Biomedical subjects

Naomi Ohnuma

Publications and source records attributed to Naomi Ohnuma.

At least 19 recordsLinked to original sources

PubMed2007

Reciprocal expression of CCAAT/enhancer binding proteins alpha and beta in hepatoblastomas and its prognostic significance.

Hepatoblastoma is one of the common pediatric solid tumors with frequent mutation of the beta-catenin gene which might be an early event of its carcinogenesis. However, the detailed molecular mechanism is still unknown. We studied the expression levels of CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPbeta, which regulate differentiation and growth of embryonic hepatocytes, to establish whether or not they were involved in affecting the clinical behavior of hepatoblastoma. The quantitative real-time reverse transcriptase-PCR revealed that expression of C/EBPalpha mRNA was significantly up-regulated in tumors 223% (p=0.013) as compared with that in adjacent normal livers, while expression of C/EBPbeta was down-regulated to 27% (p=0.002). Of interest, the immunohistochemical analysis showed that expression of C/EBPalpha was higher and that of C/EBPbeta lower in the poorly differentiated tumor cells than in the well-differentiated cells within the same tumor. Furthermore, high expression of C/EBPalpha (p=0.047) as well as low expression of C/EBPbeta (p=0.025) was significantly associated with poor prognosis of the patients. Cox hazard model suggested that expression of C/EBPalpha and that of C/EBPbeta were independent indicators to predict the prognosis from age but not from histology. Thus, expression of C/EBP proteins may play an important role in the genesis and clinical behavior of hepatoblastoma probably by inducing different stages of arrest of differentiation.

CCAAT-Enhancer-Binding Protein-alpha↗

PubMed2006

The perinatal transition of the hepatobiliary cyst size provides information about the condition of bile flow in biliary cystic malformation cases.

PURPOSE: The aim of this study was to understand the level of bile flow by perinatal transitions of the hepatobiliary cyst size in biliary cystic malformation (BCM) cases and to examine the association between the transitions of the cyst size, cholangiographic images of the intrahepatic bile ducts (IHBDs), and histological features of the liver specimens in BCM. METHODS: We measured perinatal size of the hepatobiliary cyst in 7 BCM cases, composed of 1 case with choledochal cyst and 6 cases with biliary atresia (BA). Bile excretion was inferred from the transition of cyst size and the postoperative course. The IHBD cholangiographic images were also examined. In addition, histology of liver specimens obtained at the time of initial surgery was evaluated for IHBD maturity and fibrosis. RESULTS: The size of the small cyst in 2 BA cases remained almost unchanged throughout gestation. These cases required longer postoperative period for the clearance of jaundice. Their IHBD images were indistinct, and histology showed severe fibrosis. The ratio of bile ducts to portal tracts was 0.5 in 1 of the cases. However, in other BCM cases where the cysts grew large perinatally, bile excretion was good postoperatively, and their jaundice cleared in shorter period. Their cholangiographic images demonstrated clearer periphery of the IHBDs, and their histology showed mild or moderate fibrosis, if any. CONCLUSIONS: The perinatal transition of the cyst size in BCM cases can be helpful in assessing the level of bile flow. BCM with a small cyst during gestation can include some BAs with poorer bile flow, vaguer IHBD images, and prominent liver fibrosis. For the treatment of BCM cases, especially patients with a small biliary cyst, prompt response may be required after birth.

Bile↗

PubMed2006

Pediatric gastroesophageal varices: treatment strategy and long-term results.

BACKGROUND/PURPOSE: There are various treatment strategies for gastroesophageal varices in children. We studied the therapeutic value of endoscopic variceal clipping (EVC) and ligation (EVL). METHODS: Four hundred ninety-nine endoscopic examinations performed between 1991 and 2005 were retrospectively analyzed. F2 and F3 varices with red color signs on follow-up endoscopy were treated with prophylactic EVC. In variceal rupture cases, EVC and EVL were used in combination. RESULTS: Eighty-two prophylactic EVCs were done, and variceal progression was prevented in 89.9%. However, some patients had persistent red color signs and required frequent EVC. Ten emergent procedures were done for variceal rupture, and, in 4 cases, EVL was used to arrest massive variceal bleeding. Five patients developed bleeding during follow-up cause by rupture of gastric fundal varices, which probably had been aggravated by prior treatment for esophageal varices. CONCLUSIONS: The control of gastroesophageal varices by routine EVC was satisfactory. However, ruptures during follow-up suggested the importance of controlling gastric fundal varices. Endoscopic variceal ligation is a simple, effective, and safe treatment tool, particularly for ruptured varices. However, it is difficult to treat gastric fundal varices with EVL; this disadvantage of EVL can be overcome by the concomitant use of EVC.

