Fulminant hepatic failure caused by malignant melanoma of unknown primary origin.
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Carcinoma, Hepatocellular↗
Biomedical subjects
Naohito Uchida
Publications and source records attributed to Naohito Uchida.
Enlargement of thermal ablation zone by the combination of ethanol injection and radiofrequency ablation in excised bovine liver.
The efficacy of radiofrequency ablation (RFA) and RFA with concurrent ethanol injection (EI-RFA) was compared. RFA (3-cm-electrode) was applied to bovine liver using three types of RFA equipment; Radionics, RITA and Radio Therapeutics Corporation (RTC). For EI-RFA, 5 ml of 99.5% ethanol was injected around the electrode. A total number of 40 RFA and EI-RFA treatments were performed. We compared RFA with EI-RFA by examining the size, shape of ablation zone, treatment time, power, and needle tip temperature. Liver specimens were examined for pathological changes. EI-RFA produced a larger zone of ablation than RFA alone using Radionics and RITA (Radionics, 35.3+/-7.4 cm(3) vs 23.2+/-7.7 cm(3), p<0.05; RITA, 30.7+/-10.3 cm(3) vs 19.7+/-4.7 cm(3), p<0.05), corresponding to shortest diameters of coagulation zone (Radionics, 3.7+/-0.4 cm vs 3.0+/-0.4 cm, p<0.05; RITA, 3.8+/-0.4 cm vs 3.1+/-0.3 cm, p<0.01). However, a larger ablation zone was not seen with the RTC device. The ablated volume per energy and the ablated volume per current density administered were greater with EI-RFA than with RFA using Radionics (p<0.05). The shape of the ablated zone changed from ellipsoid to spherical with EI-RFA using Radionics. No pathological differences between RFA and EI-RFA samples were detected. For a given amount of energy and current administered, ethanol injection caused a better ablation effect, in terms of the size and shape of the ablated zone, than RFA with Radionics and RITA equipment.
Animals↗
Percutaneous ethanol and lipiodol injection therapy for hepatocellular carcinoma.
Radiofrequency ablation (RFA) therapy is of great significance in the treatment of hepatocellular carcinoma (HCC) or metastatic liver tumors. RFA is able to achieve widely coagulated necrosis in a few sessions without major complications. However, HCC cases exist that are resistant to RFA therapy for several reasons. In the present study, we performed injection of the mixture of ethanol and lipiodol (percutaneous ethanol-lipiodol injection therapy: PELIT) for HCCs that lacked clear visuality of the entire shape of the tumor by ultrasonography (US) or computed tomography (CT), or that were difficult to treat with RFA alone due to their locations in the liver or due to severe liver dysfunction of the patients. Local recurrence rates of HCC treated with PELIT were shown to be low in patients followed up for at least 4 months. In all patients treated with PELIT, lipiodol was accumulated in the entire region of the tumor after several trials of PELIT and the accumulation was kept for many months. The biopsy examination from the tumor treated with PELIT showed that HCC cells were totally destroyed by the PELIT. Although RFA therapy serves as a central role for the treatment of HCCs, PELIT, considered to be milder therapy, is likely to be important as a supportive treatment for HCCs and useful for the treatment of HCCs that are difficult to treat with RFA.
Administration, Cutaneous↗
Expression of G1 phase-related cell cycle molecules in naturally developing hepatocellular carcinoma of Long-Evans Cinnamon rats.
