Remaining Issues Related to Serum Cytokines in Patients with Unresectable Hepatocellular Carcinoma Treated by Atezolizumab plus Bevacizumab Combination Treatment.

INTRODUCTION: Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. METHODS: We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev were administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. RESULTS: In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease (SD), but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. CONCLUSION: These findings reveal a need to further improve T-cell priming and to further make T-cells recognize tumor antigens in uHCC.

Hepatitis B Virus-related Membranous Nephropathy with Crescentic Formation in an Inactive Carrier of Positive Hepatitis B Surface Antigen with Undetectable DNA under Anti-viral Treatment.

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.

Importance of Atezolizumab Plus Bevacizumab Combination Treatment as First-line Therapy for Immunological Changes in Patients With Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: The atezolizumab plus bevacizumab (AteBev) therapy is recommended as first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, there remains a need to examine its efficacy with and without previous chemotherapy. Therefore, in patients with uHCC who underwent AteBev therapy, we aimed to clarify the effects of previous chemotherapy by examining serum immunological changes. PATIENTS AND METHODS: We retrospectively analyzed data of 29 patients with uHCC treated by AteBev therapy as part of a prospective study and divided participants into two groups depending on whether they had received prior chemotherapy. Dynamic computed tomography was performed after 6 weeks of treatment. Blood samples were collected at baseline and after 3 weeks of treatment. RESULTS: The group with prior treatment included 15 patients and the group without prior treatment included 14 patients. Objective response rates after six weeks of treatment were 13.3% and 28.6% in the groups with and without prior treatment, respectively. Serum levels of interleukin (IL)-6 and tumor necrosis factor-alpha showed no significant change in the group with prior treatment but increased significantly in the group without prior treatment. The percentage of regulatory T cells decreased significantly after treatment only in the group without prior treatment. CONCLUSION: In patients with uHCC, AteBev therapy can be expected to elicit an effective immune response in patients without prior treatment, but it may not do so in patients with prior treatment. Thus, AteBev appears to be more effective when used as first-line chemotherapy.

Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.

INTRODUCTION: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN. METHODS: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. RESULTS: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively. CONCLUSION: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

Effects of Lenvatinib on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduces skeletal muscle volume. Moreover, others reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluate the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC). METHODS: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4-6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography. RESULTS: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventricular ejection fraction showed no significant change. CONCLUSION: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function.

Comparison of strain elastography and shear wave elastography in diagnosis of fibrosis in nonalcoholic fatty liver disease.

PURPOSE: To reveal the ability of S-Map strain elastography to diagnose fibrosis in nonalcoholic fatty liver disease (NAFLD) and to compare its diagnostic ability with that of shear wave elastography (SWE). METHODS: Participants were patients with NAFLD who were scheduled to undergo liver biopsy at our institution between 2015 and 2019. A GE Healthcare LOGIQ E9 ultrasound system was used. For S-Map, the right lobe of the liver was visualized in the section where the heartbeat was detected by right intercostal scanning, a 4 × 2-cm region of interest (ROI) was defined at 5 cm from the liver surface, and ROI strain images were acquired. Measurements were repeated six times, with the average taken as the S-Map value. Correlations of S-Map and SWE values with fibrosis stage determined by liver biopsy were analyzed using multiple comparisons. The diagnostic performance of S-Map for fibrosis staging was assessed using receiver operating characteristic curves. RESULTS: In total, 107 patients (65 men, 42 women; mean age 51 ± 14 years) were analyzed. The S-Map value by fibrosis stage was 34.4 ± 10.9 for F0, 32.9 ± 9.1 for F1, 29.5 ± 5.6 for F2, 26.7 ± 6.0 for F3, and 22.8 ± 4.19 for F4. By fibrosis stage, the SWE value was 1.27 ± 0.25 for F0, 1.39 ± 0.20 for F1, 1.59 ± 0.20 for F2, 1.64 ± 0.17 for F3, and 1.88 ± 0.19 for F4. The diagnostic performance of S-Map (measured by area under the curve) was 0.75 for F2, 0.80 for F3, and 0.85 for F4. The diagnostic performance of SWE (measured by area under the curve) was 0.88 for F2, 0.87 for F3, and 0.92 for F4. CONCLUSION: S-Map strain elastography was inferior to SWE in terms of ability to diagnose fibrosis in NAFLD.

A case of multiple hepatocellular carcinoma experiencing complete responses to sorafenib and atezolizumab-bevacizumab and developing severe, refractory venous congestive cutaneous ulcers on either regimen.

