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Carcinoid syndrome is caused by the release of serotonin and other substances, which commonly occurs due to liver metastasis of neuroendocrine tumors. It rarely occurs due to liver metastasis of neuroendocrine carcinoma. We report the case of a patient with liver metastasis of neuroendocrine carcinoma who suffered from acute abdominal pain and diarrhea triggered by hemodialysis. Various differential diagnoses were considered, but we concluded these symptoms to be probably caused by exacerbation of carcinoid syndrome, as the serum 5HIAA level was markedly elevated, and a drug with anti-serotonin activity was effective. Prochlorperazine maleate, which has anti-serotonin activity, was effective for these symptoms, and the patient was able to continue maintenance hemodialysis, which contributed to his quality of life and prognosis. We speculated the mechanism of carcinoid exacerbation was that substances such as serotonin had entered the systemic circulation via the increased extrahepatic shunt of the portal venous blood flow, entering the inferior vena cava and that this condition had been triggered by hemodialysis via the same mechanism as portal systemic encephalopathy., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background/aim: Indocyanine green (ICG) fluorescence is useful in laparoscopic hepatectomy (LH) for tumor identification and staining, as well as determination of resection margins. At our Institution, patient-specific, three-dimensional simulations and rehearsal of surgical strategies are carried out preoperatively. We describe cases in which ICG administered preoperatively became stagnated and fluoresced in an area similar to the preoperatively established resection area and the pathological findings in these cases., Patients and Methods: Four patients who underwent LH at our hospital between 2020 and 2023 (due to hepatocellular carcinoma in two and colorectal liver metastasis in two) were enrolled in the present study. The ICG-fluorescing liver segments were resected laparoscopically and their pathological characteristics were examined using a fluorescence microscope., Results: In four cases, the areas of ICG fluorescence seen intraoperatively were due to stasis of preoperatively administered ICG, which fortuitously was equivalent to the planned resection area in the preoperative patient-specific simulation. The fluorescent areas were resected; there were no cases of bile leakage or recurrence. Fluorescence microscopy revealed areas with diffuse ICG fluorescence in normal hepatocytes on the tumor's peripheral side., Conclusion: It was suggested that resection of the liver area that was fluorescent due to stagnation of preoperatively administered ICG was rational and justified both anatomically and oncologically. This resection may also contribute to the prevention of bile leakage and recurrence., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 69-year-old man was treated with lenvatinib after three sessions of proton beam therapy (PBT) for hepatocellular carcinoma. Five months after administration of lenvatinib, a dermatitis with huge skin ulcer formed in the site of PBT irradiation. Lenvatinib was immediately withdrawn, but the skin ulcer continued growing until about 2 weeks later. With topical and antibiotic treatment, the skin ulcer resolved after about 4 months. After administration of lenvatinib, potential skin damage due to PBT at the irradiated site may have become apparent. This is the first report describing skin ulcer by the combination of lenvatinib administration and PBT., (© 2023. Japanese Society of Gastroenterology.)

By 2014, strategies to prevent antibody-mediated rejection (AMR) after ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) were established in Japan and expanded primarily to Asia, where LDLT is now the predominant form of LT owing to the scarcity of brain-dead donors. A desensitization protocol consisting of rituximab (375 mg/m 2 ), plasma pheresis, tacrolimus, and mycophenolate mofetil before LDLT, followed by standard immunosuppression, is currently the best option in terms of safety and efficacy. Rituximab administration is now known not to increase the risk of hepatocellular carcinoma recurrence, and the feasibility of rituximab for LDLT for acute liver failure and the need for desensitization before LDLT in children older than 1 y have been documented. Strategies are needed to distinguish patients at high risk of AMR from those at low risk and to adjust immunosuppression to prevent both AMR and infection. Specific single-nucleotide polymorphisms in genes encoding Fcγ receptors affecting the cytotoxicity of rituximab on B cells could be useful for adjusting immunosuppression levels to decrease infectious complications. Immunological accommodation after ABO-I transplantation could be provided by immune factors in both the grafts and recipients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

A 35-year-old man who had fever and stomachache was referred to our hospital. He underwent surgery and chemoradiotherapy for neuroblastoma as a child and subsequently developed leukemia. Frequent blood transfusions and bone marrow transplants were performed due to anemia. Abdominal contrast CT scan and contrast MRI showed tumorous lesions with a diameter of 60×42 mm in liver S6, and a tendency to increase in a short term. There was also hemochromatosis in the liver. We considered it a malignant tumor and performed a right lobectomy. Pathological examination diagnosed the tumor hepatic angiosarcoma. The postoperative course was fine and he was discharged without complications. But multiple liver metastases appeared 6 months after surgery. We performed chemotherapy but he passed away 10 months after surgery. Hepatic angiosarcoma is a rare disease among liver malignancies and has a very poor prognosis. As for the cause of hepatic angiosarcoma, many of them are unknown, but chronic exposures such as vinyl monomers have been reported in some cases. Hemochromatosis has been reported as a background factor for malignant tumors such as hepatocellular carcinoma. In this case it is possible that it contributed to the development of hepatic angiosarcoma.