Adolescent↗

PubMed2006

Preferable operative age of choledochal dilation types to prevent patients with pancreaticobiliary maljunction from developing biliary tract carcinogenesis.

BACKGROUND: Pancreaticobiliary maljunction (PBM), which frequently accompanies choledochal dilation, is a high risk factor for biliary tract (gallbladder, bile duct) carcinoma because of the continuous reflux of pancreatic juice into the biliary tract. The aim of this study was to clarify the preferable operative age in PBM patients for the prevention of biliary tract carcinogenesis, with reference to the dilation types of bile ducts. METHODS: There were 165 PBM patients in total studied, including 92 pediatric patients (< or =15 y) (cystic, 63; spindle-like, 29; nondilation, 0) and 73 adult patients (>15 y) (cystic, 45; spindle-like, 18; nondilation, 10) who underwent operative excision of extrahepatic bile ducts or cholecystectomy. We investigated incidence by age of biliary tract malignancies and the risk according to types of dilation. RESULTS: In the pediatric group, no carcinoma case could be found preoperatively or postoperatively (mean follow-up period, 11.7 y). In the adult group, bile duct carcinomas could be detected in 6 cases of a cystic type (6 of 45; 13.3%) (3 preoperative, 3 postoperative). Among the bile duct carcinoma cases, the youngest patient was a 21-year-old woman who had undergone excision of an extrahepatic bile duct 3 years previously. Gallbladder carcinomas were detected in 16 patients: 3 of 45 cystic (6.7%), 6 of 18 spindle-like (33.3%), and 8 of 10 nondilation (80.0%), in whom the youngest patient was a 41-year-old woman with a spindle-like type. CONCLUSIONS: To prevent biliary tract carcinogenesis in PBM patients, cystic-dilated choledochus should be excised in childhood before the development to a precancerous stage. In spindle-like and nondilation types, cholecystectomy is absolutely necessary in early adulthood before age 40.

Abnormalities, Multiple↗

PubMed2005

Shc family expression in neuroblastoma: high expression of shcC is associated with a poor prognosis in advanced neuroblastoma.

The biological features and prognosis of neuroblastoma, a neural crest-derived pediatric tumor, are closely associated with expression of the Trk receptor. Because the Shc family proteins (ShcA, ShcB, and ShcC) are adaptors for various receptors, including Trk receptors, and are regulators of neuronal cell development, we speculated that they may play a role in neuroblastoma. Therefore, in this study, we used semiquantitative reverse transcription-PCR to examine the expression of these three genes in 15 neuroblastoma cell lines, an all-trans-retinoic acid-treated neuroblastoma cell line, and 52 tumor samples. In neuroblastoma cell lines and tumor samples, shcA was ubiquitously and highly expressed. Little expression of shcA was observed. Also, shcB was hardly expressed in neuroblastoma cell lines, but its expression in RT-BM-1 cells was enhanced after all-trans-retinoic acid-induced differentiation, and it was highly expressed in low-stage tumors (P = 0.0095). This suggests that ShcB participates in cellular differentiation and may correlate with a favorable prognosis in neuroblastoma. Finally, the expression of shcC was observed in most of the neuroblastoma cell lines and in some stage 4 patients. Patients with a high expression of shcC had a very poor prognosis (P < 0.0001) and amplification of MYCN, and all died within 31 months after diagnosis. Therefore, ShcC seems to be associated with an aggressive tumor phenotype, perhaps by enhancing TrkB signals. Our results suggest that the expressions of shcB and shcC are important biological factors in neuroblastoma and are useful prognostic indicators.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[Treatment strategy for malignant solid tumors in childhood].

The prognosis for children with malignant solid tumors has improved dramatically in Japan. During the last two decades, various groups have conducted sequential studies of the treatment of children with neuroblastoma, Wilms' tumor, and hepatoblastoma. Most institutes participated in nonrandomized trials designed to evaluate the safety and efficacy of combination chemotherapy, surgery, and radiotherapy in each group study and treated children with these tumors The results are reviewed and areas for future investigation are identified.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas.

