Takanori Mukozu

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.

SATB1 Conditional Knockout Results in Sjögren’s Syndrome in Mice

Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissues are affected by cellular and humoral immunity. As a result, the salivary and lacrimal glands of patients with SS are damaged, leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Because experimental approaches to investigate SS pathogenesis in human patients are limited, development of a mouse model is indispensable for understanding the disease. In this study, we show that special AT-rich sequence binding protein-1 conditional knockout (SATB1cKO) mice, in which the SATB1 gene is specifically deleted from hematopoietic cells, develop SS by 4 wk of age, soon after weaning. Female mice presented an earlier onset of the disease than males, suggesting that female SATB1cKO mice are more susceptible to SS. T cell–dominant immune cell infiltration was observed in the salivary glands of 4 wk old SATB1cKO mice, and the frequency of B cells gradually increased as the mice aged. Consistently, levels of anti-SSA and anti-SSB Abs were increased around 8 wk of age, after salivary production reached its lowest level in SATB1cKO mice. These results suggest that SATB1cKO mice can be a novel SS model, in which the progression and characteristics of the disease resemble those of human SS.

Arrival time parametric imaging of the hemodynamic balance changes between the hepatic artery and the portal vein during deep inspiration, using Sonazoid-enhanced ultrasonography: A case of Budd‑Chiari syndrome

This case report concerns a 40-year-old male who had previously been treated for an esophageal varix rupture, at the age of 30 years. The medical examination at that time revealed occlusion of the inferior vena cava in the proximity of the liver, leading to the diagnosis of the patient with Budd-Chiari syndrome. The progress of the patient was therefore monitored in an outpatient clinic. The patient had no history of drinking or smoking, but had suffered an epileptic seizure in 2004. The patients family history revealed nothing of note. In February 2012, color Doppler ultrasonography (US) revealed a change in the blood flow in the right portal vein branch, from hepatopetal to hepatofugal, during deep inspiration. Arrival time parametric imaging (At-PI), using Sonazoid-enhanced US, was subsequently performed to examine the deep respiration-induced changes observed in the hepatic parenchymal perfusion. US images captured during deep inspiration demonstrated hepatic parenchymal perfusion predominantly in red, indicating that the major blood supply was the hepatic artery. During deep expiration, the portal venous blood flow remained hepatopetal, and hepatic parenchymal perfusion was displayed predominantly in yellow, indicating that the portal vein was the major source of the blood flow. The original diagnostic imaging results were reproduced one month subsequently by an identical procedure. At-PI enabled an investigation into the changes that were induced in the hepatic parenchymal perfusion by a compensatory mechanism involving the hepatic artery. These changes occurred in response to a reduction in the portal venous blood flow, as is observed in the arterialization of hepatic blood flow that is correlated with the progression of chronic hepatitis C. It has been established that the peribiliary capillary plexus is important in the regulation of hepatic arterial blood flow. However, this case demonstrated that the peribiliary capillary plexus also regulates acute changes in portal venous blood flow, in addition to the chronic reduction in blood flow that is observed in patients with chronic hepatitis C.

SATB1 is required for the development of experimental autoimmune encephalomyelitis to maintain T cell receptor responsiveness

The genome organizer special AT-rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in helper T cells. We recently reported that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impaired the phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, the in vivo T cell response upon antigen presentation in the absence of SATB1 remains unclear. We show that SATB1 modulates the T cell antigen response during the induction and effector phases. The expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for the antigen response. Therefore, we examined the role of SATB1 in the TCR response and induced experimental autoimmune encephalomyelitis (EAE) using the myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) and pertussis toxin. SATB1cKO mice were resistant to EAE and showed defects in IL-17- and IFNγ-producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, we used a tamoxifen-inducible SATB1 deletion system, SATB1cKO-ER-Cre mice. We transferred encephalitogenic T cells from MOG35-55-immunized SATB1cKO-ER-Cre mice into healthy mice. Tamoxifen-treated recipient mice before the onset of paralysis were resistant to EAE. Furthermore, recipient mice treated with tamoxifen after the onset of EAE exhibited no disease progression. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may represent a novel therapeutic target for T cell-mediated autoimmune diseases.The genome organizer special AT‐rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35‐55 (MOG35‐55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL‐17‐ and IFN‐γ‐producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen‐inducible SATB1 deletion system, SATB1cKO‐ER‐Cre mice, was used. Encephalitogenic T cells from MOG35‐55‐immunized SATB1cKO‐ER‐Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell‐mediated autoimmune diseases.

