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Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set., Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model., Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors., Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Recent advancements in systemic therapy for hepatocellular carcinoma (HCC) necessitate the establishment of resectability criteria for advanced HCC., Methods: A questionnaire survey sought to clarify the perspectives of Japanese expert hepatobiliary surgeons regarding surgical indications for HCC. Thirty-one questions were used to determine when surgery is strongly recommended (resectable: R) or not recommended (unresectable: UR)., Results: A total of 351 responses were obtained. While 64.7% of the respondents considered solitary tumors as being R, irrespective of size, opinions diverged on the upper limit of the number of tumors/tumor size for R: (1) up to three nodules with no size limit (27.9%), (2) up to three nodules ≤5 cm in diameter each (21.4%) and (3) up to three nodules ≤3 cm in diameter each (19.4%). Vp1, Vp2, Vp3, and Vp4 were considered as being R by 90.9%, 70.7%, 39.0%, and 8.0% of respondents, respectively. Half of the respondents indicated they would consider resection even for cases with extrahepatic spread under limited conditions., Conclusions: The current views of Japanese expert surgeons on the resectability criteria for HCC were clarified for the first time. The findings could serve as a basis for preparing expert consensus statements on the resectability criteria for HCC., (© 2024 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

49-year-old woman, who diagnosed advanced breast cancer with, ER-positive, HER2-positive, T4bN1M1, Stage Ⅳ. At the time of initial diagnosis, liver damage equivalent to Child-Pugh classification C due to diffuse liver metastasis was observed, but trastuzumab/pertuzumab(HP)and paclitaxel(PTX)adjusted according to liver function were administered every 3 weeks, resulting in rapid improvement of liver function, PR of the primary tumor(90% reduction), PR of the liver metastases(70% reduction), and improvement of tumor markers. Currently, chemotherapy has been switched to docetaxel (DTX)due to peripheral neuropathy caused by PTX, and treatment is continuing. In the case of HER2-positive breast cancer, good disease control may be achieved with aggressive treatment and intervention under dose adjustment and careful systemic management, even in the setting of liver injury.

Background: The current high-level hepatectomy (HLH) is certified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS), comprising only anatomical hepatectomies above Couinaud's segmentectomy. This multicenter study aimed to identify the conditions of non-HLH that satisfy equivalent technical difficulties to HLH., Methods: Between 2018 and 2021, 595 first open hepatectomies without biliary reconstruction (374 HLHs and 221 non-HLHs) were performed in the five institutions. Non-HLHs belonging to at least one of the three conditions; depth of hepatectomy ≥5 cm, number of resections ≥3 locations and at least one location with a depth of hepatectomy ≥3 cm, and hepatectomy involving the paracaval portion of the caudate lobe was proposed as the candidate for difficult non-HLH. The technical difficulty was estimated by the operative time and blood loss., Results: Difficult non-HLHs were neither associated with shorter operative time (373 min vs. 354 min, p = .184) nor lesser blood loss than those with HLHs (503 mL vs. 436 mL, p = .126). Postoperative complications such as Clavien-Dindo classification grade III or more were not significant between the two groups (18.6% vs. 13.4%, p = 0212)., Conclusions: Difficult non-HLHs were associated with no lesser technical difficulty than those with HLH., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy., Methods: We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes., Results: The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400 ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts., Conclusions: m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation., Methods: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020., Results: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates., Conclusions: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background/aim: Chemotherapy combined with anti-EGFR or anti-VEGF monoclonal antibodies (mAb) is widely used to treat patients with metastatic colorectal cancer (mCRC). Here, we investigated the effects of these antibodies on T-cell infiltration and T-cell receptor (TCR) repertoire variation in CRC liver metastases., Materials and Methods: Ten patients with mCRC received chemotherapy in combination with anti-EGFR (n=6) or anti-VEGF (n=4) mAb. T-cell infiltration was examined for CD3 and CD8 by carrying out immunohistochemistry on biopsy or surgical specimens from liver metastases before and after treatment. TCR repertoire analysis was carried out on specimens with post-treatment CD3 + T-cell infiltration., Results: T-cell infiltrations were approximately 83% (5/6) and 50% (2/4), following treatment with anti-EGFR or anti-VEGF mAb, respectively. TCR repertoire analysis revealed higher clonality and lower diversity of TCR alpha and beta (TRA and TRB) in the anti-VEGF mAb group than that in the anti-EGFR group mAb. Furthermore, the percentage of the common TCR clones between infiltrating T cells and T cells in peripheral blood was significantly lower in the anti-VEGF mAb group compared to that in the anti-EGFR mAb group., Conclusion: The population of T cells infiltrating liver metastases in the anti-VEGF mAb group differed from that in the anti-EGFR mAb group., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The patient is a woman in her 80s who underwent a partial gastrectomy for a gastric GIST 14 years ago. This time, she presented our department with upper abdominal distention and computed tomography revealed an 18 cm-sized cystic lesion in the left lobe of the liver. Since a nodule enhancement was observed in the cyst, malignant disease such as hepatic cystadenocarcinoma could not be ruled out and surgical resection was performed. Pathological examination revealed liver metastasis of gastric GIST. In Japan, only 14 cases have been reported showing such late recurrence with liver metastasis more than 10 years after resection of a primary tumor, including our case. In addition, the cystic finding in this case made preoperative diagnosis difficult because a needle biopsy could not be performed to obtain a pathological diagnosis.