Hepatoblastoma is one of the most common malignant liver tumors in young children. Recent evidences have suggested that the abnormalities in Wnt signaling pathway, as seen in frequent mutation of the beta-catenin gene, may play a role in the genesis of hepatoblastoma. However, the precise mechanism to cause the tumor has been elusive. To identify novel hepatoblastoma-related genes for unveiling the molecular mechanism of the tumorigenesis, a large-scale cloning of cDNAs and differential screening of their expression between hepatoblastomas and the corresponding normal livers were performed. We constructed four full-length-enriched cDNA libraries using an oligo-capping method from the primary tissues which included two hepatoblastomas with high levels of alpha-fetoprotein (AFP), a hepatoblastoma without production of AFP, and a normal liver tissue corresponded to the tumor. Among the 10,431 cDNAs randomly picked up and successfully sequenced, 847 (8.1%) were the genes with unknown function. Of interest, the expression profile among the two subsets of hepatoblastoma and a normal liver was extremely different. A semiquantitative RT-PCR analysis showed that 86 out of 1188 genes tested were differentially expressed between hepatoblastomas and the corresponding normal livers, but that only 11 of those were expressed at high levels in the tumors. Notably, PLK1 oncogene was expressed at very high levels in hepatoblastomas as compared to the normal infant's livers. Quantitative real-time RT-PCR analysis for the PLK1 mRNA levels in 74 primary hepatoblastomas and 29 corresponding nontumorous livers indicated that the patients with hepatoblastoma with high expression of PLK1 represented significantly poorer outcome than those with its low expression (5-year survival rate: 55.9 vs 87.0%, respectively, p=0.042), suggesting that the level of PLK1 expression is a novel marker to predict the prognosis of hepatoblastoma. Thus, the differentially expressed genes we have identified may become a useful tool to develop new diagnostic as well as therapeutic strategies of hepatoblastoma.

Cell Cycle Proteins↗

PubMed2004

Hypoxia/re-oxygenation-induced, redox-dependent activation of STAT1 (signal transducer and activator of transcription 1) confers resistance to apoptotic cell death via hsp70 induction.

STAT1 (signal transducer and activator of transcription 1) is potentially involved in cell survival, as well as cell death, in different types of cells. The present study was designed to examine the effects of STAT1 on hypoxia/re-oxygenation (H/R)-induced cell death and/or survival, and the underlying mechanisms of any such effects. H/R was shown to induce apoptotic cell death of rat hepatocytes. The addition of a STAT1-specific inhibitor, fludarabine, significantly increased the fraction of apoptotic cells after H/R. Following H/R, STAT1 was activated and sequential phosphorylation of Tyr701 and Ser727 was observed, which could be inhibited by the antioxidant N-acetyl-L-cysteine. Tyrosine and serine phosphorylation of STAT1 was mediated by Janus kinase 2 and phosphoinositide 3-kinase/Akt kinase respectively in a redox-dependent manner following H/R. STAT1-induced HSP70 (heat-shock protein 70) expression and the suppression of apoptosis occurred concomitantly. In conclusion, STAT1 activation, in a redox-dependent manner, following H/R may play crucial roles in cell survival, at least partly via HSP70 induction.

Acetylcysteine↗

PubMed2004

Optimal strategy of preoperative transcatheter arterial chemoembolization for hepatoblastoma.

PURPOSE: To investigate the optimal strategy of preoperative transcatheter arterial chemoembolization (TACE) for hepatoblastoma. METHODS: Between 1992 and 2001, 7 children with hepatoblastoma (aged 9 months to 13 years) underwent preoperative TACE. The chemoembolic agent used was an emulsion of pirarubicin and lipiodol. Four patients without distant metastasis underwent "primary" TACE without systemic chemotherapy. The other 3 with distant metastases underwent "delayed" TACE following systemic chemotherapy. These patients were all examined retrospectively using clinical data. RESULTS: The average dosage of lipiodol was 0.6 ml per tumor maximal diameter (cm). All the primary cases showed a significant decrease in alpha-fetoprotein (AFP) and a reduction in the tumor size. They consequently underwent a complete surgical resection and are now disease free. All the delayed cases showed a slight decrease in AFP and underwent complete surgical resection; however, two of them died of lung metastases, and the other died of a second malignancy. Regarding complications, liver dysfunction and pulmonary embolism occurred in one patient each. CONCLUSIONS: For patients without distant metastasis, regardless of the resectability of the primary tumor, TACE may be considered the initial and only preoperative treatment, and it may be repeated. For patients with distant metastases, their complete eradication with systemic chemotherapy prior to TACE is essential.

Adolescent↗

PubMed2004

Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct.

