The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models.

An overdose of acetaminophen (APAP), the most common cause of acute liver injury, induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis. N-acetyl-L-cysteine (NAC), the only recognized drug against APAP hepatotoxicity, is less effective the later it is administered. This study evaluated the protective effect of mitochondria-specific Mito-TEMPO (Mito-T) on APAP-induced acute liver injury in C57BL/6J male mice, and a three dimensional (3D)-cell culture model containing the human hepatoblastoma cell line HepG2. The administration of Mito-T (20 mg/kg, i.p.) 1 h after APAP (400 mg/kg, i.p.) injection markedly attenuated the APAP-induced elevated serum transaminase activity and hepatic necrosis. However, Mito-T treatment did not affect key factors in the development of APAP liver injury including the activation of c-jun N-terminal kinases (JNK), and expression of the transcription factor C/EBP homologous protein (CHOP) in the liver. However, Mito-T significantly reduced the APAP-induced increase in the hepatic oxidative stress marker, nitrotyrosine, and DNA fragmentation. Mito-T markedly attenuated cytotoxicity induced by APAP in the HepG2 3D-cell culture model. Moreover, liver regeneration after APAP hepatotoxicity was not affected by Mito-T, demonstrated by no changes in proliferating cell nuclear antigen formation. Therefore, Mito-T was hepatoprotective at the late-stage of APAP overdose in mice.

Insulin responses to selective arterial calcium infusion under hyperinsulinemic euglycemic glucose clamps: case studies in adult nesidioblastosis and childhood insulinoma.

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (approximately 100 microU/ml) euglycemic (approximately 90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.

Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid.

We report a case of hepatocellular carcinoma (HCC) arising in nonalcoholic steatohepatitis (NASH). The patient, a 64-year-old man, was incidentally found to have multiple tumors in the liver when admitted for pneumonia. He had been obese, had been receiving a standard dose of valproic acid since clipping surgery for subarachnoid hemorrhage 17 years previously, and had not consumed any alcohol since the surgery. Laboratory data revealed moderate hyperlipidemia and no evidence of diabetes mellitus, hepatitis B or C infection. The patient died of hepatic insufficiency, and an autopsy was performed. A tumor, a maximum of 13 cm in diameter, grossly occupied the entire left lobe and one third of the right lobe of the liver. Histologically, moderately differentiated HCC was found with foci of poorly differentiated HCC. The non-tumorous area showed NASH with moderate bridging fibrosis, without interface hepatitis, hemochromatosis, or copper accumulation. In this patient, obesity, hyperlipidemia, and long-term treatment with valproic acid could have all been associated with induction of NASH. The present case suggests that HCC could develop in non-cirrhotic NASH liver, and that chronic inflammation in itself could be an important risk factor in the development of HCC.

Long-term survivors after resection of carcinoma of the head of the pancreas: significance of histologically curative resection.

BACKGROUND/PURPOSE: The prognosis of patients with pancreatic cancer is said to have not been improved markedly by any procedures in the past 20 years. Since 1973, we have gradually extended the area of dissection when performing curative resection for pancreatic cancer to improve the resection rate and prognosis. Nineteen patients have survived for 3 years or more, and the 5-year survival rates of patients with cancer of the head of the pancreas were 23.9% for macroscopically curative resection and 34.3% for histologically curative resection. METHODS: We histologically observed surgical specimens, cut into 3- to 5-mm sections and compared the histologic characteristics of the 19 patients who survived for 3 years or more with those of 41 patients who died of cancer within 3 years (excluding 6 operative and hospital deaths), in order to find the conditions required for long-term survival. RESULTS: The following conditions were associated with long-term survival: (1) tumor diameter 3 cm or less; (2) either absence of lymph node metastasis or metastasis limited to the n(1) group; (3) degree of invasion of the anterior pancreatic capsule of zero (s0); and (4) either no retropancreatic invasion (rp0) or exposed retropancreatic invasion (rpe) with no cancer invasion of dissected peripancreatic tissue ew(-). CONCLUSIONS: At present, because the rpe rate is more than 70%, resection of the pancreas, including the superior mesenteric vein and the retropancreatic fusion fascia, is essential for a curative resection, because the retropancreatic tissue between the back of the pancreas and this fascia is anatomically considered to be in the position of the subserosal tissue in the gallbladder or stomach. Combined resection of the superior mesenteric artery may further improve the results of resection for pancreatic cancer, from the anatomical viewpoint.

[A case of gastric cancer patient with liver metastasis treated by radiofrequency ablation therapy combined with intra-arterial chemotherapy].

We performed radio-frequency ablation (RFA) therapy combined with intra-arterial chemotherapy for a 71-year old female gastric cancer patient with liver metastasis. She underwent total gastrectomy due to advanced gastric cancer in July of 1996. Because CT scans revealed multiple liver tumors with her, she also underwent intra-arterial chemotherapy comprising of 5-fluorouracil, cis-platinum and Leucovorin. Although her liver tumors decreased in size and number, after 9 months, we had to remove the catheter because of hepatic artery obstruction. Immediately after the removal, 5 hepatic metastases appeared, which were 3.5 cm in maximum diameter. After RFA therapy, CT scans revealed homogenously attenuated lesions. Liver biopsy demonstrated a complete coagulation necrosis. She is currently alive going into 19 months after liver metastasis and 7 months after RFA.

Primary hepatic non-Hodgkin's lymphoma in a patient with chronic hepatitis C: report of a case.

We report a case of primary hepatic non-Hodgkin's lymphoma in a 77-year-old man with chronic hepatitis C. Laboratory data revealed slightly elevated liver function parameters and positive antibody for hepatitis C virus (HCV). Abdominal ultrasonography showed a low-echogenic tumor, about 5 cm in diameter, in the left lateral segment. Abdominal computed tomography showed that the tumor was marginally enhanced in the early phase, but no enhancement was seen in the late phase. Magnetic resonance imaging showed that the tumor was hypointense in relation to the liver on T1-weighted images, but hyperintense on T2-weighted images. Hepatic angiography showed a homogeneously stained hypervascular tumor. Under the diagnosis of a liver tumor, thought to be a hepatocellular carcinoma, left lateral segmentectomy was performed. Histological examination confirmed a diagnosis of non-Hodgkin's diffuse large B-cell lymphoma that was positive for L-26 and CD79Alpha, but negative for CD3 and UCHL-1. The surrounding liver tissue showed signs of chronic active hepatitis. Multiple recurrent lesions were found in the liver, spleen, and iliac bones 4 months postoperatively. However, complete remission was achieved after five courses of systemic chemotherapy using pirarubicin, cyclophosphamide, vincristine sulfate, and prednisolone. The patient has been carefully followed up for about 1 year since his operation, and has been doing well. We review the literature on primary non-Hodgkin's lymphoma arising in the liver infected by HCV.

Fibrolamellar hepatocellular carcinoma: report of a case.

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.