It has been shown that a variety of cell cycle-related proteins play important roles in the process of carcinogenesis including hepatocarcinogenesis. In the present study, we evaluated mRNA and protein expression of G1 phase-related cell cycle molecules in the process of hepatocarcinogenesis, using Long-Evans Cinnamon (LEC) rats, an animal model of hepatocellular carcinoma (HCC). The expression of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6 was measured quantitatively by real-time polymerase chain reaction. Cyclin D1 mRNA expression was increased significantly in chronic hepatitis liver compared with normal liver, and then decreased in HCC and the surrounding precancerous liver of LEC rats. Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers. In contrast, mRNA levels of Cdk6 did not change significantly during hepatocarcinogenesis. We also evaluated the protein levels of these G1 phase-related cell cycle molecules by Western blot analyses and confirmed similar results. Total amounts of retinoblastoma protein (pRb) in the liver did not change significantly in the process of hepatocarcinogenesis in LEC rats. However, levels of phosphorylated pRb were increased markedly in the process of hepatocarcinogenesis, and the highest in HCC compared to precancerous, chronic hepatitis and normal livers. These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC.
Animals↗
Identification of p46 Shc expressed in the nuclei of hepatocytes with high proliferating activity: Study of regenerating rat liver.
The adaptor molecule Shc is a proto-oncogene product, and it is known to be associated with cell proliferation. However, the role of Shc in the proliferation and regeneration of hepatocytes remains unknown. In the present study, we report that p46 Shc is specifically expressed in the nuclei of proliferative (or regenerative) hepatocytes, suggesting that p46 Shc protein plays a role in hepatocellular proliferation. The expression of Shc was analyzed in liver tissue after partial hepatectomy (PH) or sham operation in Wistar rats by using immunohistochemistry and/or Western blot analysis. In addition, the expression of various cell cycle-related proteins, such as Cdk4, cyclin D1, PCNA, and Cdk1 was analyzed in the tissues of regenerating rat liver. Furthermore, the tyrosine phosphorylation of Shc was studied in liver tissue after PH or sham operation by immunoprecipitation using a monoclonal phosphotyrosine antibody. Although the protein levels of p52 Shc were unchanged in liver tissues after PH or sham operation, tyrosine phosphorylation was detected only in the regenerating rat liver after PH. The levels of p46 Shc protein were markedly increased in liver tissues during the liver regenerative process. In contrast, p66 Shc was not detected in the liver tissues after PH or sham operation. Western blotting and immunohistochemistry showed that the main location of p46 Shc was in the nuclei of proliferating hepatocytes after PH. These data suggest that p46 Shc expressed in hepatocellular nuclei may be closely related to the proliferation of hepatocytes. Therefore, it is suggested that p46 Shc expressed in hepatocellular nuclei may be a useful marker for detecting hepatocytes with high proliferative activity.
Adaptor Proteins, Signal Transducing↗
Proliferative capability of hepatocytes and expression of G1-related cell cycle molecules in the development of liver cirrhosis in rats.
Liver cirrhosis is the end stage of various chronic liver diseases and its prognosis is very poor. One of the most important causes of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage. Cell cycle-related molecules have been shown to play essential roles in cell proliferation. Specifically, G1-related cell cycle molecules are important, because they are requisite for the entry into the cell cycle from the quiescent state. However, the role of these cell cycle molecules during the development of liver cirrhosis remains to be examined. In the present study, liver cirrhosis was produced in rats by intraperitoneally administering dimethylnitrosamine (DMN). Proliferative capability of hepatocytes estimated immunohistochemically by proliferating cell nuclear antigen staining was markedly increased at an early stage of cirrhosis development. However, it was gradually decreased thereafter and suppressed substantially at the time of cirrhosis manifestation. Cyclin D1 expression estimated by a real-time reverse transcription-polymerase chain reaction (RT-PCR) method was also increased markedly at an early stage of cirrhosis development but decreased substantially thereafter. mRNA levels of catalytic subunits of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6, did not show significant changes during the development of liver cirrhosis. Among G1-specific Cdk inhibitors, expression of p15INK4b and p16INK4a estimated by an RT-PCR method was increased according to the progression of cirrhosis and reached a peak at the time of cirrhosis manifestation. Conversely, p18INK4c expression did not change significantly during the development of liver cirrhosis. These results suggest that cyclin D1 plays an essential role in hepatocyte proliferation in response to hepatic damage. However, with the decrease of cyclin D1 expression and increase of p15INK4b and p16INK4a expression, proliferative capability of hepatocytes is severely impaired and extracellular matrix components are deposited to retrieve space lost by the destruction of hepatic parenchyma, resulting in establishment of liver cirrhosis.
