Hayashi H.,University of Tokyo |
Mizuno T.,University of Tokyo |
Horikawa R.,National Center for Child Health and Development |
Nagasaka H.,Chiba Childrens Hospital |
And 3 more authors.
Journal of Hepatology | Year: 2012
Background & Aims: Multidrug resistance-associated protein 2 (in humans, MRP2; in rodents, Mrp2) mediates biliary excretion of bilirubin glucuronides. Therefore, upregulation of MRP2/Mrp2 expression may improve hyperbilirubinemia. We investigated the effects of 4-phenylbutyrate (4PBA), a drug used to treat ornithine transcarbamylase deficiency (OTCD), on the cell surface expression and transport function of MRP2/Mrp2 and serum T-Bil concentration. Methods: MRP2-expressing MDCKII (MRP2-MDCKII) cells and rats were studied to explore the change induced by 4PBA treatment in the cell surface expression and transport function of MRP2/Mrp2 and its underlying mechanism. Serum and liver specimens from OTCD patients were analyzed to examine the effect of 4PBA on hepatic MRP2 expression and serum T-Bil concentration in humans. Results: In MRP2-MDCKII cells and the rat liver, 4PBA increased the cell surface expression and transport function of MRP2/Mrp2. In patients with OTCD, hepatic MRP2 expression increased and serum T-Bil concentration decreased significantly after 4PBA treatment. In vitro studies designed to explore the mechanism underlying this drug action suggested that cell surface-resident MRP2/Mrp2 is degraded via ubiquitination-mediated targeting to the endosomal/lysosomal degradation pathway and that 4PBA inhibits the degradation of cell surface-resident MRP2/Mrp2 by reducing its susceptibility to ubiquitination. Conclusions: 4PBA activates MRP2/Mrp2 function through increased expression of MRP2/Mrp2 at the hepatocanalicular membrane by modulating its ubiquitination, and thereby decreases serum T-Bil concentration. 4PBA has thus therapeutic potential for improving hyperbilirubinemia. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Hishiki T.,Chiba Childrens Hospital
International Journal of Clinical Oncology | Year: 2013
Surgery is the mainstay of multimodal treatment for hepatoblastomas. Among the various staging systems used, PRETEXT is currently adopted in all major study groups worldwide as a common pretreatment staging system. Although variations of treatment strategies among study groups exist, the majority of hepatoblastoma cases currently undergo preoperative chemotherapy. It is therefore critical to determine the optimal surgical treatment during the initial courses of chemotherapy. Patients with PRETEXT IV tumors, multifocal tumors and tumors invading major vessels of the liver are candidates for liver transplantation. Liver transplantation requires preparation in advance, and consultation to a liver expertise team must take place no later than after two cycles of chemotherapy. The existence of pulmonary metastasis is a predictor of poor prognosis of the patient. Surgery for pulmonary nodules should be considered for those patients remaining positive after cycles of chemotherapy. A considerable number of patients have been reported to achieve long-term survival after resecting pulmonary metastasis. The existence of pulmonary metastasis at diagnosis is no longer a contraindication for liver transplantation, provided that the pulmonary nodules are eliminated by chemotherapy or by metastasectomy. Transcatheter arterial chemoembolization (TACE) is a useful tool for the local control of hepatoblastomas, although there are very few reports statistically supporting the significant advantage of this treatment modality. Based on individual cases, TACE could be beneficial in maximizing the anti-tumor effect with less toxic side effects. © 2013 Japan Society of Clinical Oncology.
Tanaka Y.,Kanagawa Childrens Medical Center |
Inoue T.,Osaka City General Hospital |
Horie H.,Chiba Childrens Hospital
International Journal of Clinical Oncology | Year: 2013
This review describes the pathological classification of pediatric liver cancer types and subtypes proposed at the recent international symposium (March 2011, Los Angeles, USA) and meetings involving pathologists serving as central reviewers for the Children's Oncology Group, Société Internationale d'Oncologie Pédiatrique, Gesellschaft für Pädiatrische Onkologie und Hämatologie, or Japanese Study Group for Pediatric Liver Tumors, and pediatric oncologists/surgeons specializing in liver cancers, as well as immunohistochemical panels, recommendations for submission, sampling and evaluation of diagnostic specimens. The pathological classification is intended to be standardized and clinically meaningful, thus improving future patient management and prognosis. The most common pediatric liver cancer is hepatoblastoma (HBL). HBL has two types, the wholly epithelial type and the mixed epithelial and mesenchymal (MEM) type. The wholly epithelial type was subdivided into well-differentiated fetal (pure fetal with low mitotic activity), crowded fetal (mitotically active), embryonal, epithelial mixed, small cell undifferentiated, and cholangioblastic. A macrotrabecular pattern and a pleomorphic epithelial pattern were recognized as supplemental features of epithelial components. The MEM type was subdivided into MEM without teratoid features and MEM with teratoid features. Other liver cancers in children were divided into hepatocellular carcinoma (classic hepatocellular carcinoma and fibrolamellar carcinoma) and hepatocellular malignant tumor not otherwise specified. This classification is basically applied to pretreatment specimens; the evaluation of post-chemotherapy specimens will be the subject of further studies. © 2013 Japan Society of Clinical Oncology.
