and overall survival (OS; HR 1.67, 95% CI 1.07-2.60, P = .025) than the NAR group. Among patients who lost >400 mL of blood during surgery, had chronic hepatitis, or had cirrhosis, the RFS and OS were better in the SS group than in the NAR group. In Cox proportional hazard analysis, SS offered a better prognosis than NAR. Conclusions Systematic segmentectomy decreases the risk of recurrence and improves OS in patients with primary, solitary HCC tumors of ≤3 cm in diameter.

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.

Purpose. Since laparoscopic hepatectomy (LH) became covered by national health insurance in April 2010 in Japan, the numbers of applied cases and institutions performing it have increased and the indication has expanded. We surveyed the current state and safety of LH in Japan. Methods. A questionnaire survey was performed in 41 institutions related to the Japanese Endoscopic Liver Surgery Study Group and 747 institutions certified by the Japanese Society of Gastroenterological Surgery, and responses concerning all 2962 cases of LH performed by August 2011 were obtained. Results. The surgical procedure employed was hemihepatectomy in 234 (8%), segmentectomy in 88 (3%), left lateral segmentectomy in 434 (15%), segmentectomy in 156 (5%), and partial resection in 1504 (51%) cases. The approach was pure laparoscopy in 1835 (63%), hand-assisted laparoscopic surgery in 201 (7%), and laparoscopy-assisted surgery in 926 (31%). Regarding perioperative complications, surgery was switched to laparotomy in 59 (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). Intraoperative accidents occurred in 68 (2.3%), and postoperative complications developed in 94 (3.2%). Conclusions. When the selection of cases is appropriate, LH for liver diseases can be safely performed.

OBJECTIVE Early diagnosis and treatment of cancer may contribute substantially to complete cure, but it remains unknown whether treatment of early hepatocellular carcinoma can actually result in cure. This study was performed to clarify the cancer risk of the background liver after treating early hepatocellular carcinoma. METHODS Early hepatocellular carcinoma is defined as very well-differentiated cancer containing Glisson's triad. The cumulative incidence of classical hepatocellular carcinoma, hypervascular liver cancer detected on imaging studies, after resection of early hepatocellular carcinoma positive for anti-hepatitis C antibody (early hepatocellular carcinoma group, n = 105) was compared with that in patients with chronic liver disease positive for anti-hepatitis C antibody (control group, n = 751) and propensity score-matched patients after resection of classical hepatocellular carcinoma (classical hepatocellular carcinoma group, n = 105). RESULTS After a median follow-up of 4.8 years (range, 0.3-15.0), the cumulative incidence of classical hepatocellular carcinoma at 5 years was 56.9% (95% confidence interval, 44.2-67.7%) in the early hepatocellular carcinoma group and 70.6% (52.5-81.8%) in the classical hepatocellular carcinoma group as compared with 4.6% (2.8-6.4%) in the control group. The risk of the development of classical hepatocellular carcinoma in the early hepatocellular carcinoma group was significantly higher than that in the control group (hazard ratio, 17.5; 95% confidence interval, 12.1-25.3; P

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

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.

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.

Liver cysts are observed in 83% of cases of autosomal dominant polycystic kidney disease (ADPKD). Although not as prevalent as renal cyst infection, liver cyst infection is a serious complication that is sometimes difficult to treat. We report the case of a maintenance hemodialysis patient with ADPKD who received a living donor liver transplantation alone (LDLTA) due to refractory liver cyst infection. The patient was a 67-year-old Japanese man who developed fever and right-side abdominal pain, and liver cyst infection was suspected. Treatment with multiple antibiotics was ineffective. Many liver cysts were observed on magnetic resonance imaging scans and a cyst in liver segment S6, which produced the strongest signal variation, was drained. The fever subsided temporarily, but multiple infected liver cysts were observed on follow-up imaging examination; 4 months later, hepatectomy and LDLTA were performed. Although LDLTA due to refractory liver cyst infection in maintenance hemodialysis patients with ADPKD is risky and should be carefully considered, it may be the only effective treatment.

Background & Aims Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape. Methods We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features. Results We identified 32 significantly and commonly mutated genes including TP53 , KRAS , SMAD4 , NF1 , ARID1A , PBRM1 , and ATR , some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1 , BRCA2 , RAD51D , MLH1 , or MSH2 were detected in 11% (16/146) of BTC patients. Conclusions BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information. Lay summary We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1 . Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.

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.

Background The aim of the present study was to compare the prognostic impact of anatomic resection (AR) versus non-anatomic resection (NAR) on patient survival after resection of a single hepatocellular carcinoma (HCC). Methods To control for confounding variable distributions, a 1-to-1 propensity score match was applied to compare the outcomes of AR and NAR. Among 710 patients with a primary, solitary HCC of