A man in his eighties presented with a history of bilateral leg congestive phlebitis, and multiple hepatocellular carcinoma (HCC) treated with sorafenib. When the dose was increased to 400 mg, ulcers appeared under both knees, which worsened, and the drug was discontinued 2 months after administration. However, the ulcers to 30 mm in diameter, requiring debridement and antibiotics. The HCC showed a complete response (CR) based on modified-RECIST criteria; however, after several rounds of locoregional therapy for recurrence, multiple HCCs and metastatic lesions in the Morrison's fossa were detected. Therefore, atezolizumab 1200 mg-bevacizumab 900 mg was started. After the first course, the patient complained of pain below both knees, and when the second course was administered, leg ulcers re-appeared and rapidly worsened. The ulcers were circular and multiple and progressed to deep digging, leading to tendon exposure. Bevacizumab-induced congestive venous ulcer was diagnosed, requiring skin grafts to heal. HCC then showed a CR based on m-RECIST criteria. Initially, the cause of the ulcer was thought to be immune-related adverse effects due to atezolizumab, but experience with sorafenib led us to conclude that the cause was stagnant venous ulcers due to vascular endothelial growth factor receptor inhibitor, which inhibited angiogenesis.

Lenvatinib Might Induce Activation of Host Immunity in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab, an immune checkpoint inhibitor, plus bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is an approved first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Immune checkpoint inhibitors are more effective in patients with HCC when administered with anti-VEGF drugs; however, these drugs affect host immunity. Lenvatinib is an anti-VEGF agent used to treat HCC; therefore, this study evaluated the effect of treatment of HCC with lenvatinib on host immunity in patients with chronic liver disease (CLD). METHODS: We studied adult Japanese patients with CLD and unresectable HCC treated with lenvatinib at our hospital. Lenvatinib was administered for 4 weeks (8 mg/day for bodyweight <60 kg; 12 mg/day for bodyweight >60 kg). Blood samples were collected at baseline and at 4 weeks of treatment and examined for immune-related changes. RESULTS: Forty-three patients were enrolled in this study. We found a significant increase in T helper (Th) 1 cells following 4 weeks of lenvatinib treatment, although there was no significant difference in Th2 cells and regulatory T cells. We also found a significant increase in serum levels of TNF-alpha, soluble TNF-alpha receptor I, and endothelial growth factor following 4 weeks of lenvatinib treatment. Furthermore, an increase in Th1 cells and serum levels of TNF-alpha was found in patients with partial response. CONCLUSION: Lenvatinib might induce Th1-dominant host immunity in patients with CLD and unresectable HCC treatment in patients who showed a partial response. These changes in host immunity may be a biomarker in HCC patients treated with lenvatinib.

Measurement of skeletal muscle volume is useful for predicting prognosis in patients with liver cirrhosis.

BACKGROUND: Hepatic venous pressure gradient (HVPG) and the model for end-stage liver disease (MELD) score were previously reported as prognostic factors for outcome in patients with liver cirrhosis (LC), and recently, the presence of sarcopenia was reported to be an indicator of worse prognosis in these patients. AIM: This retrospective study aimed to clarify the importance of sarcopenia as a prognostic factor in patients with LC. MATERIAL AND METHODS: The MELD-Na score, HVPG, and skeletal muscle index (SMI) were measured in 202 patients between January 2013 and August 2020. We performed linear regression analysis between HVPG and SMI and calculated suitable cutoff values of HVPG for predicting presarcopenia and of HVPG, ΔSMI (i.e. the decrease in SMI per year, for predicting survival). Overall survival rates with the HVPG and ΔSMI cutoff values were compared by Kaplan-Meier estimates and log-rank tests. Prognostic factors for survival were analyzed by Cox regression univariate and multivariate analyses. RESULTS: In total, 71% (143/202) of patients presented with presarcopenia. Linear regression showed a significantly negative correlation between HVPG and SMI. Survival was significantly worse in the group with presarcopenia than in the group without. Survival was worse also in the group with an HVPG value ≥ 15 and ΔSMI ≥ -2.4. Cox regression multivariate analyses showed that MELD-Na score, HVPG, HVPG ≥ 15, ΔSMI, and ΔSMI ≥ -2.4 were independent prognostic factors. CONCLUSION: Skeletal muscle volume, especially ΔSMI, has a prognostic value equivalent to that of the MELD-Na score and HVPG.

Usefulness of partial splenic embolization for left-sided portal hypertension in a patient with a pancreatic neuroendocrine neoplasm: a case report and review of the literature.