Recent comprehensive analyses of mtDNA and orthogonal RNA-sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt-Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt-Low condition-induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt-Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin-like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin-dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin-mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence-like cell proliferation inhibition in mt-Low-type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt-Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt-Low or the threat of CKI upregulation cancer-wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor-agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background & Aims: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy., Methods: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization., Results: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC., Conclusions: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease., Gov Number: NCT01761266., Impact and Implications: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aim: Radiofrequency ablation (RFA) is used to treat primary and metastatic tumors in the liver. However, local recurrence after RFA is frequent and subsequent salvage hepatectomy is often ineffective due to difficulty in visualization of tumor margins., Patients and Methods: In the present retrospective clinical trial, seven patients from the Department of General and Gastro-enterological Surgery, Showa University School of Medicine underwent salvage hepatectomy for recurrent hepatocellular carcinoma (HCC) (n=2), colorectal liver metastasis (n=4) and lung-carcinoid liver metastasis (n=1), after RFA, between 2011 and 2020. Tumors were labeled with indocyanine green (ICG) and resected under fluorescence guidance. Resected specimens were evaluated under fluorescence microscopy as well as by standard histopathological techniques., Results: Pathological findings revealed negative tumor margins in all patients after fluorescence-guided surgery. Six of seven resected tumors had a fluorescent rim, including both HCC and liver metastasis. Fluorescence microscopy demonstrated that viable cancer tumor cells were located only on the inside of the fluorescent rim, and no malignant cells were detected within the fluorescent rim surrounding the tumor. Fluorescence microscopy showed that the tumor margin was secured if the fluorescence signal was completely resected., Conclusion: The present results demonstrate that ICG labeling of liver tumors recurring after RFA enabled complete resection under fluorescence guidance. The present study is the first clinical study to demonstrate that tumor types that generally cannot be completely resected with bright light are fully resectable under fluorescence guidance., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: We evaluated real-world efficacy and toxicity of lenvatinib in 142 patients with advanced hepatocellular carcinoma (HCC) at six tertiary referral centres., Patients and Methods: The patients with advanced HCC treated with lenvatinib were grouped into two categories based on REFLECT criteria for analysis of efficacy and safety. The primary endpoint was progression-free survival (PFS)., Results: The objective response rate (ORR) at week 12 of therapy was 41.5%, with a median PFS of 176 days. Child-Pugh score of 5 points, the presence of extrahepatic metastasis and adverse effects grade 2 or higher were considered independent factors associated with both better PFS and ORR. The ORR for patients who fulfilled the REFLECT inclusion criteria was significantly higher than that for those who did not. However, no significant differences in PFS were observed between the two groups. The incidence rate of adverse effects grade 3 or higher was 40.1%, which was similar for the two groups., Conclusion: Lenvatinib is safe and effective for patients, whether or not they satisfy REFLECT criteria. The result warrants replication in a larger study., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We experienced a case of solitary liver tumor that developed after renal cancer surgery. Before the surgery, the tumor was suspected to be hepatocellular carcinoma and was subsequently diagnosed as renal cancer liver metastasis. An 81-year-old man underwent retroperitoneal laparoscopic nephrectomy for left renal cancer in January 2017. After that, the cancer had not recurred, but a follow-up CT examination 1 year after the operation revealed a 42 mm-sized tumor in the liver S6. Liver biopsy was performed for diagnosis, but in histopathological findings, the diagnosis was difficult to make. Eventually, the preoperative final diagnosis was hepatocellular carcinoma. Laparoscopic partial hepatectomy was performed in June 2018, and in the histopathological findings of the resected specimen, the final diagnosis was the liver metastasis from renal cancer. Generally, the prognosis of renal cancer with liver metastasis is poor, but if complete resection is possible, it is recommended in the Clinical Practical Guideline for Renal Cancer. In recent years, the number of minimally invasive laparoscopic surgeries for hepatectomy has increased, and its safety has also improved. Therefore, resection is diagnostic treatment for cases where, like this case, preoperative diagnosis for solitary liver tumor is difficult. Laparoscopic hepatectomy could be one of the effective treatment strategies.

Background: Progranulin (GP88) is an 88-kDa glycoprotein growth factor with important biological effects in tumorigenesis and tumour survival. We investigated the usefulness of measuring serum GP88 concentrations as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after treatment with direct-acting antiviral agents., Methods: We measured the serum GP88 concentrations by using a sandwich enzyme-linked immunoassay from 67 healthy control subjects and 29 patients (20 patients who did not develop hepatocellular carcinoma and 9 patients who developed hepatocellular carcinoma after treatment) with viral hepatitis C after treatment with asunaprevir and daclatasvir., Results: The serum GP88 concentrations of patients with chronic hepatitis C prior to antiviral treatment were significantly higher than those of healthy control subjects. After antiviral treatment, the serum GP88 concentrations of patients who eventually developed hepatocellular carcinoma were significantly higher than those who did not develop hepatocellular carcinoma. The changes in the serum GP88 concentrations before and after treatment in patients who developed hepatocellular carcinoma were significantly lower than those in patients who did not develop hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly higher in either patients with high serum GP88 concentrations after treatment or those with small changes of serum GP88 concentrations pre- and post-treatment., Conclusions: Sustained high concentrations of serum GP88 in patients treated with direct-acting antiviral agents are correlated with the risk of developing hepatocellular carcinoma.

Background: Recently, virtual navigation system has been applied to hepatic surgery, enabling better visualization of intrahepatic vascular branches and location of tumor. Intraoperative ultrasonography (IOUS) is the most common form of image guidance during liver surgery. However, during laparoscopic hepatectomies (LH), IOUS has several limitations and its reliability has been poorly evaluated. The objective of this work is to evaluate VRCT (virtual real-time CT-guided volume navigation) during LH. This system aims to provide accurate anatomical orientation for surgeons enhancing the safety of LH., Methods: Twenty-seven hepatic neoplasms were resected laparoscopically at our institution under reference guidance of VRCT. During operation, electromagnetic tracking of the surgical instrument was used for navigating the direction of accurate liver transection., Results: Twenty-six (96.3%) of the 27 lesions (mean diameter 11 mm) were successfully performed under VRCT guidance. Average registration time was < 2 min. Average setup time was approximately 7 min per procedure. VRCT allows the surgeon to navigate liver transection with acceptable accuracy. The mean error was 12 mm. All surgical margins were negative and the mean histologic resection margin was 9 mm., Conclusions: VRCT-guided LH is feasible and provides valuable real-time anatomical feedback during hepatic resections. Advancement of such systems to improve accuracy might greatly compensate for the limitation of laparoscopic IOUS., (© 2020. The Society for Surgery of the Alimentary Tract.)