Animals↗
Enhanced expression of adaptor molecule p46 Shc in nuclei of hepatocellular carcinoma cells: study of LEC rats.
Shc protein is known to be related to cell proliferation and carcinogenesis. However, the involvement of Shc in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that p46 Shc is probably expressed in the nuclei of hepatocytes and/or cancer cells during the development of HCC in Long-Evans Cinnamon (LEC) rats. The expression and localization of Shc in various pathological liver tissues obtained from LEC rats were analyzed by immunohistochemical study and Western blotting. Furthermore, tyrosine phosphorylation of Shc in various pathological liver tissues of LEC rats was studied by immunoprecipitation using a monoclonal anti-phosphotyrosine antibody. Although p66 Shc was detected in none of the liver tissues, regardless of pathological status, the expression of p46 Shc and that of p52 Shc increased proportionately with the development of HCC in LEC rats. Furthermore, although p52 Shc was localized only in the cytoplasm of hepatocytes and/or cancer cells, p46 Shc was found to express in both the nuclei and the cytoplasm of hepatocytes and/or cancer cells in precancerous and cancerous tissues of LEC rat liver. Tyrosine phosphorylation of p46 Shc and p52 Shc was detected only in cancer cells, and p46 Shc in such cells was much more heavily phosphorylated than p52 Shc. These results suggest that enhanced expression of p46 Shc and p52 Shc, as well as p46 Shc tyrosine phosphorylation, was involved not only in the process from normal liver to chronic hepatitis, but also in the transition from chronic hepatitis into HCC in LEC rats. Furthermore, unlike p52 Shc, p46 Shc was detected not only in the cytoplasm but also in the nuclei of hepatocytes (especially in transformed hepatocytes), and p46 Shc expressed in the nuclei may be closely related to hepatocarcinogenesis in LEC rats.
Adaptor Proteins, Signal Transducing↗
Concomitant colitis associated with primary sclerosing cholangitis.
Between 1985 and 2001, seven Japanese patients (four males and three females) were diagnosed as having primary sclerosing cholangitis (PSC) in our hospital. All seven patients received total colonoscopy with distal ileoscopy. All four male patients were diagnosed as having colitis by colonoscopy, while none of the three female patients had colitis. The four patients with colitis did not have any symptoms attributable to colitis, such as diarrhea or hematochezia. In three of the four patients, unclassified colitis was the most suitable diagnosis, because there were no typical findings of ulcerative colitis or Crohn's disease. The remaining patient was diagnosed as having eosinophilic colitis. By colonoscopic visualization, the right-sided colon, including the terminal ileum, was mainly involved, but the lesions were not severe. The main findings were redness, erosion, stenosis, and insufficiency of haustral formation. Histologically, these lesions were nonspecific inflammatory changes in the three patients with unclassified colitis. In the patient with eosinophilic colitis, remarkable infiltration of eosinophils was observed. Thus, unclassified colitis appeared to be the main complication in these patients with PSC. Males predominated in regard to concomitant colitis, and they had no symptoms of the colitis. Colonoscopic examination revealed that the lesions were not severe. The main lesions were found in the right-sided colon, with nonspecific inflammatory changes. These results suggest that colonoscopic surveillance of patients with PSC should be performed even if they do not have any colitis symptoms.
Adult↗
Abnormal bile flow in patients with achalasia.