Left-side portal hypertension (LSPH) is caused by isolated obstruction of the splenic vein and is associated with esophagogastric varices that extend from the lower esophagus to the greater curvature of the gastric body. Here, we report on a 74-year-old man with a pancreatic neuroendocrine neoplasm (NEN) in the pancreatic tail with multiple liver metastases. We decided that partial splenic embolization (PSE) was the best course of treatment to prevent rupture of the gastric varices, which were classified as markedly enlarged, nodular, or tumor-shaped and showed erosion of the mucosa. After PSE, the patient had no major complications and was discharged. At 3 and 6 months after the procedure, esophagogastroduodenoscopy and enhanced computerized tomography showed that the gastric varices had improved. This case demonstrates the usefulness of PSE for LSPH in patients with unresected pancreatic NEN.

Arrival-Time Parametric Imaging in Contrast-Enhanced Ultrasound for Diagnosing Fibrosis in Primary Biliary Cholangitis.

Liver biopsy is usually required for diagnosing fibrosis in primary biliary cholangitis (PBC), but contrast-enhanced ultrasonography (CEUS) is a possible alternative. The aim of this study was to investigate arrival-time parametric imaging (At-PI) in for diagnosing fibrosis in PBC. Forty-eight patients (male/female, 8/40; mean age, 60 ± 13 years) with PBC diagnosed by liver biopsy underwent CEUS during 2009-2019. Of these, 27 who also underwent shear wave elastography (SWE) were further analyzed. Perflubutane was intravenously injected and CEUS performed. Contrast dynamics of hepatic segment V and the right kidney were recorded and At-PI generated. The ratio of red indicating contrast arrival time <5 seconds to the entire liver contrast-enhanced area was calculated and compared with shear wave velocity (Vs) measured by SWE by fibrosis stage (F0-F3), bile duct loss score, cholangitis activity, hepatitis activity (HA0-HA3), and disease stage, as determined by liver biopsy. Ratio of red significantly differed between F0 and F2-F3 and between F1 and F2-F3. Using ratio of red to diagnose ≥F1 (≥F2), area under the receiver operating characteristic curve was 0.77 (0.92) (cutoff, 36.7% [47.1%]; sensitivity, 0.75 [0.92]; specificity, 0.82 [0.81]). At-PI was useful for diagnosing fibrosis, especially F2 or worse, in PBC, suggesting that At-PI can correctly diagnose fibrosis regardless of hepatic inflammation.

Adaptation of lenvatinib treatment in patients with hepatocellular carcinoma and portal vein tumor thrombosis.

PURPOSE: The aim of this study was to clarify the adaptation of lenvatinib treatment in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHOD: Fifty-three patients with HCC were treated with lenvatinib. Before and after treatment blood sampling, patients were examined by computed tomography and ultrasonography. In patients with portal trunk invasion (Vp4), the analysis focused on the degree of occlusion due to the tumor in the portal trunk. In patients without major PVTT {ie, invasion of the primary branch of the portal vein [Vp3] or Vp4}, portal blood flow volume was measured by Doppler analysis; however, Doppler analysis is difficult to perform in patients with major PVTT, so the time from administration of the contrast agent to when it reached the primary branch of the portal vein (portal vein arrival time) was evaluated with the contrast agent Sonazoid. RESULTS: Patients with Vp4 had a significantly worse prognosis than patients with Vp3 and a significant increase in Child-Pugh score at 2 months. Patients with major PVTT had a poor prognosis if the degree of occlusion of the portal trunk was 70% or more. In patients without major PVTT, portal blood flow was significantly decreased after administration of lenvatinib; and in patients with major PVTT, the hepatic artery and portal vein arrival times were significantly increased. CONCLUSION: Lenvatinib treatment should be avoided in patients with Vp4 with a high degree of portal trunk occlusion because of concerns about decreased portal blood flow.

The ultrasound-guided attenuation parameter is useful in quantification of hepatic steatosis in non-alcoholic fatty liver disease.