Aim: To evaluate the clinicopathological and computed tomography (CT) and magnetic resonance imaging (MRI) findings of steatohepatitic hepatocellular carcinoma (SH-HCC)., Materials and Methods: Clinicopathological and radiological features were evaluated in 20 patients with SH-HCC. The diagnosis of SH-HCC was made histologically if the tumour had four of the following five characteristics: steatosis (>5% tumour cells), ballooning, Mallory-Denk bodies, interstitial fibrosis, and inflammation. All patients underwent dynamic CT and MRI. CT and MRI images were reviewed for morphological features including tumour size, presence, and distribution of fat, and patterns and degree of contrast enhancement., Results: Obesity, hypertension, and history of heavy alcohol intake were common clinical findings observed in 10 (50%), 13 (65%), and 11 (55%) of the 20 patients, respectively. Steatosis and steatohepatitis were pronounced in the background liver in 12 (60%) and 10 (50%) patients, respectively. SH-HCC was moderately differentiated in 18 patients (90%) and well differentiated in two (10%). Pathologically, steatohepatitic features were diffuse in 12 (60%) of the 20 tumours and focal in eight (40%). Tumour size and the percentage of intratumoural steatosis were not correlated (r=0.17, p=0.47). On CT, 16 (80%) patients showed arterial phase enhancement and delayed washout. On MRI, 16 (80%) of 20 tumours showed prominent fatty deposition (10 diffusely, six focally) with arterial phase enhancement., Conclusions: SH-HCC is likely to show prominent fatty deposits with arterial phase enhancement on CT and MRI. A hypervascular lesion with prominent fatty change should raise the diagnostic suspicion of SH-HCC., (Copyright © 2020. Published by Elsevier Ltd.)

Background/aim: To evaluate the complication rates and risk factors associated with transumbilical wounds and investigate the usefulness of an incision for organ removal in laparoscopic hepatectomy (Lap-H)., Patients and Methods: We enrolled 42 patients who underwent Lap-H excluding a small partial resection in our hospital between 2013 and 2018. The occurrences of superficial surgical site infection (SSI) and transumbilical port-site incisional hernia were recorded., Results: SSI was not observed, and hernia occurred in 3 patients (7.14%). Univariate analysis revealed that body mass index (BMI) (p=0.004) was significantly associated with the risk of hernia formation., Conclusion: High BMI is a risk factor for hernia formation in patients undergoing Lap-H with transumbilical incision; hence, wound closure should be performed carefully. The construction of the transumbilical wound for organ removal was feasible with rationality, with no need to create a new wound., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC)., Patients and Methods: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase)., Results: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified., Conclusion: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

The patient was a 67-year-old man with advanced hepatocellular carcinoma (HCC) due to chronic hepatitis B. Due to refractoriness to radiofrequency ablation and transcatheter arterial chemoembolization, lenvatinib, a new oral mutikinase inhibitor, was started with a daily dose of 12 mg. However, on day 6 the patient developed acute-onset, right upper quadrant pain associated with fever; laboratory tests revealed leukocytosis and liver dysfunction. CT scan showed the swollen gallbladder with wall thickening with no evidence of gallstones, and the diagnosis of acute acalculous cholecystitis was made. After the resolution of cholecystitis by antibiotics and endoscopic nasogallbladder drainage placement, lenvatinib was resumed at a reduced daily dose of 4 mg. However, acute acalculous cholecystitis recurred, supporting lenvatinib as a cause of acute acalculous cholecystitis. Using the Naranjo adverse drug reaction probability scale, a score of 6 was derived, which indicates that this adverse event was probably caused by lenvatinib. In summary, we present a patient with advanced HCC who underwent repeated episodes of acute acalculous cholecystitis as a rare adverse event associated with lenvatinib.

Background/aim: This study investigated the use of near-infrared fluorescent imaging for securing safe margins during liver resection., Patients and Methods: This study included 125 patients who underwent liver tumor resection in 2014-2018. Indocyanine green testing was performed 2-14 days before surgery. Histopathological specimens of hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) were evaluated using fluorescent microscopy., Results: Fluorescence microscopy identified signals in 26/53 (49.0%) and 36/72 (50%) cases of HCC and CRLM, respectively. HCC demonstrated total, partial, rim, and combined fluorescence patterns; CRLM uniformly demonstrated rim fluorescence. Although rim fluorescence was seen in both HCC and CRLM, no malignancy was confirmed pathologically in the peritumoral area demonstrating fluorescence. The median widths of fluorescence from the tumor edge in HCC and CRLM were 1227.5 μm and 1608 μm, respectively, with no significant difference., Conclusion: Near-infrared fluorescent imaging can reliably detect safe surgical margins intraoperatively during liver resection., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

During routine ultrasound examination, a hyperechoic mass was detected in the anterior segment of the liver in an 80-year-old woman with hepatitis C virus-related cirrhosis. Computed tomography and magnetic resonance imaging findings suggested a malignant tumor with abundant fibrous stroma, similar to cholangiolocellular carcinoma. However, subsequent partial hepatectomy revealed a mass characterized by abundant fibrosis without tumor cells, dilated blood vessels, and marginal ductular reaction. Accordingly, focal confluent fibrosis was diagnosed. Generally, the diagnosis of focal confluent fibrosis is straightforward because of its well-established imaging characteristics. However, its differentiation from a malignant tumor can occasionally be difficult because of variation in presentation depending on the amount of fibrous stroma and the degree of inflammatory cell infiltration. In the present case, diagnosis was difficult because the lesion was more localized than usual, presenting a mass-like shape, and there was obvious hyperintensity on T2-weighted imaging and ring-shaped hyperintensity on diffusion-weighted imaging. Moreover, hepatic capsular retraction was indistinct, which can be one of the key findings of focal confluent fibrosis. When a hepatic mass is associated with a fibrous lesion, focal confluent fibrosis should be considered in the differential diagnosis, even though the lesion is associated with several atypical findings.

The case presented is a 72-year-old male with no history of hepatitis B or C. Dynamic CT revealed a 2 cm mass in the liver (S8), with arterial phase hyperenhancement and delayed phase washout. The patient underwent an open S8 subsegmentectomy. The mass was pathologically diagnosed as well-to-moderately differentiated hepatocellular carcinoma(T2N0M0, Stage Ⅱ). At 2 years 10 months postoperatively, MRI showed a 4 cm mass in contact with the pancreatic head, inferior vena cava, and duodenum. The mass had moderate FDG uptake on PET scan, and early phase hyperenhancement and delayed phase washout on dynamic CT. We performed laparoscopic mass resection, suspecting lymph node metastasis of the hepatocellular carcinoma, which was confirmed by the pathological diagnosis. The patient has survived for 1 year without recurrence. Lymph node metastasis of hepatocellular carcinoma is rare. It is unclear whether surgical resection is feasible in such cases. Here, we report a case of lymph node metastasis of hepatocellular carcinoma resected by laparoscopic surgery.