Background/aim: Surgical resection remains the mainstay of treatment for hepatocellular carcinoma (HCC). However, reducing the risk of postoperative recurrence is urgently needed. We planned a prospective observational study to investigate the efficacy and safety of adding sorafenib in a maintenance setting after surgery in HCC patients with high risk of recurrence., Patients and Methods: Patients with HCC (invasion of the hepatic vein or inferior vena cava or tumor size >7 cm or tumor to nontumor standardized uptake value ratio >2 by fluorodeoxyglucose positron emission tomography) who underwent macroscopically curative resection were eligible. Dose and schedule of sorafenib were set at 800 mg/day for six months after hepatic resection. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival and safety. This study was registered with the UMIN Clinical Trials Registry (UMIN000013089)., Results: Ten patients were evaluated. Six patients completed the pre-planned treatment. Three patients discontinued treatment because of disease progression (lung metastasis in two patients and liver metastasis in one), and one patient discontinued because of pneumonia. The most common drug-related adverse event was increased γ-glutamyl transpeptidase (γGTP). None of the patients suffered grade 4 adverse events. The median progression-free survival was 380 (range=38-1,555) days. The median overall survival was 1000 (range=850-1,705) days. Four patients survived without disease progression for more than 800 days., Conclusion: Although the sample size was limited, this is the first study to demonstrate the safety and efficacy of sorafenib in a maintenance setting after surgery for HCC patients with high risk of recurrence., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated., Methods: Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing., Results: The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells., Conclusion: Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity., (© 2022. Society of Surgical Oncology.)

Objective: Major liver resection is an effective treatment option for patients with liver malignancy. The future liver remnant (FLR) volume and complications after portal vein embolization (PVE) were compared between the ipsilateral right portal vein (PTPE) and transileocolic (TIPE) approaches., Methods: A total of 42 patients (TIPE, n = 22; PTPE, n = 20) underwent right lobectomy after PVE. CT and hepatobiliary scintigraphy were repeated before and after PVE. The blood examination findings and the FLR values (FLR CT : calculated from CT, %FLR CT : FLR CT ratio, %FLR SPECT : FLR ratio using single photon emission CT, FLR CT /BS: FLR CT to body surface ratio) were compared between two approach sites. The complications and mortality were also analyzed after PVE and major right hepatectomy., Results: There were no significant differences in the patient characteristics, blood examination findings or FLR values between two groups. Adequate liver regeneration was observed without significant differences between PTPE and TIPE (increased ratio of FLR CT : 8.7% vs 19.2%, p = 0.15 [25-75 percentile: 17.1-60.4], %FLR CT : 11.2% vs 8.3%, p = 0.25 [6.3-13.3], %FLR SPECT : 15.4% vs 19.2%, p = 0.09 [16.0-22.4], FLR CT /BS: 33.6% vs 47.1%, p = 0.19 [17.2-60.4], respectively), but TIPE required a significantly longer procedure time than PTPE [181.4 min vs 108.7 min, p < 0.01 (103.3-193.5)]. However, one patient was converted to TIPE due to bleeding during PTPE. After right lobectomy, portal vein stenosis or thrombosis was noted in three patients [two with TIPE (9.1%) and one with PTPE (5%)] and three TIPE patients died within 90 days (13.6%) after right hepatectomy., Conclusion: FLR volume significantly increased after PVE, regardless of the approach sites; however, PTPE is a useful technique with a shorter procedure time.

Background: Cancer stem cells (CSCs) are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) which possess enhanced chemoresistance and metastatic potential. To enable the development of targeted therapy against CSLCs, we identified a gene responsible for this phenotype in CSLC., Methods: Human hepatoma cell line SK-HEP-1 was used for CSLC induction with a unique sphere inducing medium, and HuH-7 cells were used as non-sphere forming cells in the same condition. RNA-sequencing was performed followed by validation with quantitative RT-PCR and western blotting. Knockdown experiments were done by using CRISPR-Cas9 genome-editing, and the rescue experiments were performed using the expressing plasmid vector. Chemoresistance and liver metastasis of the cells, was studied following the splenic injection of cells to severely immune deficient mice and evaluated using the MTS assay. Quantification of exosomes in the medium was done using ELISA., Results: RAB3B was identified as an up-regulated gene in both CSLCs and prognostically poor hepatocellular carcinoma (HCC) by RNA-sequencing. RAB3B-KD cells showed altered CSLC phenotypes such as sphere formation, chemoresistance, and metastatic potentials, and those were rescued by RAB3B complementation. Increased exosome secretion was observed in CSLCs, and it was not observed in the RAB3B-KD cells. In addition, the RAB3B expression correlated with the expression of ABCG2, APOE, LEPR, LXN, and TSPAN13., Conclusion: The up regulation of RAB3B may play an important role in the chemoresistance and metastatic potential of CSLCs., (© 2022. The Author(s).)

A 49-year-old man came to our department for the purpose of scrutinizing liver tumor. CA19-9 and CA125 increased, and AFP and PIVKA-Ⅱ were within the normal range. CT showed a large number of early ring enhanced tumor, and a tumor thrombus in the left branch of the portal vein. Tumor biopsy revealed adenocarcinoma. Chemotherapy(gemcitabine, cisplatin plus S-1: GCS)was performed for intrahepatic cholangiocarcinoma(r/o combined hepatocellular carcinoma and cholangiocarcinoma). Lenvatinib was administered because portal vein tumor thrombus and PIVKA-Ⅱ increased after GCS therapy. Two months later, CA19-9 and PIVKA-Ⅱ were decreased and portal vein tumor thrombus was shrunk. Extended left hepatectomy was performed for the purpose of disease control. Histopathological examination revealed some hepatocellular carcinoma components in intrahepatic cholangiocarcinoma. Tumor thrombus was vitrified and necrotic. After hepatectomy, administration of lenvatinib was continued for the residual lesion, and no significant tumor growth was observed.

