Atsushi Takebe

ARID3B Induces Malignant Transformation of Mouse Embryonic Fibroblasts and Is Strongly Associated with Malignant Neuroblastoma

ARID3B, a member of the AT-rich interaction domain (ARID) family of proteins, plays an essential role in the survival of neural crest during embryogenesis. Here, we report evidence that ARID3B is involved in the development of malignant neuroblastoma, a childhood tumor derived from neural crest. (a) ARID3B is expressed by all five cell lines derived from neuroblastoma tested by us. (b) Analysis of published DNA microarray data of fresh neuroblastoma tumors showed that ARID3B is expressed in 80% of stage IV tumors, whereas only in 9% of stage I-III+IVs tumors. (c) In vitro growth of several neuroblastoma cell lines is suppressed significantly by antisense as well as siRNA treatment. (d) An increase of the ARID3B expression level by transfection in the SY5Y neuroblastoma cell line enhances the malignancy in tumor growth assays in nu/nu mice. (e) ARID3B by itself can immortalize mouse embryonic fibroblasts (MEFs) in vitro and confers malignancy to MEF when transfected together with MYCN, the best characterized oncogene for neuroblastoma. Thus, ARID3B seems to play a key role in the malignant transformation of neuroblastoma and may serve not only as a marker of malignancy but also as a potential target for cancer therapy of stage IV neuroblastoma for which there is currently no effective treatment available.

Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-α.

Background: Phf14 is identified as a novel gene that regulates proliferation of mesenchymal cells. Results: Phf14-null mice show interstitial pulmonary hyperplasia and mesenchymal fibroblasts exhibit increased proliferation rates accompanied by enhanced expression of PDGFRα. Conclusion: Phf14 acts as a negative regulator of PDGFRα expression in mesenchymal cells. Significance: Phf14 has potential as a target for the treatment of lung fibrosis. The regulation of mesenchymal cell growth by signaling molecules plays an important role in maintaining tissue functions. Aberrant mesenchymal cell proliferation caused by disruption of this regulatory process leads to pathogenetic events such as fibrosis. In the current study we have identified a novel nuclear factor, Phf14, which controls the proliferation of mesenchymal cells by regulating PDGFRα expression. Phf14-null mice died just after birth due to respiratory failure. Histological analyses of the lungs of these mice showed interstitial hyperplasia with an increased number of PDGFRα+ mesenchymal cells. PDGFRα expression was elevated in Phf14-null mesenchymal fibroblasts, resulting in increased proliferation. We demonstrated that Phf14 acts as a transcription factor that directly represses PDGFRα expression. Based on these results, we used an antibody against PDGFRα to successfully treat mouse lung fibrosis. This study shows that Phf14 acts as a negative regulator of PDGFRα expression in mesenchymal cells undergoing normal and abnormal proliferation, and is a potential target for new treatments of lung fibrosis.

Extended right liver grafts obtained by an ex situ split can be used safely for primary and secondary transplantation with acceptable biliary morbidity

Split liver transplantation (SLT) is clearly beneficial for pediatric recipients. However, the increased risk of biliary complications in adult recipients of SLT in comparison with whole liver transplantation (WLT) remains controversial. The objective of this study was to investigate the incidence and clinical outcome of biliary complications in an SLT group using split extended right grafts (ERGs) after ex situ splitting in comparison with WLT in adults. The retrospectively collected data for 80 consecutive liver transplants using ERGs after ex situ splitting between 1998 and 2007 were compared with the data for 80 liver transplants using whole liver grafts in a matched‐pair analysis paired by the donor age, recipient age, indications, Model for End‐Stage Liver Disease score, and high‐urgency status. The cold ischemic time was significantly longer in the SLT group (P = 0.006). As expected, bile leakage from the transected surface occurred only in the SLT group (15%) without any mortality or graft loss. The incidence of all other early or late biliary complications (eg, anastomotic leakage and stenosis) was not different between SLT and WLT. The 1‐ and 5‐year patient and graft survival rates showed no statistical difference between SLT and WLT [83.2% and 82.0% versus 88.5% and 79.8% (P = 0.92) and 70.8% and 67.5% versus 83.6% and 70.0% (P = 0.16), respectively]. In conclusion, ERGs can be used safely without any increased mortality and with acceptable morbidity, and they should also be considered for retransplantation. The significantly longer cold ischemic time in the SLT group indicates the potential for improved results and should thus be considered in the design of allocation policies. Liver Transpl 15:730–737, 2009.

Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P < 0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.