Hepatic adrenal rest include ectopic adrenal tissue in the liver and adrenohepatic fusion. Long-lasting hyperstimulation of that tissue induces hyperplasia sometimes simulating true tumors. True autonomic tumors originating from ectopic adrenal tissue with or without hyperfunction are rare. Hepatic adrenal rest sometimes has similar imaging findings to lipid-rich hepatocellular carcinoma or angiomyolipoma, containing obvious lipid component. But in our cases, tumors showed hypervascular patterns similar to hepatocellular adenoma or carcinoma. Therefore, adrenocortical scintigraphy with SPECT/CT should be taken into consideration to diagnose tumoral lesions in the posterior segment of the right hepatic lobe with or without an obvious lipid component.

Glypican-3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. To confirm the effectiveness of GPC3 as a biomarker in HCC, we analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. Preoperative plasma GPC3 levels were determined with an immunoassay, and expression of GPC3 in resected tumors was analyzed by immunohistochemical staining. Median plasma GPC3 level in all HCC cases was 4.6 pg/mL, and tended to be higher in patients with hepatitis C virus (HCV)-related HCC (HCV group) (9.9 pg/mL) than in patients with hepatitis B virus (HBV)-related HCC (HBV group) (2.6 pg/mL) or in those without virus infection (None group) (3.0 pg/mL), suggesting that the virus type most likely influences GPC3 secretion. Median percentage of GPC3 + cells in tumors was also higher in the HCV (26.2%) and HBV (11.1%) groups than in the None group (4.2%). In the HCV group, there was a positive correlation between the two parameters (r = 0.66, P < .01). Moreover, receiver operating characteristic analysis predicted >10% GPC3 + cells in a tumor if the cut-off value was 6.8 pg/mL (sensitivity 80%, specificity 100%; area under the curve 0.875, 95% confidence interval 0.726-1) in the HCV group. Plasma concentration of GPC3 could be a predictive marker of tumoral GPC3 expression in patients with HCV-related HCC, suggesting a useful biomarker for immunotherapies targeting GPC3, although larger-scale validations are needed., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported., Methods: The intent-to-treat population enrolled in Japan was analyzed., Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm., Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC., Trial Registration Id: ClinicalTrials.gov. No. NCT01761266.

Purpose: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy., Methods: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy., Results: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy., Conclusion: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.

A 50-year-old woman was diagnosed as having pancreatic head cancer with multiple hepatic metastases. FOLFIRINOX therapy was initiated. After completing 18 courses of therapy, partial remission(PR)was achieved based on images, and surgery was then planed. The subtotal stomach-preserving pancreaticoduodenectomy and hepatic S7 partial resection were performed. Macroscopically, complete resection was achieved. Regarding pathological findings of the primary lesion and hepatic metastatic lesions, fibrous formation and hyalinizing condition induced by chemotherapy were noted; moreover, complete disappearance of cancer cells was detected. However, metastasis of poorly differentiated adenocarcinoma was detected in 12b lymph node tissue. One month after the surgery, postoperative adjunctive chemotherapy with S-1 was initiated. However, new hepatic metastasis was detected 3 months after the surgery. Although recurrence treatment was initiated, the disease progressed, and the patient died 11 months after the surgery.

Epithelial cell polarity regulator Crumbs3 (Crb3), a mammalian homolog within the Drosophila Crb gene family, was initially identified as an essential embryonic development factor. It is recently implicated in tumor suppression, though its specific functions are controversial. We here demonstrate that Crb3 strongly promotes tumor invasion and metastasis of human colon adenocarcinoma cells. Crb3 centrality to tumor migration was supported by strong expression at invasive front and metastatic foci of colonic adenocarcinoma of the patient tissues. Accordingly, two different Crb3-knockout (KO) lines, Crb3-KO (Crb3 -/-) DLD-1 and Crb3-KO WiDr from human colonic adenocarcinomas, were generated by the CRISPR-Cas9 system. Crb3-KO DLD-1 cells exhibited loss of cellular mobility in vitro and dramatic suppression of liver metastases in vivo in contrast to the wild type of DLD-1. Unlike DLD-1, Crb3-KO WiDr mobility and metastasis were unaffected, which were similar to wild-type WiDr. Proteome analysis of Crb3-coimmunopreciptated proteins identified different respective fibroblast growth factor receptor (FGFR) isotypes specifically bound to Crb3 isoform a through their intracellular domain. In DLD-1, Crb3 showed membranous localization of FGFR1 leading to its functional activation, whereas Crb3 bound to cytoplasmic FGFR4 in WiDr without FGFR1 expression, leading to cellular growth. Correlative expression between Crb3 and FGFR1 was consistently detected in primary and metastatic colorectal cancer patient tissues. Taking these together, Crb3 critically accelerates cell migration, namely invasion and metastasis of human colon cancers, through specific interaction to FGFR1 on colon cancer cells., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in < 1 person in 1,000,000 individuals. For accurate diagnosis, information regarding multiple graphic modalities in HEH is required. However, there is very little information concerning Sonazoid® contrast enhanced ultrasonography (CEUS) in HEH., Case Presentation: The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50's. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase., Conclusions: The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.