Background: Laparoscopic liver resection is beneficial compared to open liver resection. This study aimed to evaluate whether laparoscopic liver resection could reduce postoperative infections., Methods: This study included 125 and 115 patients with liver tumors who underwent open and pure laparoscopic partial resections or left lateral sectionectomies, respectively. Propensity score matching and stabilized inverse probability of treatment weighting were carried out to compare the postoperative infectious complication rates between the two groups., Results: Patients with tumors located in Couinaud segment 1, 7, or 8; with tumors adjacent to major vessels; or who underwent repeated resections were more likely to receive open resection. After propensity score matching, the superficial incisional surgical site infection rate tended to be lower in the laparoscopic liver resection group than in the open liver resection group. Moreover, overall infectious complication rate and superficial incisional surgical site infection rate were lower in the laparoscopic group (the cohort formed by the stabilized inverse probability of treatment weighting)., Conclusions: Using the laparoscopic approach for partial resections and left lateral sectionectomies for liver tumors, the superficial incisional surgical site infection rate could be reduced., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background/aim: Cancer is the most fatal disease worldwide whose most lethal characteristics are invasion and metastasis. Hepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide. HCC often shows encapsulation, which is related to better prognosis. In this study, proteomic analysis of HCC tissues with and without encapsulation was performed, in order to elucidate the factors which play important roles in encapsulation., Materials and Methods: Five HCC tissues surrounded by a capsule and five HCC tissues which broke the capsule were obtained from patients diagnosed with HCC who underwent surgical liver resection. Protein samples from these tissues were separated by two-dimensional gel electrophoresis (2-DE), and the protein spots whose expression was different between encapsulated and non-encapsulated HCC tissues were identified through gel imaging analysis software. The selected protein spots were analyzed and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: Two-DE analysis showed 14 spots whose expression was different between encapsulated and non-encapsulated HCC tissues. Of these, 9 were up-regulated and 5 were down-regulated in HCC tissues without encapsulation. The validation by Western blot confirmed that leucine aminopeptidase 3 (LAP3) and phosphoenolpyruvate carboxykinase mitochondrial (PCK2) were up-regulated significantly in HCC tissues with a capsule, compared to HCC tissues that broke the capsule., Conclusion: These findings suggest that LAP3 and PCK2 could be factors responsible for the maintenance of encapsulation in HCC tissues., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: A proteomic analysis of hepatocellular carcinoma (HCC) has revealed that Heat Shock Protein 70 (HSP70) is among the cancer antigen proteins of HCC. Moreover, we confirmed that HSP70 was highly expressed in HCC by immunohistochemical staining. Based on these results, we developed an HSP70 mRNA-transfected dendritic cell (DC) therapy for treating unresectable or recurrent HCC, and the phase I trial was completed successfully. Thus, we aimed to investigate the safety and efficacy of this therapy as a postoperative adjuvant treatment after curative resection for HCC to prevent recurrence by conducting a phase I/II randomized controlled clinical trial., Methods: Patients (n = 45) with resectable HCC of stages II-IVa were registered and randomly assigned into two groups (DC group: 31 patients, control group: 14 patients) before surgery. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were safety and overall survival. The DC therapy was initially administered at approximately 1 week after surgery, and twice every 3-4 weeks thereafter., Results: No adverse events specific to the immunotherapy were observed in the DC group. There was no difference in DFS between the DC and control groups (p = 0.666). However, in the subgroup with HSP70-expressing HCC, DFS of the DC group tended to be better (p = 0.090) and OS of the DC group was significantly longer (p = 0.003) than those of the control group., Conclusion: The HSP70 mRNA-transfected DC therapy was performed safely as an adjuvant therapy. The prognosis of HSP70-expressing HCC cases could be expected to improve with this therapy.

A 61‒year‒old woman observed that she had a lower limb edema approximately 1 month ago and began to feel a general malaise. The symptom was caused by multiple liver metastases, and the primary lesion was suspected to be an ovarian cancer. Peritoneal disseminations throughout the abdominal cavity were found in the exploratory laparotomy. No obvious primary lesion could be found in the searchable gastrointestinal tract. The patient was diagnosed with a gastrointestinal stromal tumor(GIST)based on the biopsy results of the peritoneal dissemination. Treatment with imatinib mesylate(imatinib) was initiated 13 days after surgery. The severe lower extremity edema disappeared within 2 months. Computed tomography (CT)scan showed a reduction of the multiple liver metastases and peritoneal dissemination, and the appearance and increase of calcifications in the tumor and cystic degeneration inside the liver metastasis. The abnormal accumulation observed by bone scintigraphy also disappeared. Imatinib has a long‒term effect on GIST of unknown primary origin with multiple liver metastases, peritoneal dissemination, and bone metastasis. Five years after the initiation of the treatment, the patient is still alive, and new lesions have not developed.

Hepatocellular carcinoma (HCC) is a representative primary liver cancer caused by long-term and repetitive liver injury. Surgical resection is generally selected as the radical cure treatment. Because the early recurrence of HCC after resection is associated with low overall survival, the prediction of recurrence after resection is clinically important. However, the pathological characteristics of the early recurrence of HCC have not yet been elucidated. We attempted to predict the early recurrence of HCC after resection based on digital pathologic images of hematoxylin and eosin-stained specimens and machine learning applying a support vector machine (SVM). The 158 HCC patients meeting the Milan criteria who underwent surgical resection were included in this study. The patients were categorized into three groups: Group I, patients with HCC recurrence within 1 year after resection (16 for training and 23 for test); Group II, patients with HCC recurrence between 1 and 2 years after resection (22 and 28); and Group III, patients with no HCC recurrence within 4 years after resection (31 and 38). The SVM-based prediction method separated the three groups with 89.9% (80/89) accuracy. Prediction of Groups I was consistent for all cases, while Group II was predicted to be Group III in one case, and Group III was predicted to be Group II in 8 cases. The use of digital pathology and machine learning could be used for highly accurate prediction of HCC recurrence after surgical resection, especially that for early recurrence. Currently, in most cases after HCC resection, regular blood tests and diagnostic imaging are used for follow-up observation; however, the use of digital pathology coupled with machine learning offers potential as a method for objective postoprative follow-up observation.