Hepatic arterialization can predict the development of collateral veins in patients with HCV-related liver disease

PurposeArrival time parametric imaging (At-PI) using contrast-enhanced ultrasonography (CEUS) is a procedure for evaluating liver disease progression in chronic hepatitis C infection (CHC). We investigated At-PI diagnostic efficacy in predicting development of collateral veins.MethodsIn total, 171 CHC patients underwent CEUS and upper gastrointestinal (UGI) endoscopy before liver biopsy. Conventional US was performed before CEUS to identify paraumbilical veins (PV) or splenorenal shunts (SRS). After intravenous perflubutane, contrast dynamics of liver segments 5–6 and the right kidney were saved as raw data. At-PI image ratio of red (ROR) pixels to the entire liver was analyzed. Receiver operating characteristic (ROC) curves were generated to investigate the utility of At-PI for collateral vein identification.ResultsConventional US revealed PV in two patients and SRS in five patients; UGI endoscopy detected esophageal varices (EV) in eight patients. Diagnostic capability of At-PI for detecting PV, SRS, and EV was satisfactory, and high for PV and SRS [PV; area under the ROC curve (AUROC) 0.929, cutoff value 77.9%, SRS; AUROC 0.970, cutoff value 82.0%, EV; AUROC 0.883, cutoff value 66.9%].ConclusionsEvaluation of hepatic arterialization by At-PI was useful for predicting collateral vein development in CHC patients.SommarioScopoL’imaging parametrico con calcolo del tempo di arrivo (At-PI) mediante l’uso dell’ecografia con mezzo di contrasto ( CEUS) è una procedura che può valutare la progressione della malattia cronica di fegato in corso di epatite HCV relata (CHC). Gli Autori hanno indagato l’efficacia diagnostica di At-PI nel predire lo sviluppo di circoli collaterali.MetodiIn totale 171 pazienti sono stati sottoposti a CEUS e ad endoscopia del tratto digestivo superiore (UGI) prima della biopsia epatica. Un’ecografia convenzionale è stata eseguita prima della CEUS per identificare pervietà della v. ombelicale (PV) o di shunt spleno-renale spontaneo (SRS). Dopo iniezione e.v. di perflubutano sono stati salvati i dati grezzi della dinamica del m.d.c. raccolti dai segmenti 5 e 6. E’ stato inoltre analizzato il rapporto dell’immagine At-pi con i pixel rossi (ROR) dell’intero fegato. Sono state ottenute delle curve ROC per valutare l’utilità della At-PI nell’identificare circoli collaterali.RisultatiL’ecografia di base ha identificato PV in due pazienti e SRS in cinque pazienti; UGI ha diagnosticato varici esofagee in otto pazienti. La capacità diagnostica di At-PI per identificare PV, SRS e varici esofagee è stata soddisfacente ed elevata per PV ed SRS (PV : area sotto la curva ROC (AUROC) = 0,929 con valore di cut-off = 77,9%; SRS : AUROC = 0,970 con cut-off = 82;0% ; varici esofagee : AUROC = 0,883 con cut-off = 66,9 ).ConclusioniLa valutazione dell’arterializzazione epatica mediante At-PI è stata utile nel predire circoli collaterali spontanei nei pazienti con malattia cronica di fegato HCV relata.