BACKGROUND/AIMS: To clarify the association between the reovirus infection of the hepatobiliary tree and the development of infantile obstructive cholangiopathy (IOC) including biliary atresia (BA) and congenital dilatation of the bile duct (CBD). METHODS: We designed reovirus common primers for nested RT-PCR based on the L3 gene segment. The spectrum and the sensitivity of common primers were evaluated with purified reoviral RNAs and reovirus mixed with stool samples. Then, nested RT-PCRs were performed with hepatobiliary and fecal samples obtained from patients with BA, CBD, and control diseases. Additionally, electron microscopy of stool samples was performed. RESULTS: The L3 common primers could amplify cDNAs synthesized from RNAs of three prototypes of reovirus, and detect as much as 5.0x10(3) plaque forming unit of serotype 3 Dearing strain in 100 mg of fecal samples. However, no amplification product was detected in 136 hepatobiliary tissues taken from 67 patients including 26 BAs and 28 CBDs, or in 65 fecal samples obtained from 15 patients including 10 BAs and 1 CBD. Additionally, viral particles were not found in any stool specimens by the electron microscope. CONCLUSIONS: These data do not suggest that reoviruses play a major role in the etiology of IOC or BA.

Bile Ducts↗

PubMed2004

Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SOD.

BACKGROUND/AIMS: Hypoxia/reoxygenation (H/R) causes oxidative stress to the cell and induces apoptotic cell death. Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration, and has recently been shown to protect cells against various pathogens. In order to investigate the hepatoprotective effects of Stat3, we examined whether it protects against H/R-induced injury in primary hepatocytes. METHODS: Primary cultured hepatocytes were prepared from SD rats. Adenoviruses and cytokines were added 2 days and 1h prior to the H/R insult, respectively. Hepatocytes and culture media were harvested for the assays before and after H/R insult. RESULTS: Interleukin-6 and cardiotropin-1, which may function mainly through Stat3 activation, protected cells from H/R-induced apoptosis. Adenoviral overexpression of the constitutively activated form of Stat3 (Stat3-C) reduced H/R-induced apoptosis as well as generation of reactive oxygen species (ROS) in hepatocytes. Interestingly, Stat3-C induced Mn-SOD, but not Cu/Zn-SOD, both at the protein and mRNA levels. Overexpression of Mn-SOD significantly reduced H/R-induced ROS and apoptosis by inhibiting redox-sensitive activation of caspase-3 activity. CONCLUSIONS: Stat3 protects hepatocytes from H/R-induced cell injury at least partly by upregulating Mn-SOD and inactivating caspase-3.

Adenoviridae↗

PubMed2004

Postoperative corticosteroid therapy for bile drainage in biliary atresia--a nationwide survey.

PURPOSE: Members of the Japanese Biliary Atresia Society were surveyed to determine their current practice regarding early use of corticosteroids after Kasai's operation. METHODS: Questions included the patient's background data, dosage, timing, complications, and outcome. Anicteric survival with the native liver was statistically compared between groups categorized by steroid dosage using Kaplan-Meier analysis. RESULTS: Among 54 institutions surveyed, a total of 222 patients with uncorrectable BA were collected from 34 responders, including 208 patients who received steroid therapy and 14 without it. Prednisolone was started during the first postoperative week in 31% and during the second week in 64%. Perforation and peritonitis occurred in 1 patient given 3 mg/kg/d of prednisolone on postoperative day 1. The survival rates of the steroid and nonsteroid groups were 58.0% and 35.7%, respectively (P = .052). The initial dose of prednisolone was or=4.0 mg/kg/d in 108 patients. The survival rates of the group receiving >or=4.0 mg/kg/d and the nonsteroid group were 58.9% and 35.7%, respectively (P = .0494). CONCLUSIONS: (1) Most surgeons use steroids. (2) Although the anicteric survival rate was higher in the steroid group, the number of patients in the nonsteroid group was too small to draw conclusions. (3) The recommended initial steroid dose is >or=4.0 mg/kg/d. (4) Complications are uncommon if administration is not started too early.

Adrenal Cortex Hormones↗

PubMed2004

Efficacy of ERCP via the accessory papilla in children with choledochal cysts.