Objective: To identify optimal surgical methods and the risk factors for long-term survival in patients with hepatocellular carcinoma accompanied by macroscopic bile duct tumor thrombus (BDTT)., Summary Background Data: Prognoses of patients with hepatocellular carcinoma accompanied by BDTT have been known to be poor. There have been significant controversies regarding optimal surgical approaches and risk factors because of the low incidence and small number of cases in previous reports., Methods: Records of 257 patients from 32 centers in Korea and Japan (1992-2014) were analyzed for overall survival and recurrence rate using the Cox proportional hazard model., Results: Curative surgery was performed in 244 (94.9%) patients with an operative mortality of 5.1%. Overall survival and recurrence rate at 5 years was 43.6% and 74.2%, respectively. TNM Stage (P < 0.001) and the presence of fibrosis/cirrhosis (P = 0.002) were independent predictors of long-term survival in the Cox proportional hazards regression model. Both performing liver resection equal to or greater than hemihepatectomy and combined bile duct resection significantly increased overall survival [hazard ratio, HR = 0.61 (0.38-0.99); P = 0.044 and HR = 0.51 (0.31-0.84); P = 0.008, respectively] and decreased recurrence rate [HR = 0.59 (0.38-0.91); P = 0.018 and HR = 0.61 (0.42-0.89); P = 0.009, respectively]., Conclusions: Clinical outcomes were mostly influenced by tumor stage and underlying liver function, and the impact of BDTT to survival seemed less prominent than vascular invasion. Therefore, an aggressive surgical approach, including major liver resection combined with bile duct resection, to increase the chance of R0 resection is strongly recommended.

Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees [defined as mild (NASH A), moderate (NASH B) and severe (NASH C)] of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic stellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The optimal type of surgery (e.g., anatomic or non-anatomic resection) or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is still under debate despite numerous comparative studies based on overall survival. This debate continues not only because these endpoints are influenced by non-surgical factors, such as liver function, but because the definition of non-anatomic resection for HCC has remained unclear. The optimal surgery could be logically determined based on the mechanism of local intrahepatic metastasis, that is, the drainage of tumour blood flow (TBF), because HCC spreads locally through tumour blood flowing to the peri-tumourous liver parenchyma. Since TBF is clearly demonstrated by CT scan under hepatic arteriography, the surgical margin can be determined individually based on the drainage of TBF without deteriorating local curability. Controversy regarding RFA and surgery does not result from the curability of treatment itself but from the lack of scientific evidence on safety margins. Based on proper concepts and self-evident truths, an algorithm of loco-regional treatment for HCC is proposed., (© 2020 S. Karger AG, Basel.)

The patient was a 17-year-old woman. An abnormal urinalysis was observed, and abdominal echography showed a pancreatic cystic mass. At the first examination, computed tomography(CT)and endoscopic ultrasound(EUS)showed a unilocular cystic mass of 60mm in size in the pancreatic body and tail, and no malignant findings were observed. After 14 months, CT and positron emission tomography-computed tomography(PET-CT)showed that the cystic mass had a mural nodule with FDG accumulation, and presence of a tumor in hepatic S8 with FDG accumulation. Laparoscopic distal pancreatectomy and hepatic subsegmentectomy of S8 were performed for diagnostic and therapeutic purposes. The pathological diagnosis was mucinous cystadenocarcinoma(MCC)and metastatic liver cancer in the form of MCC. S-1 was administered after surgery. Nine months after resection, multiple metastatic liver tumors were found, and GEM plus nab-PTX was administered. After 2 courses of treatment, the patient is still alive without new lesions.

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole-exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage-matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A-to-C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM-associated" genes were overrepresented for extracellular matrix-receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1-substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We have performed a combination therapy of hepatic arterial infusion chemotherapy(HAIC), radiation therapy(RT), and surgical resection for the treatment of hepatocellular carcinoma(HCC)with portal vein tumor thrombosis(PVTT)since 2013. We retrospectively analyzed 36 patients with HCC with PVTT who underwent hepatectomy between 1995 and 2016 to evaluate the clinical outcomes. Ten patients received preoperative HAIC, 7 underwent RT, and 14 received postoperative HAIC. The median survival time(MST)was 19.3 months, and the MST was significantly longer in the patients who underwent curative resection than those in patients who did not. In the non-curative resection group, postoperative HAIC prolonged the survival.

Background/aim: Inferior vena cava (IVC) resection and reconstruction with concomitant liver resection sometimes represent the only chance for patients with liver tumors involving the IVC to get cured. However, surgical outcomes of liver resection with IVC resection and reconstruction using an artificial vascular graft have not been well investigated., Methods: Out of a total of 1,179 cases, only 12 involving liver resection between 1998 and 2016 at our institution included IVC resection and reconstruction using an artificial vascular graft. An expanded polytetrafluoroethylene graft was used for the IVC reconstruction in all 12 cases. We investigated the surgical outcomes of these combined surgeries., Results: The median operative time was 650 min and the median blood loss was 2,600 mL. Postoperative complications (≥ grade III in the Clavien-Dindo classification) developed in 2 patients - 1 case of bleeding and one of bile leakage. There were no cases of operative mortality. No complications associated with the vascular graft were observed throughout the postoperative follow-up period, and the grafts remained patent in all cases., Conclusions: These results indicate favorable surgical outcomes of liver resection combined with IVC resection and reconstruction., (© 2018 S. Karger AG, Basel.)