Relative adrenal insufficiency manifested with multiple organ dysfunction in a liver transplant patient

Relative adrenal insufficiency is now a well‐known clinical condition that occurs in critically ill patients particularly with septic complication. However, this pathology has long been unrecognized until recently in liver transplantation patients, for whom postoperative immunosuppressive therapies almost always comprise corticosteroids. We report an obvious case of relative adrenal insufficiency manifested by severe multiple organ dysfunction in a recipient after living donor liver transplantation (LDLT). A 38‐year‐old woman with multiple hepatocellular carcinoma developed refractory liver failure 2 months after the completion of the dual treatment; namely a cytoreductive right hepatectomy for bulky main tumors followed by 2 courses of percutaneous isolated hepatic perfusion for residual tumors in the remnant liver. She underwent a right‐lobe LDLT, and postoperative immunosuppression was initiated with a low‐dose tacrolimus monotherapy without corticosteroid because of a severe septic condition before transplantation. Postoperatively, she developed progressive hyperbilirubinemia, renal dysfunction, and coagulopathy. As the corticotropin stimulation test suggested the relative adrenal insufficiency, corticosteroid was commenced 40 days after LDLT. Thereafter, multiple organ dysfunction resolved dramatically and promptly. The patient is presently alive and well with completely normalized liver function 45 months after LDLT. Liver Transp 12:1896–1899, 2006.

Role of percutaneous transhepatic gallbladder aspiration in the early management of acute cholecystitis

Early cholecystectomy is currently the gold standard treatment for acute cholecystitis (AC). However, the acceptability and safety of this strategy remain in dispute. The aim of this study was to clarify the role of percutaneous transhepatic gallbladder aspiration (PTGBA) in the early management of AC in a single center.

Two-stage treatment with hepatectomy and carbon-ion radiotherapy for multiple hepatic epithelioid hemangioendotheliomas.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare neoplasm of vascular origin with variable malignant potential. Because most patients with this condition have multiple bilobar lesions, liver transplantation is the standard treatment, and hepatectomy is much less frequently indicated. We describe a case of a 35-year-old woman with unresectable multiple bilobar HEH successfully treated by combination treatment with hepatectomy and carbon-ion radiotherapy. This case is very meaningful since it demonstrated the effectiveness of carbon-ion radiotherapy for HEH and the possibility of expanding the curative treatment options for multiple bilobar hepatic tumors.

Contrast-Enhanced Intraoperative Ultrasonic Cholangiography for Real-Time Biliary Navigation in Hepatobiliary Surgery

Recent progress in medical technology, perioperative management, and surgical technique has contributed greatly to the safety of hepatobiliary surgery. In particular, imaging techniques, including intraoperative imaging, have played a major role in advancing the success of these operations. Precise assessment of biliary anatomy before and during surgery reduces biliary complications. More than 42% of the population is reported to have anatomical variations of the biliary tree. If a biliary anatomical variation is suspected before surgery, confirmatory intraoperative cholangiography (IOC) is recommended. Using radiography and iodinated contrast medium, IOC was first reported by Mirizzi in 1937 and has been widely used to define the biliary tree in surgery for benign and malignant diseases. However, radiographic IOC has several drawbacks; it exposes patients and medical staff to radiation, it requires a large C-arm machine for fluoroscopy and an attendant to operate it, and it requires special techniques to generate 3-dimensional (3D) images. Intraoperative ultrasonography, specifically, contrast-enhanced intraoperative ultrasonic cholangiography (CE-IOUSC), can address these issues. Intraoperative ultrasonography has become an essential tool for the identification of intrahepatic vessels, tumor location, and definition of surgical margins for safe and effective hepatic surgery. Its diagnostic accuracy has been enhanced by the introduction of intravascular ultrasound contrast agents. However, it is still limited in visualization of nondilated bile ducts.

Morphometric analysis of conformational changes in hepatic venous system after right lobe living donor liver transplantation

Aim:  After living donor liver transplantation (LDLT), the graft liver regenerates to the standard liver volume. However, little is known about the influence of this phenomenon on the hepatic venous system.

Analysis of Portal Vein Reconstruction Technique with High-Grade Portal Vein Thrombus in Living Donor Liver Transplantation

BACKGROUND Portal vein thrombus (PVT) has been an absolute contraindication for liver transplantation because of technical difficulties and inadequate vessel graft supply. With recent surgical innovations many difficulties have been overcome and PVT is no longer a contraindication to liver transplantation. MATERIAL AND METHODS From June 2000 to December 2014, 72 patients underwent living donor liver transplantation at Kobe University Hospital, with a focus on the high-grade PVT cases and analysis of modified PV reconstruction technique and clinical course. RESULTS Four recipients (5.6%) developed Yerdel classification grade III PVT and 2 recipients (2.8%) developed grade IV PVT. There were no statistically significant differences between the severity of PVT grades by sex (p=0.77), recipient age (p=0.49), model for end-stage liver disease (MELD) score (p=0.68), graft-recipient weight ratio (GWRW) (p=0.15), graft type of right or left lobe (p=0.55), original liver disease (p=0.09), or intra-operative bleeding (p=0.21). Four grade III recipients were anastomosed with SMV, and 2 grade IV recipients were anastomosed with coronary vein, both of which were interpositioned with vein grafts. Only 1 recipient had died of hepatocellular carcinoma recurrence by 1.5 years after liver transplantation, and all 5 remaining severe PVT recipients survived. Overall 1- and 5-year survival rates for grade 0, I, and II recipients were 78.8% and 62.4%, respectively; 75.0% and 75.0%, respectively, for grade III recipients; and 100% and 100%, respectively, for grade IV recipients (p=0.54). CONCLUSIONS High-grade PVT had comparable survival without the recurrence of PVT after living donor liver transplantation.