Murakami T.,Chiba Childrens Hospital |
Tateno S.,Chiba Cardiovascular Center |
Kawasoe Y.,Chiba Cardiovascular Center |
Niwa K.,St. Lukes International Hospital
International Journal of Cardiology | Year: 2014
Background: Excessive aortic pressure wave reflection is one of the risk factors of cardiovascular diseases. In some clinical course of congenital heart diseases, the elevated pressure wave reflection has been reported. The purpose of this study is to elucidate the risk factors of the enhanced pressure wave reflection in adult patients with congenital heart disease. Methods: We enrolled 99 adult (≥ 20 years) patients with congenital heart disease. We measured their radial pressure augmentation index and examined the relationship between it and various clinical variables. Results: The radial pressure augmentation index was 77.1 ± 19.1% and it had a significant correlation with the history of aorto-pulmonary shunt (t = 4.194; p < 0.0001), age (t = 4.091; p < 0.0001), height (t = - 3.580; p = 0.001) and the history of direct aortic surgery (t = 2.253; p = 0.027). Forty-four patients (44.4%) demonstrated high radial augmentation index (> 1 SD of age- and gender matched control) and the determinants of the elevated radial augmentation index were the history of aorto-pulmonary shunt (odds ratio, 21.32; 95% confidence interval, 5.47-83.14; p < 0.0001) and the direct aortic surgery (4.18; 1.38-12.72; p = 0.012). Conclusions: The history of aortic surgeries enhances aortic pressure wave reflection in adult patients with congenital heart disease. The enhanced aortic pressure wave reflection is one of the risk factors for cardiovascular diseases. Therefore, the adult patients with congenital heart disease after aortic surgeries should be carefully observed and tightly controlled concerning the risk factors for cardiovascular diseases. © 2014 Elsevier Ireland Ltd. All rights reserved.
Fukasawa C.,Chiba Childrens Hospital
Kansenshōgaku zasshi. The Journal of the Japanese Association for Infectious Diseases | Year: 2013
While the incidence of Haemophilus influenzae type b (Hib) meningitis is expected to decrease with the widespread use of the Hib vaccine, the resistance of Hib has actually increased. Therefore, selection of the initial antibiotics used for treatment must be performed with resistant bacteria, including beta-lactamase negative ampicillin resistant H. influenzae (BLNAR), in mind. Tazobactam/piperacillin (TAZ/PIPC) has a satisfactory minimum inhibitory concentration (MIC) against BLNAR and is a beta-lactamase inhibitor. Although there is no insurance coverage for its use in patients with meningitis, the penetration of TAZ/PIPC into cerebrospinal fluid (CSF) in animal experiments promises a satisfactory result, and we have been using a combination of ceftriaxone (CTRX) and TAZ/PIPC as an initial treatment and a resistant bacteria countermeasure in patients with Hib meningitis at our hospital since 2008. We examined the concentration of TAZ/PIPC in CSF to further investigate the possibility of using TAZ/PIPC as an antibiotic treatment against bacterial meningitis. In cases treated with a 1: 8 drug formulation of TAZ/PIPC against Hib meningitis at our hospital, we used the remaining portion of a CSF sample collected after the initiation of TAZ/PIPC administration and then measured the concentrations of TAZ and PIPC in the CSF. Six specimens from 5 patients between the ages of 6 and 59 months were examined. The dosage of TAZ/PIPC was 95.7-113.6 mg/kg/dose x 3 times/day, and the CSF concentrations at 0-105 minutes after the completion of the administration were 0.319-1.32 microg/mL for TAZ and 2.54-7.74 microg/mL for PIPC. With the approved dosage, the peak concentration level during the acute period indicated a sufficient CSF concentration level for the antibacterial and beta-lactamase inhibition effects against Hib. As an antibiotic treatment for H. influenzae meningitis, the combined usage of TAZ/PIPC is likely to be effective as a resistant bacteria countermeasure, in addition to third-generation cephem drugs and meropenem.