The prognosis of hepatocellular carcinoma (HCC) patients with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is extremely poor. We reviewed the recent surgical treatments and outcomes of this form of advanced HCC. TT is classified into three types according to its anatomic location relative to the heart: the inferior hepatic type (type I), where the TT is in the IVC below the diaphragm; the superior hepatic type (type II), where the TT is in the IVC above the diaphragm, but still outside the RA; and the intracardiac type (type III), where the TT is above the diaphragm and has entered the RA. Type I can be treated relatively easily by standard radical hepatectomy. For type II, the intrathoracic IVC is approached via the abdominal cavity and an incision in the diaphragm with total hepatic vascular exclusion (THVE). For type III, hepatectomy plus thrombectomy is generally performed under cardiopulmonary bypass. If the TT is only just inside the RA, THVE can be performed by mobilizing the liver caudally. The median overall survival of HCC patients with TT in the IVC or RA, who undergo curative resection, is 19.0-30.8 months. As postoperative recurrence is likely to develop, even after curative surgery, effective postoperative adjuvant chemotherapy is required.

The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT‑qPCR analysis of the stroma showed that the expression levels of miR‑221 and miR‑222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT‑qPCR analysis of 101 CRC samples showed that a high expression level of miR‑221 or miR‑222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR‑221 and miR‑222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC.

Background: Hepatic arterial infusion chemotherapy plus sorafenib in phase 2 trials has shown favourable tumour control and a manageable safety profile in patients with advanced, unresectable hepatocellular carcinoma. However, no randomised phase 3 trial has tested the combination of sorafenib with continuous arterial infusion chemotherapy. We aimed to compare continuous hepatic arterial infusion chemotherapy plus sorafenib with sorafenib alone in patients with advanced, unresectable hepatocellular carcinoma., Methods: We did an open-label, randomised, phase 3 trial (SILIUS) at 31 sites in Japan. Eligible patients were aged 20 years or older, with advanced hepatocellular carcinoma not suitable for resection, local ablation, or transarterial chemoembolisation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Child-Pugh score 7 or lower; and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) via an interactive web response system with a computer-generated sequence to receive 400 mg sorafenib orally twice daily or 400 mg sorafenib orally twice daily plus hepatic arterial infusion chemotherapy (cisplatin 20 mg/m 2 on days 1 and 8 and fluorouracil 330 mg/m 2 continuously on days 1-5 and 8-12 of every 28-day cycle via an implanted catheter system). The primary endpoint was overall survival. The primary efficacy analysis comprised all randomised patients (the intention-to-treat population), and the safety analysis comprised all randomised patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01214343., Findings: Between Nov 4, 2010, and June 10, 2014, 206 patients were randomly assigned (103 to the sorafenib group, 103 to the sorafenib plus hepatic arterial infusion chemotherapy group). One patient in the sorafenib plus hepatic arterial infusion chemotherapy group withdrew after randomisation. Median overall survival was similar in the sorafenib plus hepatic arterial infusion chemotherapy (n=102) and sorafenib monotherapy (n=103) groups (11·8 months [95% CI 9·1-14·5] vs 11·5 months [8·2-14·8]; hazard ratio 1·009 [95% CI 0·743-1·371]; p=0·955). Grade 3-4 adverse events that were more frequent in the sorafenib plus hepatic arterial infusion chemotherapy group than in the sorafenib monotherapy group included anaemia (15 [17%] of 88 vs six [6%] of 102), neutropenia (15 [17%] vs one [1%]), thrombocytopenia (30 [34%] vs 12 [12%]), and anorexia (12 [14%] vs six [6%])., Interpretation: Addition of hepatic arterial infusion chemotherapy to sorafenib did not significantly improve overall survival in patients with advanced hepatocellular carcinoma., Funding: Japanese Ministry of Health, Labour and Welfare., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cancer stem cells (CSCs) are thought to play important roles in cancer malignancy. Previously, we successfully induced sphere cancer stem-like cells (CSLCs) from several cell lines and observed the property of chemoresistance. In the present study, we examined the metastatic potential of these induced CSLCs. Sphere cancer stem-like cells were induced from a human hepatoma cell line (SK-HEP-1) in a unique medium containing neural survival factor-1. Splenic injection of cells into immune-deficient mice was used to assess hematogenous liver metastasis. Transcriptomic strand-specific RNA-sequencing analysis, quantitative real-time PCR, and flow cytometry were carried out to examine the expression of epithelial-mesenchymal transition (EMT)-related genes. Splenic injection of CSLCs resulted in a significantly increased frequency of liver metastasis compared to parental cancer cells (P < .05). In CSLCs, a mesenchymal marker, Vimentin, and EMT-promoting transcription factors, Snail and Twist1, were upregulated compared to parental cells. Correspondingly, significant enrichment of the molecular signature of the EMT in CSLCs relative to parental cancer cells was shown (q < 0.01) by RNA-sequencing analysis. This analysis also revealed differential expression of CD44 isoforms between CSLCs and parental cancer cells. Increasing CD44 isoforms containing an extra exon were observed, and the standard CD44 isoform decreased in CSLCs compared to parental cells. Interestingly, another CD44 variant isoform encoding a short cytoplasmic tail was also upregulated in CSLCs (11.7-fold). Our induced CSLCs possess an increased liver metastatic potential in which promotion of the EMT and upregulation of CD44 variant isoforms, especially short-tail, were observed., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients., Methods: We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score., Results: Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients., Conclusions: In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