Background: Transcatheter arterial chemoembolization (TACE) is widely used for unresectable hepatocellular carcinoma (HCC). The purpose of this study was to investigate incidence and risk factors of contrast-induced nephropathy (CIN) after TACE in patients with HCC., Methods: In this single-center retrospective study, we examined 461 consecutive TACE sessions in 260 patients between January 2003 and October 2015. CIN was defined as an increase in serum creatinine levels by ≥ 0.5 mg/dl or ≥ 25% from baseline within 72 h after TACE. We calculated incidence rate of CIN and tried to identify its risk factors by logistic regression analysis., Results: Twenty-one cases of CIN (5%) were observed in 461 TACE sessions. One patient required subsequent hemodialysis transiently. In univariate analysis, tumor size > 5 cm [odds ratio (OR) 5.76, 95% confidence interval (CI) 2.34-14.14, p < 0.001], chronic kidney disease (OR 2.54, 95% CI 1.05-6.14, p = 0.04), serum hemoglobin level [OR 0.79 (per 1 g/dl increase), 95% CI 0.64-0.98, p = 0.03] and serum albumin level [OR 0.44 (per 1 g/dl increase), 95% CI 0.19-1.02, p = 0.05] were associated with the development of CIN. Stepwise logistic regression methods showed that tumor size > 5 cm (OR 7.81, 95% CI 2.99-20.46, p < 0.001) and serum albumin [OR 0.29 (per 1 g/dl increase), 95% CI 0.11-0.75, p = 0.01] were risk factors of CIN., Conclusions: In this study, HCC tumor size and lower serum albumin level were independent predictors of CIN after TACE.

Objective : Gemcitabine and cisplatin (GC) combination chemotherapy is the current standard of care for patients with advanced biliary tract cancer (BTC). Recently, a randomized controlled trial showed the non-inferiority in overall survival of gemcitabine and S-1 (GS) compared to GC. Because leucovorin is known to enhance the activity of S-1, we conducted this study to evaluate the feasibility of combination therapy of gemcitabine, S-1 and leucovorin (GSL). Methods : Advanced BTC patients without prior treatment other than surgery or adjuvant chemotherapy were eligible to this study. Gemcitabine was administered at a dose of 1000 mg/m 2 on day 1, and oral S-1 at a dose of 40 mg/m 2 and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. The primary endpoint was PFS and the secondary endpoints included OS, objective tumour response and the safety. Results : Between June 2013 and December 2015, 20 patients with advanced BTC (12 gallbladder, 4 extrahepatic, 2 intrahepatic, 2 ampulla) including 16 unresectable disease and 4 recurrent disease were enroled. The median PFS and OS were 5.5 (95% confidence interval [CI], 1.8 - not reached) and 16.0 (95% CI, 6.4-20.8) months, respectively. A partial response was achieved in 3 (15%) and stable disease in 8 (40%), giving a disease control rate of 55%. Major grade 3/4 toxicities included neutropenia (30%), anaemia (5%), stomatitis (15%), diarrhoea (15%) and anorexia (10%). There were no treatment-related deaths. Conclusions : This study showed the feasibility and potential efficacy of GSL as a first-line treatment in patients with advanced BTC.

The Fontan procedure is an open heart procedure performed in pediatric patients with a particular congenital cardiac anomaly known as a univentricular heart. The procedure is used to reroute the systemic venous blood from the inferior vena cava directly to the pulmonary artery. It improves patients' prognoses, but various late-phase extracardiac complications that manifest when patients reach adolescence have been recognized. These complications, pulmonary arteriovenous fistula and protein losing gastroenteropathy, for example, present significant challenges in the management of adults with Fontan circulation. Liver fibrosis is another possible late-phase complication and one of the most serious. Development of a neoplasm, usually a hepatocellular carcinoma, is sometimes reported. We encountered a young patient in whom Fontan circulation led to the development of a histologically unusual liver cancer that resembled the poorly differentiated hepatocellular carcinoma or the combined hepatocellular-cholangiocarcinoma with stem-cell features described in the latest WHO classification., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Purpose: Irreversible electroporation (IRE) differs from thermal radiofrequency (RF) ablation, especially in terms of the reparative process in the ablation zone induced. To elucidate this, the systemic immune responses after 2 mechanistically different types of ablation (IRE and RF ablation) were evaluated in patients with hepatocellular carcinoma (HCC)., Materials and Methods: Twenty-one patients with HCC who underwent either RF ablation (n = 11) or IRE (n = 10) were studied. Peripheral blood samples were collected from all patients at 4 timepoints: before ablation, within 1 hour after ablation, 1 day after ablation, and 4 days after ablation. The phenotypes and functions of immune cells in peripheral blood and serum levels of cytokines and chemokines were monitored and analyzed using the mixed-effects model. Follow-up radiological images were also obtained to assess temporal changes in the ablation zone., Results: The most significant difference was seen in the levels of macrophage migration inhibitory factor (MIF) in the IRE group compared to the RF ablation group (P = .0011): the serum levels of MIF in the IRE group significantly increased immediately after IRE and then rapidly decreased to the pre-ablation range 1 day after IRE, but, in contrast, no consistent trend was observed in the RF ablation group. The axial diameter (P = .0009) and area (P = .0192) of the ablation zone of IRE were significantly smaller than those of RF ablation 1 year after ablation., Conclusions: IRE was found to be associated with a significant early increase in MIF levels, which may facilitate the early reparative process and result in significant shrinkage of the ablation zone., (Copyright © 2019 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