AIM: To determine the utility of the ultrasound-guided attenuation parameter (UGAP) for quantifying hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). METHODS: Subjects were 84 patients with NAFLD (53 men, 31 women; mean age 54 [20-81] years) who underwent liver biopsy and ultrasonography using a GE LOGIQ E9 system and C1-6 probe at our hospital between 2017 and 2020. B-Mode imaging of segment V in the liver was acquired and echo attenuation was assessed using UGAP. Steatosis score (S0: <5%; S1: 5%-33%; S2: 34%-66%; S3: ≥67%) from liver specimens was compared with the attenuation coefficient (AC; dB/cm/MHz) using UGAP. RESULTS: Steatosis score was S0 for 9 patients, S1 for 40, S2 for 21, and S3 for 14. AC by steatosis score was 0.52 ± 0.07, 0.63 ± 0.07, 0.74 ± 0.06, and 0.78 ± 0.06 dB/cm/MHz for S0, S1, S2, and S3, respectively. AC by UGAP differed significantly between S0 and S1, S0 and S2, S0 and S3, S1 and S2, and S1 and S3 (all P < 0.01), demonstrating a significant increase with steatosis score. Receiver operating characteristic analysis showed good diagnostic performance of UGAP for patients with steatosis score ≥1, ≥2, and ≥3 (AUROC = 0.94, 0.95, and 0.88, respectively). Liver fat content (%) from liver specimens and AC (r = 0.81, P < 0.01) showed a significant positive correlation. CONCLUSION: UGAP is useful for quantifying hepatic steatosis in patients with NAFLD.

Usefulness of virtual touch tissue quantification for predicting the presence of esophageal varices in patients with liver cirrhosis.

BACKGROUND AND AIM: Measuring the hepatic venous pressure gradient (HVPG) is an established technique to detect increased portal pressure and predict the presence of esophageal varices (EVs); however, the risk of the test is greater than the information it provides. This study aimed to clarify the usefulness of virtual touch tissue quantification (VTQ), which assesses liver stiffness, in predicting the presence of EVs in patients with liver cirrhosis by comparing it with HVPG. METHODS: Two hundred seventeen patients with liver cirrhosis underwent VTQ, HVPG measurement, and upper endoscopy. Patients were divided into three groups: group V, hepatitis C virus liver cirrhosis (n = 40); group A, alcoholic liver cirrhosis (n = 116); and group N, other liver cirrhosis (n = 61). In each group, we performed linear regression analysis of VTQ and HVPG data. The accuracy of VTQ and HVPG measurement in predicting the presence of EVs and high-risk EVs (EV category F2 and F3) was assessed by area under the receiver operating characteristic curve (AUROC). RESULTS: VTQ was significantly correlated with the HVPG in the whole patients and in each group, and both VTQ and HVPG values were significantly higher in patients with EVs and high-risk EVs than in those without. The AUROC for the presence of EVs for VTQ was 0.76 in the whole sample, 0.76 in group V, 0.79 in group A, and 0.67 in group N; and for HVPG, 0.92, 0.94, 0.93, and 0.88, respectively. For VTQ, the AUROC for the presence of high-risk EVs was 0.78 in the whole sample, 0.78 in group V, 0.73 in group A, and 0.73 in group N; and for HVPG, it was 0.85, 0.82, 0.85, and 0.82, respectively. CONCLUSION: VTQ was reliable at predicting the presence of EVs and high-risk EVs. Therefore, we propose that VTQ is a useful, noninvasive tool for predicting the presence of EVs in daily medical care.

Tivantinib Decreases Hepatocyte Growth Factor-Induced BCRP Expression in Hepatocellular Carcinoma HepG2 Cells.

Tivantinib, a mesenchymal-epithelial transition factor (cMET) inhibitor, is a molecular targeting drug that kills hepatocellular carcinoma (HCC) cells. Tivantinib alone does not affect the overall survival of patients with HCC, and combination treatment with tivantinib and other therapies has not been evaluated. This study was conducted to clarify the effect of the tivantinib in regulating breast cancer therapy-resistant protein (BCRP), a key transporter of 5-fluorouracil (5-FU), and dihydropyridine dehydrogenase (DPYD), a major metabolic enzyme of 5-FU. To this end, cMET gene expression was determined by RT-PCR in HepG2 (human hepatoma) cells. The transcriptional start sites of BCRP were determined by 5'-rapid amplification of cDNA ends (5'-RACE). BCRP and DPYD mRNA levels were determined by real-time RT-PCR, and promoter activities were measured by dual-luciferase assays. Results show that hepatocyte growth factor (HGF) upregulated the mRNA level of BCRP, but not DPYD, in HepG2 cells. The upregulation of BCRP expression by HGF was down-regulated by tivantinib. We also identified two transcriptional start sites (E1α, E1ß) in BCRP by 5'-RACE. The transcriptional activity of the region -287 to E1α of BCRP was upregulated by HGF, which was decreased by tivantinib, whereas activity of the region -297 to E1ßo f BCRP was not affected by tivantinib. Therefore, tivantinib regulates BCRP expression upstream of exon 1α. Combination treatment of tivantinib and 5-FU should be further evaluated for HCC therapy.

Sorafenib Might Induce Sarcopenia in Patients With Hepatocellular Carcinoma by Inhibiting Carnitine Absorption.