Background & Aims: To improve prognosis in patients with hepatocellular carcinoma (HCC), the molecular mechanisms of tumor thrombus formation and metastasis must be clarified. The epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles in tumor invasion and metastasis. This study aimed to reveal the clinical significance of the expression of the functional CSC marker, CD13, and investigate the correlation between CD13 expression and two EMT markers, E-cadherin and vimentin., Methods: We acquired clinical samples from 86 patients with HCC that underwent radical liver resections. We performed immunohistochemistry to evaluate CD13, E-cadherin and vimentin expression. We investigated the relationships among protein expression levels, clinicopathological factors and prognosis., Results: Based on CD13 expression, patients were categorized into CD13high (n = 30, 34.9%) and CD13low (n = 56, 65.1%) groups. The mean tumor size was significantly larger in the CD13high group than in the CD13low group (P = 0.049). Compared with the CD13low group, the CD13high group showed significantly earlier recurrences and shorter survival times. In the multivariate analysis, CD13high was an independent prognostic factor for overall survival (hazard ratio, 1.98; P = 0.044). The disease-free survival time was shorter in the vimentin-positive group than that in the vimentin-negative group (P = 0.014). In an analysis of the relationship between CD13 and EMT, there was no significant correlation between CD13 and EMT markers., Conclusions: Our findings suggested that CD13 enrichment was correlated with early recurrences, and poor prognosis in patients with HCC and that vimentin was associated with early recurrences. CD13 represents a potential therapeutic target for HCC, because CSC regulation and EMT suppression are essential in cancer therapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We report 2 cases of laparoscopic simultaneous resection for synchronous liver metastasis of colon cancer. Case 1: A 76- year-old woman was diagnosed with advanced cecum cancer(type 3)with synchronous liver metastasis(segment 5: 23mm), Laparoscopic ileocecal resection and partial liver resection were performed for 414 minutes, with 20 mL of blood loss. The patient was discharged 11 days after the operation. Case 2: A 78-year-old woman was diagnosed with advanced sigmoid colon cancer(type 2)with synchronous liver metastasis(segment 2: 70mm). Laparoscopic sigmoidectomy and extrahepatic resection were performed for 382 minutes, with 10 mL of blood loss. Portal vein thrombus(umbilicus)was recognized but relieved with warfarin. The patient was discharged 15 days after the operation. Simultaneous laparoscopic colon and hepatectomy for synchronous liver metastasis of colorectal cancer can be safely performed for selected indications.

A 50-year-old man with complaints of epigastralgia, pyrexia, and malaise was diagnosed with sigmoid colon cancer, descending colon cancer, and unresectable colorectal liver metastases. Because the prognosticator was liver metastases, he went through chemotherapy(biweekly CapeOX plus cetuximab)as soon as possible. After 6 courses of this regimen, multiple liver metastases were markedly reduced in size(partial response[PR]), resulting in conversion therapy with complete resection. Recently, some reports showed that patients who had R0 resection after conversion chemotherapy could expect favorable long-term prognosis. It is important to select the appropriate first-line chemotherapy and the timing of the conversion resection.

We report a case of colorectal cancer with peritoneal dissemination and liver metastasis that achieved R0 resection by preoperative chemotherapy and CRS plus HIPEC. A 33-year-old man presented with a complaint of abdominal bloating. After further examination, he was diagnosed with transverse colon cancer with peritoneal dissemination and liver metastasis. After 9 courses of preoperative XELOX plus cetuximab and 4 courses of preoperative XELIRI plus bevacizumab, he underwent transverse colon resection, peritoneal resection, and HIPEC(MMC 20mg/4,000mL physiological saline, 40mins). There was little histological evidence of peritoneal dissemination around the region of the primary tumor. Moreover, no tumor cells were found in other peritoneal disseminations or in the liver metastasis. As a result, he was able to undergo curative resection. Colorectal cancer with peritoneal dissemination still has a poor prognosis, but combination therapy with chemotherapy and CRS plus HIPEC is expected to improve prognosis.

Objectives: We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer., Methods: A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21)., Results: In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133)., Conclusions: The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.

Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin-eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT)., Methods: From 16 Japanese LT centers, data were collected on 182 recipients with HCC who underwent living donor liver transplantation (LDLT) between February 2005 and November 2013. PET-positive status was defined as increased uptake of FDG in the tumor compared to the surrounding non-tumor liver tissue. The median follow-up after LDLT was 54.5 months (range 1-125 months)., Results: Postoperative HCC recurrence occurred in 23 patients. Multivariate analysis revealed that exceeding the Milan criteria (MC), alpha-fetoprotein (AFP) level ≥115 ng/ml, and PET-positive status were significant and independent risk factors for recurrence. In the over-MC group, a subgroup of patients with AFP level <115 ng/ml and PET-negative status (n = 22) had a significantly lower 5-year recurrence rate than the other patients (n = 27, 19% vs. 53%, P = 0.019)., Conclusions: These results suggest that preoperative FDG-PET status offers additional information on HCC recurrence risk after LT. Over-MC patients with PET-negative status and lower AFP level may achieve successful outcome comparable to that of within-MC patients., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Several reports have suggested that hepatic resection provides a survival benefit in patients with hepatocellular carcinoma (HCC) at the intermediate stage of the Barcelona Clinic Liver Cancer classification (BCLC-B). The operative indications for multiple BCLC-B have not been established, however. The aim of this study was to clarify the survival benefit of hepatic resection for multinodular BCLC-B HCC., Methods: We retrospectively analyzed 85 patients with BCLC-B HCC who underwent liver resection. To evaluate clinicopathologic factors and survival, we divided the patients into 3 types based on radiologic findings regarding tumor number and maximum tumor diameter: type 1, up to 3 lesions <5 cm; type 2, up to 3 lesions ≥5 cm or 4 nodules of any size; type 3, >4 nodules., Results: Thirty-four patients were classified as type 1, 32 as type 2, and 19 as type 3. The 1-, 3-, and 5-year survival in type 1 were 97.1%, 87.4%, and 75.2%, respectively. Those in type 2 were 84.0%, 74.0%, and 63.0%, and those in type 3 were 64.9%, 55.7%, and 37.1%, respectively. The overall survival of type 1 patients was significantly better than that of type 3 patients. The prognosis of type 2 patients was worse than that of type 1 patients and better than that of type 3. Multivariate analysis identified radiologic tumor size and tumor number as independent prognostic factors., Conclusion: Our findings suggest that hepatic resection should be considered a radical treatment for multinodular BCLC-B HCC. Our subclassification can be applied to select the initial treatment and when making decisions regarding hepatic resection of BCLC-B HCC with multiple nodules., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Case 1: A 57-year-old woman with chronic hepatitis related to the hepatitis B virus was found to have a liver tumor on ultrasonography(US). Computed tomography(CT), magnetic resonance imaging(MRI), and angiography revealed 2 tumors in the liver. The patient underwent right anterior sectorectomy, and histopathologic analysis revealed mucosa-associated lymphoid tissue(MALT)lymphoma. Thirty months later, recurrence was confirmed using liver biopsy. CR was confirmed after radiation and chemotherapy, and the patient has survived. Case 2: A 71-year-old woman came to our hospital for rheumatism treatment. US, CT, and MRI revealed a tumor in the left lateral segment of the liver. The patient underwent laparoscopic partial liver resection and histopathologic analysis revealed MALT lymphoma. The patient has survived.