Background: Brain involvement of hepatosplenic T cell lymphoma (HSTL) has not been reported so far., Case Description: We observed an extremely rare case of HSTL, which is a rare and aggressive variant of peripheral T cell lymphoma, generally showing predominant infiltration to the liver, spleen, and bone marrow and involving the brain. A 41-year-old Japanese woman presented with dysarthria and numbness of the right hand. Radiologic examination revealed a single 3-cm mass in the left frontal cortex, which was totally removed. Pathologic examination of the specimen demonstrated T cell lymphoma with a γδ cytotoxic T cell phenotype. Multiplex polymerase chain reaction analyses confirmed monoclonality of T cell receptor γ. Systemic examination revealed infiltration of atypical T lymphoid cells of the same phenotype in bone marrow and the presence of hepatosplenomegaly. We diagnosed HSTL involving the brain. The patient was treated with several courses of intensive chemotherapy, but it failed to achieve remission. She died of sepsis 4 months after the surgery., Conclusions: HSTL can involve the brain. A diagnosis of HSTL involving the brain needs careful systemic evaluation. Timely and precise diagnosis that considers the systemic condition is important for appropriate treatment and better outcome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sorafenib is a multi-kinase inhibitor for treatment of advanced hepatocellular carcinoma (HCC). Beyond its clinical benefit against advanced HCC, the efficacy and safety of sorafenib chemotherapy are critical concerns. In this study, we addressed the lipid profiles associated with the efficacy and safety of sorafenib chemotherapy. Plasma samples from HCC patients before sorafenib chemotherapy (N = 44) were collected and subjected to lipidomic analysis. We measured the levels of 176 lipids belonging to 8 classes of phosphoglycerolipids, 2 classes of sphingolipids, 3 classes of neutral lipids, and 4 other classes of lipids. To characterize lipids associated with efficacy, we compared the responder group (N = 21; partial response and stable disease) with non-responder group (N = 22; progressive disease). To characterize lipids associated with hand-foot skin reaction (HFSR), we compared the susceptible group (N = 12; grade 2 and 3) with non-susceptible group (N = 32; grade 0 and 1). The levels of 8 lipids, including phosphatidylcholine (PC)[34:2], PC[34:3]a, PC[35:2], PC[36:4]a, PC[34:3e], acylcarnitine (Car)[18:0], cholesterol ester[20:2], and diacylglycerol (DG)[34:2], were significantly lower in the responder group, and 6 out of 8 these lipids contained FA(18:2). In addition, the levels of 7 lipids (Car[12:0], Car[18:0], Car[18:1], Car[20:1] and fatty acid amides (FAA[16:0], FAA[18:0], and FAA[18:1]b)) were significantly lower in the group susceptible to HFSR. Our comprehensive lipidomics study using samples from sorafenib-treated patients with HCC revealed that significant differences in the lipid profiles of pre-treatment plasma were associated with sorafenib efficacy and sorafenib-induced HFSR. Validation using another set of patient plasma samples and elucidating the molecular basis of these changes will lead to better treatment with sorafenib chemotherapy.

Background: We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored., Methods: The anti-HCV effect of brusatol was investigated by analyzing HCV RNA and proteins in a hepatic cell line persistently-infected with HCV, HPI cells, and by analyzing HCV replication in a replicon-replicating hepatic cell line, OR6 cells. Then, dual anti-HCV and anticancer effects of brusatol and enhancement of the effects by the combination of brusatol with anticancer drugs including sorafenib, which has been reported to have the dual effects, were then investigated., Results: Brusatol suppressed the persistent HCV infection at both the RNA and protein levels in association with a reduction in Nrf2 protein in the HPI cells. Analysis of the OR6 cells treated with brusatol indicated that brusatol inhibited HCV persistence by inhibiting HCV replication. Combination of brusatol with an anticancer drug not only enhanced the anticancer effect but also, in the case of the combination with sorafenib, strongly suppressed HCV infection., Conclusions: Brusatol has dual anti-HCV and anticancer effects and can enhance the comparable effects of sorafenib. There is therefore the potential for combination therapy of brusatol and sorafenib for HCV-related hepatocellular carcinoma.

Background Recently, diffusion-weighted imaging (DWI) and quantitative enhancement ratio measured at the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has been established as an effective method for evaluating liver fibrosis. Purpose To evaluate which is a more favorable surrogate marker in predicting high-stage liver fibrosis, apparently diffusion coefficient (ADC) value or quantitative enhancement ratio measured on HBP. Material and Methods Eighty-three patients with 99 surgically resected hepatic lesions were enrolled in this study. DWI was performed with b-values of 100 and 800 s/mm 2 . Regions of interest were set on ADC map, and the HBP of Gd-EOB-DTPA-enhanced MRI, to calculate ADC value, liver-to-muscle ratio (LMR), liver-to-spleen ratio (LSR), and contrast enhancement index (CEI) of liver. We compared these parameters between low-stage fibrosis (F0, F1, and F2) and high-stage fibrosis (F3 and F4). Receiver operating characteristic analysis was performed to compare the diagnostic performance when distinguishing low-stage fibrosis from high-stage fibrosis. Results LMR and CEI were significantly lower at high-stage fibrosis than at the low stage ( P < 0.01 and P = 0.04, respectively), whereas LSR did not show a significant difference ( P = 0.053). No significant difference was observed in diagnostic performance between LMR and CEI ( P = 0.185). The best sensitivity and specificity, when an LMR of 2.80 or higher was considered to be low-stage fibrosis, were 82.4% and 75.6%, respectively. ADC value showed no significant differences among fibrosis grades ( P = 0.320). Conclusion LMR and CEI were both adequate surrogate parameters to distinguish high-stage fibrosis from low-stage fibrosis.

Background: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma., Methods: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266., Findings: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib., Interpretation: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed., Funding: Eisai Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS), contrast-enhanced multiphase CT (CECT), and gadoxetic acid-enhanced MRI (EOB-MRI) in identifying residual tumor in the subacute follow-up of patients with malignant hepatic tumors treated by irreversible electroporation (IRE)., Methods: We enrolled 16 patients with 21 hepatic lesions treated by IRE and examined by CEUS and CECT at 1 day after IRE and by EOB-MRI at 7 days after IRE. Follow-up examinations by EOB-MRI or CECT and CEUS were performed at 3-month intervals. Two radiologists independently reviewed the images and assessed the probability of residual tumor using a five-point scale with receiver operating characteristic (ROC) curve analysis. The sensitivity and specificity were also evaluated. Verifiable local recurrence was assessed using follow-up imaging as the reference standard., Results: The mean area under the ROC curve was significantly higher for CEUS (0.980) than for CECT (0.742, P < 0.01) and EOB-MRI (0.806, P < 0.01), as were the sensitivity and specificity (mean 85.7 and 85.7% for CEUS, respectively, vs 64.3 and 46.4% for CECT and 78.6 and 64.3% for EOB-MRI)., Conclusion: CEUS was found to be superior to CECT and EOB-MRI for the diagnosis of residual tumor in the subacute phase following IRE.

