In the past decade, there has been remarkable progress in surgical treatment for hepatocellular carcinoma (HCC) based on evidence created by epoch-making prospective trials or national registry big data analysis. A head-to-head randomized controlled trial comparing liver resection and local ablation for small oligo HCCs (SURF trial) demonstrated comparable recurrence-free survival provided both modalities are feasible. Survival benefit of liver resection for HCC with vascular invasion was demonstrated by two propensity scored matched analyses based on Japanese national data. Furthermore, expanded HCC criteria for living donor liver transplantation were developed based on Japanese national data, and this "5-5-500 rule" was accepted by the social insurance system in Japan. The recent remarkable progress in promising new anti-HCC agents may open the door for effective neoadjuvant or adjuvant treatment in combination with surgery.

Immune checkpoint inhibitors have entered clinical practice for the treatment of hepatocellular carcinoma (HCC). Several previous studies for other cancers have revealed that tumor mutation burden, tumor PD-L1 expression and cytotoxic T-cell infiltration are predictive of treatment response. The genetic analysis of HCC has shown that β-catenin mutation might be a biomarker predicting the poor response against immune checkpoint inhibitors. β-catenin is a transcription factor downstream of WNT signaling and somatic mutations of this gene are the third most common in HCC. WNT signaling is an important signal for organogenesis and is also involved in the maintenance of stem cells in several organs. Recently, clinical and basic studies have shown the specific roles of WNT/β-catenin signaling in many aspects of hepatic function and carcinogenesis including metabolic zonation and inflammation, and sub-classification and radiologic features of HCC. Base on the review on the recent advances of research investigating WNT/β-catenin signaling associated with hepatocytes, we speculate the clinical role of this signal on the immunotherapy for HCC, which suggests that an era of genetic mutation profiles may be coming to add to the HCC treatment algorithm.

Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancerrelated death globally. Clinical guidelines for HCC have been established and revised by many countries and regions. We summarized and compared the treatment algorithms in the updated HCC guidelines established by Japan, China, Hong Kong, the Asian-Pacific Association for the Study of the Liver, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer. Variations in treatment algorithms between the guidelines is inevitable, considering the differences in the prevalence and etiology of HCC, local clinical practice, and medical and insurance systems between countries or regions, and this might be confusing for practitioners worldwide. A comprehensive understanding of the guidelines that are globally available might be useful for future improvement of each guideline.

The positive relationship between volume and outcome in hepatobiliary surgery has been demonstrated for many years. As for other complex surgical procedures, both improved short- and long-term outcomes have been associated with a higher volume of procedures. However, whether the centralization of complex hepatobiliary procedures makes full sense because it should be associated with higher quality of care, as reported in the literature, precise criteria on what to centralize, where to centralize, and who should be entitled to perform complex procedures are still missing. Indeed, despite the generalized consensus on centralization in hepatobiliary surgery, this topic remains very complex because many determinants are involved in such a centralization process, of which some of them cannot be easily controlled. In the context of different health systems worldwide, such as national health systems and private insurance, there are different stakeholders that demand different needs: politicians, patients, surgeons, institutions and medical associations do not always have the same needs. Starting from a review of the literature on centralization in hepatobiliary surgery, we will propose some guidelines that, while not data-driven due to low evidence in the literature, will be based on good clinical practice.

The advent of preoperative 3-dimensional (3D) simulation software has made a variety of unprecedented surgical simulations possible. Since 2004, we have performed more than 2,000 preoperative simulations in the University of Tokyo Hospital, and they have enabled us to obtain a great deal of information, such as the detailed shape of liver segments, the precise volume of each segment, and the volume of hepatic venous drainage areas. As a result, we have been able to perform more aggressive and complicated surgery safely. The next step is to create a navigation system that will accurately reproduce the preoperative plan. Real-time virtual sonography (RVS) is a navigation system that provides fusion images of ultrasonography and reconstructed computed tomography images or magnetic resonance images. The RVS system facilitates the surgeon's understanding of interpretation of ultrasound images and the detection of tumors that are difficult to find by ultrasound alone. In the near future, surgical navigation systems may evolve to the point where they will be able to inform surgeons intraoperatively in real time about not only intrahepatic structures, such as vessels and tumors, but also the portal territory, hepatic vein drainage areas, and resection lines that have been planned preoperatively.

Primary liver cancer (PLC) is currently the fourth most common malignancy and accounts for the second most cancer-related deaths in China. Since 2017, a great deal of high-level evidence, and particularly evidence based on Chinese studies and practice, has emerged in terms of diagnosis, staging, and treatment. A new version of the guidelines for the management of PLC specifying the diagnosis and treatment of PLC (2019 edition) has recently been published. The guidelines feature major changes in the techniques for early diagnosis, the combination of surgery, local therapy, and systemic treatment, and the use of traditional Chinese medicine. The guidelines need to be further implemented in clinical practice to demonstrate their validity.