Background: Local recurrence is a specific problem after radiofrequency ablation of small hepatocellular carcinoma, and additional treatment is an important issue. We aimed to investigate the outcome of salvage hepatectomy in patients who develop local, recurrent hepatocellular carcinoma after treatment with radiofrequency ablation., Methods: From 2001-2013, we reviewed 58 patients from 6 university hospitals with local, recurrent hepatocellular carcinoma who underwent salvage hepatectomy after their initial radiofrequency ablation treatment. Pathologic characteristics and prognostic factors influencing overall survival were analyzed., Results: Noncurative resection, des-gamma carboxy prothrombin levels >40 mAU/mL, and multiple preceding treatments before salvage hepatectomy were negative prognostic factors for overall survival. The 5-year survivals for the prognostic factors were 0%, 24%, and 30%, respectively, after salvage hepatectomy, and 0%, 54%, and 54% after initial radiofrequency ablation treatment, respectively. As for the pathologic finding of local, recurrent hepatocellular carcinoma after radiofrequency ablation, vascular invasion was observed frequently in patients with increases in des-gamma carboxy prothrombin levels and with multiple preceding treatments before salvage hepatectomy with a frequency of 59% and 53%, respectively (P < .01 and .05)., Conclusion: Noncurative resection, increases in serum des-gamma carboxy prothrombin, and multiple preceding treatments were prognostic factors for subsequent salvage hepatectomy; nevertheless, survival outcomes were still acceptable when a curative salvage hepatectomy was performed. Increases in serum des-gamma carboxy prothrombin and multiple preceding treatments were positive predictors for pathologic vascular invasion. These factors should be taken into consideration when selecting treatment modalities for locally recurrent hepatocellular carcinoma following radiofrequency ablation. Repetition of unsuccessful, loco-regional treatment would appear to decrease the potential survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification., Competing Interests: None of the authors have any potential conflicts of interest to report.

Background: Transcatheter arterial chemoembolization (TACE) is a widely used and well-established treatment for hepatocellular carcinoma (HCC). However, TACE loses its therapeutic efficacy when performed repeatedly, a phenomenon termed TACE refractoriness. c-Met is associated with malignant potential and with resistance to anti-tumor therapies in some kinds of cancers., Aims: The aim of this study is to investigate the clinical impact of TACE on c-Met expression with the aim of understanding the mechanism underlying TACE refractoriness., Methods: The effect of TACE on the c-Met expression level was investigated in vitro in HCC cell lines, and it was shown that c-Met expression is upregulated in HCC cell lines cultured under hypoxia and/or exposed to chemotherapeutic agents. The in vitro results were validated using 82 clinical samples of HCC with and without preoperative TACE treatment., Results: c-Met upregulation was observed significantly more frequently in clinical samples of HCC that were treated with preoperative TACE than in samples with no TACE treatment. Increased c-Met expression was significantly associated with poor prognosis. Furthermore, the incidence of c-Met-positive expression was significantly higher in TACE-refractory HCC samples., Conclusions: TACE treatment upregulates c-Met expression in HCC and the upregulated c-Met expression may be responsible for TACE refractoriness.

Background and Objectives: Preoperatively evaluating reserved liver function is critical in preventing posthepatectomy liver failure (PHLF) in patients undergoing liver resection. The commonly used indocyanine green (ICG) clearance test has several drawbacks. Patients would benefit from a more reliable and straightforward means of assessing the risk of PHLF., Methods: This study included 277 patients with hepatocellular carcinoma (HCC) undergoing liver resection. The predictive value of known risk factors for PHLF was compared to that of ICG., Results: PHLF was identified in 25 out of 277 patients (9.0%). Multivariate logistic regression analysis for identifying predictors for the PHLF development revealed platelet count and resected liver volume as significant independent predictors. In a subgroup analysis based on resected liver volume, platelet count was significantly correlated with PHLF in both larger volume (≥100 g) and smaller volume resection groups (<100 g), although ICG R15 level was associated with PHLF only in larger volume group., Conclusions: Platelet count is superior to ICG R15 level in predicting PHLF development in HCC patients. J. Surg. Oncol. 2016;113:565-569. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

A 65-year-old woman underwent sigmoidectomy for colon cancer in January 2002. She had multiple liver metastases and received systemic chemotherapy (UFT-E plus CPT-11) for 6 months. She underwent partial hepatectomy of S7 and S3 and cholecystectomy in July 2003. After 4 years without recurrence, right adrenal and para-aortic lymph nodes metastases were detected and she underwent right adrenalectomy and para-aortic lymphadenectomy in July 2007. In July 2008, local recurrence (1 cm in size) was identified in the cavity of the right adrenal gland. She received chemotherapy (mFOLFOX6 plus bevacizumab) for 5 years. In May 2013, PET-CT showed abnormal accumulation of FDG in S7 of the liver (SUVmax 6.7). The enhanced EOB-MRI showed a mass lesion in S7 (3 cm in size) and 2 nodules (1 cm in size) in S3 and S4. We scheduled for liver surgery with reconstruction of the inferior vena cava (IVC) after systemic chemotherapy (FOLFIRI plus cetuximab). The patient underwent partial hepatectomy of the tumor in S7 combined with resection of the diaphragm and IVC. Reconstruction of the IVC was performed using a ringed Gore-Tex tube graft in February 2014. The patient is still alive without recurrence 18 months after surgery.