BACKGROUND: It has been reported that esophageal achalasia is frequently associated with the dysmotility of other digestive organs. However, the prevalence of extraesophageal complications in patients with achalasia still remains poorly understood. We performed cholescintigraphy, using (99m)Tc-pyridoxyl-5-methyl-tryptophan, in patients with esophageal achalasia to assess any possible dysfunction of the sphincter of Oddi associated with achalasia. METHODS: Eight patients (two men and six women) were examined to determine the time required for bile to flow from the bile duct to the duodenum. RESULTS: Excretion time of bile was markedly prolonged in five of the eight patients with achalasia. Scintigraphic findings were not correlated with the radiographic classification of achalasia or with the grading of achalasia. CONCLUSIONS: The present results suggest that a considerable number of patients with achalasia have dysfunction of the sphincter of Oddi, irrespective of the morphological type of achalasia and the grade of esophageal dilatation.
Adult↗
Aberrant cytokeratin expression and high susceptibility to apoptosis in autoimmune hepatitis.
Immunopathological differences between autoimmune hepatitis (AIH) and chronic hepatitis C (CH-C) have not been well investigated. Therefore, we immunohistochemically examined the expression of various cytokeratins (CKs) not only in liver tissues of AIH but also in those of CH-C at the active stage. Furthermore, to evaluate the immune surveillance system and the susceptibility to apoptosis, immunohistochemical staining of human leukocyte antigen (HLA)-DRalpha, cathepsin D, B cell leukemia-2 (bcl-2), bcl-2-associated X protein (bax) and caspase 3 was also performed. Heterogeneous expression of CK 8 and CK 18 was observed in hepatocytes of AIH, while homogeneous expression was observed in hepatocytes of CH-C. Aberrant expression of CK 7 and CK 19 was observed in hepatocytes of AIH, while it was not in hepatocytes of CH-C. Expression of HLA-DRalpha was observed in hepatocytes of AIH but not in those of CH-C. Furthermore, expression of cathepsin D, bax and caspase 3 was much stronger in hepatocytes of AIH than in those of CH-C. These results indicate that cytoskeletal alterations of hepatocytes in AIH may increase the susceptibility to apoptosis and induce hepatocyte destruction.
Journal Article↗
Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis.
Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCV-induced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC.
Aged↗
Combination of assay of human telomerase reverse transcriptase mRNA and cytology using bile obtained by endoscopic transpapillary catheterization into the gallbladder for diagnosis of gallbladder carcinoma.
OBJECTIVES: It is difficult to make accurate diagnoses of polypoid lesions in the gallbladder. To increase the diagnostic accuracy, we have developed an endoscopic technique to obtain gallbladder bile, termed endoscopic transpapillary catheterization into the gallbladder (ETCG). We evaluated the usefulness of a molecular biological approach to the diagnosis of gallbladder carcinoma, in which gallbladder bile obtained by the ETCG technique is used. METHODS: Twenty patients undergoing an operation because of suspicion of gallbladder carcinoma were enrolled. Twelve patients were confirmed to have gallbladder carcinoma, and four were found to have chronic cholecystitis. Two patients with polypoid lesion were diagnosed as having an inflammatory polyp and a hyperplastic polyp, respectively. The remaining two patients with polypoid lesions were diagnosed as having a cholesterol polyp. Gallbladder bile collected by the ETCG technique was evaluated cytologically and also analyzed for telomerase activity and mRNA for human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase. In 14 patients, hTERT mRNA in resected specimens (fixed in 10% formalin and embedded in paraffin) was also examined. RESULTS: Cytology of gallbladder bile was positive in eight of 11 examined patients (72.7%) with gallbladder carcinoma. hTERT mRNA was detectable in gallbladder bile as well as in resected neoplastic tissues in four of 12 patients (33.3%) with carcinoma. Conversely, telomerase activity was negative in all eight examined patients with carcinoma. Overall, either cytology or hTERT mRNA of gallbladder bile was positive in 10 of 12 patients (83.3%) with gallbladder carcinoma. Cytology, hTERT mRNA, and telomerase activity were negative in eight patients with benign disease. CONCLUSIONS: The combination of cytology and hTERT mRNA analysis of gallbladder bile might be helpful for the preoperative diagnosis of gallbladder carcinoma.