In Hong Kong, liver cancer is the fifth most common cancer and the third most common cause of cancer deaths. The prevalence of hepatitis B is high in Hong Kong because of the high rate of hepatitis B virus infection, and chronic hepatitis B has remained the leading cause of hepatocellular carcinoma in the city, accounting for 80% of all cases in the period from 1992 to 2016. In view of the different etiologies of hepatocellular carcinoma around the world, a group of liver experts in Hong Kong developed the Hong Kong Liver Cancer staging system in order to provide more aggressive treatment guidance (predominantly a wider use of surgical resection) for Asian patients of hepatocellular carcinoma. In this article focussing on the Hong Kong Liver Cancer staging system, we briefly reviewed the screening criteria adopted in Hong Kong for liver resection, local ablation, transcatheter arterial chemoembolization, transcatheter arterial radioembolization, stereotactic body radiation therapy, and systemic therapy.

To clarify the early hemodynamics of hepatocellular carcinoma (HCC), we defined the early portal phase of contrast-enhanced ultrasound (CEUS) and examined the reliability of this modality for determining HCC differentiation. Starting in 2007, we performed Sonazoid CEUS in 146 pathologically confirmed hepatic nodules; 118 HCC (8 poorly [Pd], 73 moderately [Md] and 37 well-differentiated [Wd]) and 28 benign nodules. We focused on the pure arterial and early portal phases up to 45 seconds after Sonazoid injection, and then the subsequent phase up to 30 minutes. We calculated covariance-adjusted sensitivities for nodule enhancement combinations of these three phases. Nodule enhancements were divided into hypo, iso and hyper. A positive predictive value of 100% was obtained for the following patterns: iso-iso-hypo, hypo-iso-iso, and hypo-hypo-hypo for Wd, hyper-iso-hypo and hyper-hypo-hypo for Md, hypo-hyper-hypo for Pd, and hyper-hyper-hyper for benign nodules. In Wd HCC (early HCC), there were seven enhancement patterns, thought to be characterized by various hemodynamic changes from early to advanced HCC. Two patterns allowing a diagnosis of Wd HCC were hypo in the pure arterial phase. Subsequent iso-enhancement in the early portal phase indicated a portal blood supply. Decreased enhancement in the early portal phase allows a diagnosis of Md HCC. However, gradual enhancement observed from the pure arterial to the early portal phase allows a diagnosis of Pd HCC. Therefore, even in the early portal phase, hemodynamic changes were visible not only in Wd but also in Md and Pd HCC. In conclusion, with division of the early phase hemodynamics into pure arterial and early portal phases, CEUS can provide information useful for determining the likely degree of HCC differentiation and for distinguishing early stage HCC from benign nodules.

Models of liver corrosion were developed by injecting colored Mercox, epoxy resin, silicon rubber and other materials into the portal vein, hepatic artery, bile duct and hepatic vein of autopsied livers. The glissonean or venous branches that obstructed the view of the caudate lobe of the liver were subsequently removed. The detailed anatomy of the caudate vessels was studied and the three parts of the caudate lobe (Spiegel lobe, paracaval portion and caudate process) were defined based on portal segmentation. Caudate portal branches should be defined as dorsal branches arising from the main trunk, or from the first order branches of the portal vein covering the hepatic region in front of the inferior vena cava. The hepatic region, where the internal branches from segment eight cover the front of the inferior vena cava, should be defined as segment eight, and not as the paracaval portion. Prof. Couinaud defined the right side of the caudate lobe as segment IX based on the spatial position; however, this classification of the caudate section seemed to lack consistency with that of other hepatic segments, which were defined based on portal segmentation. We have sustained the dogma that any hepatic segment should be defined based on portal segmentation, and our classification of the definition and boundary of the caudate lobe, which was published in 1985, has sufficient consistency to be used as an international standard.

Lausanne University Hospital is in the Francophone part of Switzerland and services a catchment population of about 1 million people. We recorded and analyzed baseline characteristics and surgical outcomes for 400 consecutive patients who underwent liver resection there between January 2014 and February 2020. Their pathological results were primary liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma): 21.8%, extrahepatic cholangiocarcinoma (including perihilar cholangiocarcinoma and gallbladder cancer): 5.3%, liver metastases: 51.8%, echinococcosis: 10.8%, adenoma: 3.0%, and other diagnoses: 7.5%. Global morbidity rate (Clavien-Dindo classification ≥ 1) was 45.5% with major complication (Clavien-Dindo classification ≥ 3) identified in 81 patients (20.3%). Of the 400 patients, two died within 30 days of surgery (0.5%) and five died within 90 days (1.3%). The 2017-2019 subgroup had a significantly greater percentage of patients aged ≥ 75 years (20.5%) than did the 2014-2016 subgroup (10.9%; p = 0.011) and a higher percentage of laparoscopic procedures than the earlier subgroup (2014-2016: 9.2%, 2017-2019: 32.5%; p < 0.001). We conclude that as the patient population ages, preoperative management and surgical techniques should be constantly improved.