We report a case of locally advanced huge hepatocellular carcinoma (HCC) invading the diaphragm and the right lung, which was controlled by sorafenib, thereby allowing curative resection. A 72-year-old man was diagnosed with advanced HCC invading the diaphragm and the right lung. At the time of diagnosis, his tumor was considered unresectable and he underwent transarterial embolization (TAE)/transcatheter arterial chemoembolization (TACE) 3 times. Assessment with enhanced CT after TAE/TACE showed that a viable lesion remained. Subsequently, he was treated with sorafenib for 15 months. Reassessment showed that the main tumor remained stable in size, and he was admitted to our hospital for surgery. Preoperative evaluation by enhanced CT and MRI detected an intrahepatic metastasis in segment 4 of the liver. After TACE was performed for this nodule, extended right hemihepatectomy with right diaphragmatic and right lung partial resection was performed. He had no postoperative complications and was discharged 27 days after surgery. He remains alive without recurrence 10 months after surgery.

We report a case of hepatocellular carcinoma (HCC) with a Vp4 tumor thrombus treated successfully with multidisciplinary therapy. A 59-year-old woman who complained of abdominal distension was diagnosed as having HCC associated with hepatitis B virus (HBV) infection. The tumor was located in the left lobe, caudate lobe, and S6, and the tumor thrombus extended into the main portal and right portal veins. Extended left lobectomy with thrombectomy and S6 partial hepatectomy were performed after intrahepatic arterial infusion chemotherapy with radiation. During the surgery, the collateral circulation was preserved for bleeding control and residual liver function preservation. The patient was alive 12 months after surgery. Cases of advanced HCC with Vp4 can be successfully treated by multidisciplinary therapy.

The patient was a 65-year-old man. In July 2014, he was diagnosed with rectal cancer in a different hospital and underwent high anterior resection(type 2, T3N0M0, StageⅡ [TMN classification, 7th edition]). During the operation, a small nodule was detected in segment 4 of the liver. Contrast-enhanced abdominal CT revealed a tumor measuring 5 cm in diameter located in segment 4/8 of the liver with a tumor thrombus in the main trunk of the portal vein. In August 2014, the patient was referred to our hospital for further examination and treatment. MR imaging showed a lobulated tumor located in segment 4/8 of the liver. Gadoxeticac id-enhanced hepatobiliary phase MR imaging showed that the tumor was less enhanced than was the adjacent liver parenchyma. 18F-FDG-PET/CT demonstrated abnormal accumulation of 18F-FDG in the main tumor(SUVmax=18.3). There was no obvious abnormal accumulation in the other organs. In September 2014, he underwent extended left hepatectomy and portal vein tumor thrombectomy. The resected specimen showed a well-differentiated adenocarcinoma. Immunohistochemical staining results were CK7/CK20 (-/+) and CDX2 (+), which suggested that the tumor was derived from the gastrointestinal tract rather than the liver. The pathological diagnosis was a liver metastasis from rectal cancer. In the 6 months after the operation, intrahepatic recurrence was detected, and the patient was treated with systemicchemotherapy.

Background: The aim of the present study was to clarify the surgical outcome and long-term prognosis of laparoscopic liver resection (LLR) compared with conventional open liver resection (OLR) in patients with colorectal liver metastases (CRLM)., Methods: A one-to-two propensity score matching (PSM) analysis was applied. Covariates (P < 0.2) used for PSM estimation included preoperative levels of CEA and CA19-9; primary tumor differentiation; primary pathological lymph node metastasis; number, size, location, and distribution of CRLM; existence of extrahepatic metastasis; extent of hepatic resection; total bilirubin and prothrombin activity levels; and preoperative chemotherapy. Perioperative data and long-term survival were compared., Results: From 2005 to 2010, 1,331 patients with hepatic resection for CRLM were enrolled. By PSM, 171 LLR and 342 OLR patients showed similar preoperative clinical characteristics. Median estimated blood loss (163 g vs 415 g, P < 0.001) and median postoperative hospital stay (12 days vs 14 days; P < 0.001) were significantly reduced in the LLR group. Morbidity and mortality were similar. Five-year rates of recurrence-free, overall, and disease-specific survival did not differ significantly. The R0 resection rate was similar., Conclusions: In selected CRLM patients, LLR is strongly associated with lower blood loss and shorter hospital stay and has equivalent long-term survival comparable with OLR., (© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: The clinical significance of the surgical resection of metastatic lymph nodes (LN) from patients with hepatocellular carcinoma (HCC) remains controversial. The aim of this study was to evaluate the significance of the surgical resection of LN metastasis of HCC., Methods: Among 961 patients who underwent surgical resection for HCC in our hospital, LN metastasis was identified in 38 patients. In these patients, the metastatic LN were removed completely in 22 patients (complete removal group), and incompletely or not removed in 16 patients (control group). The long-term prognosis after LN metastasis was compared between the two groups., Results: The overall survival rate after LN metastasis was significantly better in the complete removal group (1-, 3- and 5-year: 71.2, 58.0 and 49.7%, respectively) than in the control group (45.9, 23.0 and 15.3%, respectively, p = 0.0477). LN metastasis was not the cause of death in any of the patients in the complete removal group, whereas it was a cause in some patients in the control group. No local LN recurrence was identified in the complete removal group., Conclusions: The present results suggest that the complete removal of metastatic LN from HCC is clinically beneficial in selected patients.