Adult↗
Aldehyde dehydrogenase-2 genotypes and HLA haplotypes in Japanese patients with esophageal cancer.
The aim of this study was to examine how aldehyde dehydrogenase-2 (ALDH2) genotypes and human leukocyte antigen (HLA) haplotypes contribute to the risk for esophageal cancer. We examined ALDH2 genotypes and HLA haplotypes in 29 Japanese patients with esophageal cancer. The ratio of patients who experienced current or former intense vasodilatation upon consuming alcohol (flushing type) was much higher in individuals with the inactive form of ALDH2 encoded by the ALDH2(2)/2(2) or ALDH2(1)/2(2) genotype than in those with the active form of ALDH2 encoded by the ALDH2(1)/2(1) genotype. The ratio of inactive ALDH2 was significantly higher in patients with esophageal cancer than in control normal subjects, suggesting that alcoholics with inactive ALDH2 were susceptible to esophageal cancer. HLA haplotypes A24, A26, B54, B61 and DR9 were prevalent in patients with esophageal cancer (82.8, 24.1, 34.5, 37.9 and 44.8%, respectively). HLA haplotype of A24 and inactive ALDH2 were simultaneously found in 58.6% of patients with esophageal cancer. Furthermore, we found other primary malignancies in 6 of 29 (20.7%) patients with esophageal cancer, and 4 of these 6 patients had both the inactive form of ALDH2 and the HLA A24 haplotype. The present study showed the high prevalence of the inactive form of ALDH2 and HLA haplotypes A24, A26, B54, B61 and DR9 in Japanese patients with esophageal cancer. Therefore, the examination of genotypes of ALDH2 loci and HLA haplotypes may allow the early detection of esophageal cancer in the Japanese population.
Adult↗
Conversion from external nasobiliary drainage to internal drainage using endoscopically available scissor forceps.
Endoscopic nasobiliary drainage may cause undue stress, such as pharyngeal discomfort. We converted external drainage to internal drainage by cutting the external drainage tube with endoscopically available scissor forceps. Endoscopic nasobiliary drainage tubes were cut in the vicinity of the papilla using scissor forceps in 4 patients. The drainage tube was successfully cut in all patients. The tube was left for short-term internal drainage in 3 patients until the operation or endoscopic treatment was performed. The remaining patient with pancreatic head cancer was followed as an outpatient and the tube stent was occluded 62 days after cutting. Although further studies using a larger number of patients are needed, our procedure is thought to be beneficial to patients undergoing endoscopic nasobiliary drainage.
Aged↗
Effect of an aldose reductase inhibitor on esophageal dysfunction in diabetic patients.
BACKGROUND/AIMS: Disorders of the digestive tract in diabetic patients are mainly ascribed to disorders of the vagus nerve. Although aldose reductase inhibitors (ARIs) have been shown to be effective against diabetic peripheral neuropathy, their effectiveness on diabetic digestive neuropathy remains to be evaluated. The aim of the present study is to examine the effect of an ARI on the esophageal dysfunction in diabetic patients by monitoring pH and motility of the esophagus. METHODOLOGY: Eight type 2 diabetic patients with peripheral neuropathy were administered with the ARI epalrestat (150 mg/day) for 90 days, and esophageal pH and motility were monitored before and after the ARI treatment. RESULTS: Parameters related to the gastroesophageal acid reflux and the esophageal motility, such as % time of pH<4, DeMeester score, duration of the longest reflux episode, reflux episodes longer than 5 min, ratios of peristaltic waves with the amplitude greater than 25 mmHg and ratios of effective peristalsis were remarkably improved by the ARI treatment. CONCLUSIONS: Because the present study clearly demonstrated the effectiveness of an ARI on the esophageal dysfunction in diabetic patients, ARI may be useful for the treatment of diabetic digestive disorders.
Aged↗