Background: Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice., Results: By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice., Conclusions: Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface protein overexpressed in hepatocellular carcinoma(HCC), and its overexpression is associated with poor prognosis. The diagnostic potential of GPC3 as a serum marker has been reported. In the present study, we evaluated the usefulness of plasma GPC3 as a predictor for recurrence after surgical resection in stage I HCC patients by newly developed an enzyme-linked immunosorbent assay (ELISA) system. Current study demonstrated that high levels of preoperative plasma GPC3 patients tended to experience postoperative recurrence. On the other hand, pre- and postoperative plasma GPC3 positivity of non-recurrence patients was very low. Moreover, even after surgery, approximately half of patients who experienced recurrence were positive for plasma GPC3. Postoperative plasma GPC3 positivity was significantly correlated with worse recurrence-free survival. Immuohistochemical analysis also showed positive rate of GPC3-expression in HCC was higher in recurrence patients than in non-recurrence patients. These results suggested that both pre- and postoperative plasma GPC3 levels may be accurate predictors for recurrence after curative resection of early-stage HCC. It should be noted that the current study only examined a small number of cases; thus, a larger sample size is necessary to validate GPC3 as a predictor for HCC recurrence.

Background: To evaluate the usefulness of differentiation of histological grade in hepatocellular carcinoma (HCC) using three-dimensional (3D) analysis of apparent diffusion coefficient (ADC) histograms retrospectively., Methods: The subjects consisted of 53 patients with 56 HCCs. The subjects included 12 well-differentiated, 35 moderately differentiated, and nine poorly differentiated HCCs. Diffusion-weighted imaging (b-values of 100 and 800 s/mm 2 ) were obtained within 3 months before surgery. Regions of interest (ROIs) covered the entire tumor. The data acquired from each slice were summated to derive voxel-by-voxel ADCs for the entire tumor. The following parameters were derived from the ADC histogram: mean, standard deviation, minimum, maximum, mode, percentiles (5th, 10th, 25th, 50th, 75th, and 90th), skew, and kurtosis. These parameters were analyzed according to histological grade. After eliminating steatosis lesions, these parameters were re-analyzed., Results: A weak correlation was observed in minimum ADC and 5th percentile for each histological grade (r = -0.340 and r = -0.268, respectively). The minimum ADCs of well, moderately, and poorly differentiated HCC were 585 ± 388, 411 ± 278, and 235 ± 102 × 10 -6 mm 2 /s, respectively. Minimum ADC showed significant differences among tumor histological grades (P = 0.009). The minimum ADC of poorly differentiated HCC and that of combined well and moderately differentiated HCC were 236 ± 102 and 437 ± 299 × 10 -6 mm 2 /s. The minimum ADC of poorly differentiated HCC was significantly lower than that of combined well and moderately differentiated HCC (P = 0.001). The sensitivity and specificity, when a minimum ADC of 400 × 10 -6 mm 2 /s or lower was considered to be poorly differentiated HCC, were 100 and 54%, respectively. After exclusion of the effect of steatosis, the sensitivity and specificity did not change, although the statistical differences became strong (P < 0.0001)., Conclusion: Minimum ADC was most useful to differentiate poorly differentiated HCC in 3D analysis of ADC histograms.

Introduction: The aim of this study to evaluate the effectiveness of enhanced diffusion-weighted imaging (DWI) for distinguishing liver haemangiomas from metastatic tumours (mets)., Methods: This study included 23 patients with 27 haemangiomas and 26 patients with 46 mets. Breath-holding diffusion-weighted imaging (DWI) (b-values of 0, 50, 100, 150, 200, 400 and 800 s/mm 2 ) were obtained before and 20 min after injection of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Lesion contrast-to-noise ratios (CNRs) were calculated. The data were processed using the bi-exponential model of intravoxel incoherent motion (IVIM). Receiver operating characteristic analysis was performed to compare the diagnostic performance when distinguishing haemangioma from mets., Results: The CNRs of haemangioma and mets at post-contrast enhancement increased. All IVIM parameters for liver haemangioma and mets showed no significant differences between pre- and post-contrast enhancement. The highest A z value of CNR and IVIM parameters occurred at a post-contrast b-value of 0 s/mm 2 and true diffusion (D). The highest qualitative evaluation occurred at a b-value of 800 s/mm 2 . The sensitivity and specificity, with a CNR of 100 or higher at a post-contrast b-value of 0 s/mm 2 and considered to be haemangioma, were 89% and 67% (<10 mm, 91%, 77%) respectively. The sensitivity and specificity, when D was higher than 1.4 × 10 -3 mm 2 /s, were 74% and 83% (<10 mm, 64%, 77%) respectively. The sensitivity and specificity of qualitative evaluation by enhanced DWI were 74% and 76% (<10 mm, 64%, 80%) respectively., Conclusions: The accuracy of the CNR was highest with b = 0; however, examination at high b-values had advantages in the qualitative evaluation of some small-size lesions., (© 2016 The Royal Australian and New Zealand College of Radiologists.)

Background: To evaluate the association between the therapeutic outcomes of sorafenib for advanced hepatocellular carcinoma (HCC) and the parameters of intravoxel incoherent motion (IVIM)., Methods: Nine patients were evaluated prospectively. All patients were Child-Pugh score A. The mean dimension of the lesion was 32 mm (range: 15-74 mm). MR images were obtained using a 1.5-Tesla superconductive MRI system. Diffusion-weighted imaging was performed under breath-holding using b-values of 0, 50, 100, 150, 200, 400, and 800 s/mm(2). The following IVIM parameters were calculated: apparent diffusion coefficient, true diffusion coefficient (DC), pseudo-diffusion coefficient, and perfusion fraction. MRI was performed before treatment and at 1, 2, and 4 weeks after beginning treatment. Tumor response at 4 weeks was assessed by CT or MRI using modified RECIST. IVIM parameters of the treatment responders and non-responders were compared., Results: The DC of responders at baseline was significantly higher than that of the non-responders. The sensitivity and specificity, when a DC of 0.8 (10(-3) mm(2)/s) or higher was considered to be a responder, were 100 % and 67 %, respectively. No significant differences were found in the other parameters between the responders and the non-responders. All IVIM parameters of the responders and non-responders did not change significantly after treatment., Conclusion: The DC before treatment may be a useful parameter for predicting the therapeutic outcome of sorafenib for advanced HCC.