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers. Sorafenib, an oral multi-target TKI, improves the median overall survival time in patients with hepatocellular carcinoma (HCC). It also inhibits the absorption of carnitine by down-regulating the human organic cationic transporter OCTN2 located largely in the small intestinal mucosa and skeletal muscle. The aim of the study was to determine, by assessing carnitine metabolism, whether sarcopenia is induced in patients with HCC who are receiving sorafenib. PATIENTS AND METHODS: This retrospective study included 110 adult Japanese patients with liver cirrhosis and HCC who received sorafenib. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment, and serum carnitine fraction and myostatin levels were measured. Cross-sectional areas (cm2) of the skeletal muscles at the third lumbar vertebra level were determined by manually outlining computed tomography images before and after treatment. The cross-sectional areas were normalized for height [skeletal muscle index (SMI), cm2/m2]. RESULTS: Patients were allocated to two groups according to Child-Pugh (CP) class; 81 had CP-A liver function, and 29 had CP-B. SMI after treatment was significantly lower than that before treatment in both groups. Serum levels of total carnitine and free carnitine after treatment were significantly lower than those before treatment in both groups. There were no differences in serum levels of myostatin before and after treatment in either group. CONCLUSION: Sorafenib might decrease serum levels of carnitine by inhibiting carnitine absorption. Decreasing of serum levels of carnitine might lead to presarcopenia.

The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE.

OBJECTIVE: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC. METHODS: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed. RESULTS: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128). CONCLUSION: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.

Whole hepatic lipid volume quantification and color mapping by multi-slice and multi-point magnetic resonance imaging.

AIM: Current approaches for hepatic steatosis assess only a small point within the liver and might cause inaccuracy for longitudinal observation. We aimed to establish a reliable non-invasive method for whole hepatic lipid content evaluation. METHODS: A total of 52 patients with hepatic steatosis underwent liver biopsy. Hepatic lipid content was assessed by Dixon in-phase/out-of-phase magnetic resonance imaging and proton magnetic resonance spectroscopy. Using multi-slice and multi-point magnetic resonance imaging, we calculated the lipid intensity of every voxel throughout the liver and showed the color-mapped lipid distributions. This new analysis could also quantify the whole hepatic lipid and whole liver volumes absolutely. The diagnostic performance of hepatic lipid content between the new analysis and proton magnetic resonance spectroscopy methods was compared by receiver operating characteristic curve analysis referring to the steatosis scores of the liver biopsy. RESULTS: Areas under the receiver operating characteristic for the diagnosis of steatosis scores ≥1, ≥2, and ≥3 using magnetic resonance imaging and proton magnetic resonance spectroscopy were 0.86 (95% confidence interval [CI] 0.70-1.00) and 0.98 (95% CI 0.93-1.00), 0.94 (95% CI 0.87-1.00) and 0.93 (95% CI 0.86-1.00), and 0.95 (95% CI 0.89-1.00) and 0.97 (95% CI 0.93-1.00), respectively, showing comparable diagnostic accuracies. However, color mapping showed some inconsistencies between the methods. CONCLUSIONS: We described a non-invasive and repeatable evaluation method of whole hepatic lipid accumulation with absolute quantification and color mapping. Hepatic steatosis was accurately evaluated regardless of heterogeneous lipid accumulation. The whole hepatic lean volume, reflecting the hepatic parenchymal condition, can also be determined by this method.

A New Method to Quantify Concentration of Microbubbles in Attenuating Media Using Bubble Destruction Curve Analysis of the Contrast-Enhanced Ultrasound.

It is known that the microbubbles of Sonazoid are accumulated in the liver parenchyma due to the phagocytosis of Kupffer cells in the sinusoid. Because this phagocytic function decreases due to the progression of fibrosis in chronic liver disease, the deterioration of the liver function may be quantified by measuring the concentration of the accumulated Sonazoid microbubbles. In this article, a new method to quantify the concentration of microbubbles accumulated in attenuating media is proposed. This method utilizes the contrast-enhanced imaging with high mechanical index, measures the depth of the bubble destruction for each frame and analyze the shape of the destruction curve to estimate the concentration of the bubbles. A phantom experiment was performed with various concentrations of the contrast agent Sonazoid solution as well as various attenuation coefficients of the viscous media. Because of the theoretical model proposed, the estimated attenuation indexes, related to the concentration of Sonazoid microbubbles, were independent of the background attenuation of the propagating medium. The result suggest it has a potential to quantify Sonazoid concentration in the liver parenchyma more precisely against different liver attenuation conditions.