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.

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.

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.

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.

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.

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.

Comparison of Sorafenib and Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Study.

BACKGROUND/AIMS: This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib vs hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma. METHODOLOGY: Forty-seven patients treated with sorafenib (sorafenib group) and 77 patients treated with HAIC (HAIC group) were investigated retrospectively using propensity score matching (PSM) to minimize selection bias. The cumulative survival rate was investigated before and after PSM in each of the sorafenib and HAIC groups. The cumulative survival rate was compared between the sorafenib and HAIC groups, and among the TNM stage by the Liver Cancer Study Group of Japan (LCSGJ TNM stage). RESULTS: No significant difference was noted in overall survival (OS) between the sorafenib and HAIC groups regardless of before or after PSM. On comparison of the cumulative survival rate between the groups by the same LCSGJ TNM stage, significant prolongation of OS was noted in stage IVB only in the sorafenib group (p = 0.032) after PSM. CONCLUSIONS: It may be better to actively introduce sorafenib for stage IVB, i.e., patients with extrahepatic metastasis.

Host Immunity Influences the Efficacy of Combined Intra-Arterial Chemotherapy for Advanced Hepatocellular Carcinoma in Liver Cirrhosis Patients.

BACKGROUND/AIMS: It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC). METHODOLOGY: Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC. RESULTS: Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC. CONCLUSIONS: The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

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.

Influence of etiology on host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy.

BACKGROUND/AIMS: We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC. METHODOLOGY: Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers. RESULTS: Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group. CONCLUSIONS: These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

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.

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.

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.

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.

Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma.

PURPOSE: It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy. METHODS: Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment. RESULTS: Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group. CONCLUSIONS: These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC.

Effect of probiotics on serum bile acids in patients with ulcerative colitis.

BACKGROUND/AIMS: Evaluation of bile acids (BA) is useful for assessing the changes of intestinal flora in patients with ulcerative colitis (UC). During enterohepatic circulation, the intestinal micro flora cause 7 alpha-dehydroxylation of cholic acid (CA) and chenodeoxycholic acid (CDCA), yielding deoxycholic acid(DCA) and lithocholic acid, respectively. The aim of the present study was to investigate the effects of probiotics in patients with UC by examining changes of the serum BA profile. METHODOLOGY: Twenty-seven patients were divided into the following 2 groups based on endoscopic findings: Fifteen patients with distal UC (dUC group) and 12 patients with pancolitis (pUC group). After treatment with mesalazine or salazosulfapyridine (5-ASA), all patients achieved remission. Then they were given 5-ASA plus the probiotic Clostridium butyricum Miyairi (3.0 g/day) for 4 weeks. RESULTS: After 4 weeks of probiotic treatment, %CDCA was significantly higher and %DCA was significantly lower in the pUC group than in the HV group. In contrast, the dUC group showed no significant differences of %CDCA or %DCA from the HV group after 4 weeks. CONCLUSIONS: Probiotic therapy restored intestinal flora involved in 7 alpha-dehydroxylation in the dUC group, but not in the pUC group.

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.

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.

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.

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.