BACKGROUND: ERCP via the major duodenal papilla in children with choledochal cyst may not clearly visualize the entire pancreatic duct and the junction of the pancreatic and biliary ducts. This may be caused by obstruction of the pancreatic duct by a dilated common bile duct. METHODS: Patients with choledochal cysts who underwent ERCP with injection of contrast medium at the major duodenal papilla were classified as either belonging to a MP group, in which the entire pancreatic duct and junction of the pancreatic and biliary ducts were visualized, or to a M/AP group, in which these structures were either partially visualized or not visualized. ERCP via the accessory papilla subsequently was performed in the M/AP group by using 0.6- or 0.8-mm metal-tip catheters. The efficacy of ERCP via the accessory papilla in children with choledochal cysts was evaluated. OBSERVATIONS: ERCP was performed in 13 patients. Seven were assigned to the MP group and 6 to the M/AP group. ERCP via the accessory papilla in the M/AP group was successful in 5 of the 6 patients; pancreas divisum was demonstrated in one, a protein plug at the main pancreatic duct in another, and the entire pancreatic duct and junction of the pancreatic and biliary ducts in the remaining 3 patients. No patient developed pancreatitis as a result of ERCP, including ERCP via the accessory papilla. CONCLUSIONS: In children with choledochal cyst, ERCP via the accessory papilla is an effective method for visualization of the detailed structure of the entire pancreatic ductal system and junction of the pancreatic and biliary ducts when ERCP via the major duodenal papilla is unsuccessful.

Child, Preschool↗

PubMed2003

Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma.

For better total survival rate of children with hepatoblastoma, the therapeutic strategy for recurrent or metastatic hepatoblastoma should be improved. From 1991 to 1999, 134 cases of hepatoblastoma were treated by surgery and combination chemotherapy of cisplatin (CDDP) and THP-Adriamycin (THP-ADR) based on the JPLT-1 protocol. In 114 non-metastatic cases, 90 primary liver tumors were resected completely by partial hepatectomy, but 12 recurrences were observed in the liver (4 cases) and the lungs (8 cases). Distant metastases on the diagnosis were observed in 20 cases. The treatment outcome of these 12 recurrent and 20 metastatic tumors was analyzed. In four recurrent liver tumors, surgical resection was performed in all four cases, and all the patients were alive and well. In eight recurrent lung tumors, surgical resection was performed completely in six cases with unilateral lung disease, and five of the six patients were alive and well. In stage IV tumors, the survival rate of the patients having primary tumors within two hepatic sections was significantly higher than that of the patients having primary tumors over three hepatic sections. Active surgical intervention to lung metastases and a more intensive chemotherapy to facilitate complete resection of primary hepatic tumor could improve survival rate of children with refractory hepatoblastoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Nephron-sparing surgery for multilocular cyst of the kidney in a child.

Multilocular cyst of the kidney is an uncommon benign renal neoplasm. Because of its benign nature, this lesion is best managed by nephron-sparing surgery. This report describes a child who underwent a partial nephrectomy for a multilocular cyst of the kidney. After reviewing other cases, we discuss the clinical characteristics of multilocular cyst of the kidney and emphasize the cystic partially differentiated nephroblastoma as a differential diagnosis.

Child↗

PubMed2002

Endoscopic internal biliary drainage in a child with malignant obstructive jaundice caused by neuroblastoma.

We describe a 13-year-old girl who underwent insertion of a Flexima biliary stent for obstructive jaundice due to compression of the extrahepatic bile duct by an enlarged lymph node secondary to neuroblastoma. This novel endoscopic internal biliary drainage procedure was safe and effective even for a child, and improved her quality of life. We further review other treatment options available for malignant obstructive jaundice in children.

Bile Ducts, Intrahepatic↗

PubMed2002

Endosonographic evaluation in two children with esophageal stenosis.

The authors report the successful use of endoscopic ultrasonography (EUS) for finding the etiology and subsequent treatment strategy for esophageal stenosis in 2 children. In case 1, EUS showed anterior wall thickening and multiple low echoic regions in the mp layer. These regions were believed to be cartilage. Esophageal resection therefore was performed. In case 2, EUS showed disruption of the sm and mp layers at the stenosis, leading us to speculate that the stenosis was caused by gastroesophageal reflux. After balloon dilatation, he underwent antireflux surgery of Nissen's fundoplication. EUS was useful for determining the etiology of esophageal stenosis and, thus, the appropriate treatment strategy.

Endosonography↗

PubMed2002

Paraovarian cyst with torsion in children.

Paraovarian cyst is very uncommon in children, and its preoperative diagnosis is difficult. This report describes 2 cases of surgically proven paraovarian cyst with torsion. It is important to be aware of torsion as a complication of paraovarian cyst.

Adolescent↗