A 58-year-old woman was admitted to our hospital for evaluation of left flank pain. Abdominal computed tomography showed a greatly enlarged splenic tumor with a massive portal vein tumor thrombosis (PVTT). We suspected non-Hodgkin lymphoma (NHL) based on the high values of serum soluble interleukin-2 receptor and lactate dehydrogenase. Because there was no superficial lymph node enlargement, ultrasound-guided percutaneous trans-hepatic needle biopsy was performed to obtain a pathological diagnosis of PVTT, instead of a splenectomy, after the patient had provided informed consent. This procedure was thought to be less invasive than splenectomy. Histologic examination revealed CD20-positive NHL. A complete response was achieved after six courses of R-CHOP and it was confirmed by splenectomy. A PVTT due to NHL is extremely rare as compared with that due to hepatocellular carcinoma, gastric cancer, and colon cancer. However, NHL should be considered in the differential diagnosis for a patient with a PVTT, because B cell-NHL tends to have a good prognosis when rituximab combined chemotherapy is administered. We suggest that a percutaneous trans-hepatic needle biopsy may be useful for diagnosing PVTT due to NHL.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the 5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α-fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers, such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article, we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.

Purpose: This clinical study was conducted to evaluate the safety and short-term outcomes of irreversible electroporation (IRE) for the treatment of patients with hepatocellular carcinoma (HCC) in Japan., Materials and Methods: The study was designed in a prospective setting. Five patients (3 men and 2 women; mean age, 66.6 ± 5.8 years) with 6 HCCs were enrolled and treated using percutaneous ultrasound (US)-guided IRE. Safety was assessed based on adverse events and laboratory values. Local control was assessed using contrast-enhanced US with a perflubutane microbubble contrast agent, contrast-enhanced multiphase CT, and gadoxetic acid-enhanced MRI (EOB-MRI) at designated points., Results: The tumors ranged in diameter from 11 to 28 mm (mean diameter, 17.5 ± 6.3 mm). Five of the 6 tumors (83 %) were successfully treated, with no local recurrence to date (mean follow-up 244 ± 55 days). In 1 lesion located in liver segment 1, residual tumor was diagnosed at 7 days after intervention by follow-up EOB-MRI. No serious complications related to the IRE procedure were observed., Conclusion: The results of this study suggest that image-guided percutaneous IRE can achieve satisfactory local disease control, particularly for small HCCs, and is well tolerated by patients.

Purpose: To assess the value of shear wave elastography (SWE) for predicting the presence of hepatocellular carcinoma (HCC) and esophagogastric varices (EGV) in patients with chronic liver disease., Methods: Liver tissue stiffness, as well as various other parameters potentially associated with HCC and portal hypertension, was measured by SWE in 273 patients with chronic liver disease. Among these patients, HCC was present in 89 and absent in 184, and EGV were present in 16 and absent in 257. The diagnostic performance of liver tissue stiffness and other clinical parameters in predicting the presence of HCC and EGV was evaluated using receiver operating characteristic (ROC) curves and the area under the ROC curve (AUROC)., Results: With regard to HCC, liver tissue stiffness was significantly higher in patients with HCC (18.65 ± 10.78 kPa) than in those without HCC (10.64 ± 8.04 kPa; P < 0.0001). Significant differences in patient age (P < 0.0001), albumin (P < 0.0001), platelet count (P < 0.0001), AFP (P < 0.0001), and DCP (P < 0.0001) were also observed between patients with and without HCC. Liver tissue stiffness showed the largest AUROC (0.791). With regard to EGV, liver tissue stiffness was significantly higher in patients with EGV (22.65 ± 10.19 kPa) than in those without EGV (12.67 ± 9.45 kPa; P < 0.0001). Significant differences in albumin (P < 0.0001) and platelet count (P < 0.0001) were also observed between patients with and without EGV., Conclusions: Liver tissue stiffness measured by SWE is an independent factor for predicting the presence of HCC and EGV in patients with chronic liver disease.

Objective: The objective was to evaluate the efficacy of diffusion-weighted imaging (DWI) in predicting the development of vascularization in hypovascular hepatocellular lesions (HHLs)., Materials and Methods: Forty-two HHLs that were diagnosed by computed tomographic (CT) arteriography were evaluated retrospectively. The lesion on DWI was classified as isointense, hypointense, or hyperintense. Follow-up studies that included intravenous dynamic CT or magnetic resonance imaging were performed., Results: The 730-day cumulative developments of vascularization in hypointense, isointense, and hyperintense lesions were 17%, 30%, and 40%, respectively. The differences among these developments were not statistically significant., Conclusion: The signal intensity on DWI showed no significant difference in the development of vascularization., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An 84-year-old Japanese man was admitted with hepatocellular carcinoma (HCC). He underwent transcatheter arterial chemoembolization and percutaneous radiofrequency ablation (RFA). Three weeks later, he developed sudden-onset right pleural effusion mixed with bile. Drip infusion cholangiography-computed tomography revealed leakage of the contrast agent, which passed from the HCC to the pleural cavity through a perforation in the diaphragm. The patient's condition improved after thoracic and endoscopic nasobiliary drainage. The occurrence of pleural effusion mixed with bile is a rare complication of RFA. This case provides important information about the morbidity, prevention, and treatment of this complication.

The aim of this study was to assess quantitatively the Kupffer-phase enhancement patterns of hepatic hemangiomas in contrast-enhanced ultrasound (CEUS) with Sonazoid. A total of 46 patients with 46 hepatic hemangiomas (17.1 ± 6.2 mm in diameter, 34 typical type and 12 high-flow type) underwent CEUS in the Kupffer phase. The lesion-to-liver contrast ratio in the Kupffer phase was quantitatively assessed for both types of hemangioma. Most of the hepatic hemangiomas, whether or not they were the high-flow type, were iso- to hypo-echoic relative to the surrounding liver parenchyma. The contrast ratio was -5.33 ± 6.70 dB for the high-flow hemangiomas and -4.54 ± 6.28 dB for the typical hemangiomas. There was no significant difference in contrast ratio between the two types of lesions (p = 0.73). All of the hemangiomas, whether of typical or high-flow type, are iso- to hypo-echoic relative to the surrounding liver parenchyma on Kupffer-phase imaging., (Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)