Right Hepatic Artery Pseudoaneurysm Complicating Acute Pancreatitis: A Case Report

Objective: To report a rare case of right hepatic artery pseudoaneurysm complicating acute pancreatitis based upon imaging findings obtained before and after the development of pseudoaneurysm. Clinical Presentation and Intervention: A 32-year-old male with a history of acute pancreatitis 1 year prior was readmitted for acute pancreatitis. Computed tomography (CT) and angiography after admission revealed pseudoaneurysm of the right hepatic artery. Transcatheter arterial embolization with coils was used to successfully treat the pseudoaneurysm. A CT and angiography 1 year earlier did not reveal any pseudoaneurysm. Conclusion: This patient with a rare right hepatic artery pseudoaneurysm complicating acute pancreatitis was successfully treated with coil embolization.

Su2039 Changes of Cytokines in Cirrhosis Patients With Advanced Hepatocellular Carcinoma Treated by Sorafenib

PURPOSE:Sorafenib is multi-kinase inhibitor against RAF, involved in the growth of cancer cells and VEGFR(Vascular Endotherial Growth Factor Receptor), involved in angiogenesis around cancer. It is known that tumor stain is reduced by the administration of sorafenib. We retrospectively evaluated whether the decrease of blood flow after the administration of sorafenib affect the overall survival (OS) or not. METHODS:From May 2009 to November 2011, 127 patients out of 201 patients with advanced hepatocellular carcinoma (HCC) were treated with sorafenib and included in the present study. Patients received CE-CT or GdEOB-DTPA-MRI before treatment and every 4~6 weeks were evaluated to find the therapeutic effect. Patients were divided into 3 groups (No change group, partially decrease group, partially disappearance group) of tumor vascularity. We calculated OS of these 3 groups. RESULT:In the decrease group (85 cases, partially decrease group and partially disappearance group), the median OS was 19.6 months (95%C.I. 14.7-24.9). In the no change group (42 cases), the median OS was 8.6 months (95%C.I. 5.6-12.0). There were statistically significant differences between the two groups (p<0.001). In the partially disappearance group (51 cases), the median OS was 19.9 months (95%C.I. 11.3-28.6). In the partially decrease group (34 cases), the median OS was 22.0months (95%C.I. 12.2-32.0). There were no statistically significant differences between the two groups (p=0.59). CONCLUSION:In the treatment of sorafenib for advanced HCC, even if there is no necrosis, decrease of blood flow improves the OS.

Su2043 Serum VEGF Level and the Response to Combined Intra-Arterial Chemotherapy in Patients With Advanced Hepatocellular Carcinoma

A S L D A b st ra ct s 40.1±19.9kPa, p=0.01) and patients with nodules in the right liver lobe compared to the left lobe (46±20.4kPa vs 27.3±10.8kPa, p 15), patients with nodules >50mm had a significantly higher LSM value (71.8 ±4.8kPa vs 42.2±16.1kPa, p=0.001). Conclusion: There is a good correlation between liver stiffness assessed by Fibroscan® and HCC nodule size, in cirrhotic patients. Our data suggests that higher LSM values are registered in the presence of nodules >50mm in patients with low MELD score (< 15). Aggressive screening for HCC in cirrhotic patients with low MELD score and high LSM is mandatory, in order to early detect patients within Milan criteria for liver transplantation.

Su2041 Sorafenib Cancels Mechanisms to Escape From the Host Immune System in Cirrhosis Patients With Advanced Hepatocellular Carcinoma

A S L D A b st ra ct s 40.1±19.9kPa, p=0.01) and patients with nodules in the right liver lobe compared to the left lobe (46±20.4kPa vs 27.3±10.8kPa, p 15), patients with nodules >50mm had a significantly higher LSM value (71.8 ±4.8kPa vs 42.2±16.1kPa, p=0.001). Conclusion: There is a good correlation between liver stiffness assessed by Fibroscan® and HCC nodule size, in cirrhotic patients. Our data suggests that higher LSM values are registered in the presence of nodules >50mm in patients with low MELD score (< 15). Aggressive screening for HCC in cirrhotic patients with low MELD score and high LSM is mandatory, in order to early detect patients within Milan criteria for liver transplantation.