Hideaki Miura

Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma

BACKGROUND/AIMS Angiogenesis is critical for the development and progression of solid tumors. The purpose of this study was to evaluate the possible role of vascular endothelial growth factor (which is considered to be one of the most important factors involved in tumor-associated angiogenesis), in human hepatocellular carcinoma. METHODS Vascular endothelial growth factor gene and protein expression were analyzed by means of Northern hybridization and immunohistochemical methods in 5 hepatocellular carcinoma cell lines. Secretion of vascular endothelial growth factor was evaluated by immunoblotting of conditioned medium of these hepatocellular carcinoma cells. Further, we compared the level of vascular endothelial growth factor expression in hepatocellular carcinoma tissues along with that in surrounding tumor-free tissues obtained from 20 patients. We also analyzed mRNA expression of Flt-1, one of the vascular endothelial growth factor specific high-affinity receptors, in hepatocellular carcinoma cell lines. RESULTS Northern hybridization analysis and immunohistochemistry revealed that all cultured hepatocellular carcinoma cells exhibited a high level of vascular endothelial growth factor mRNA. In addition, vascular endothelial growth factor secretion by Hep G2, one of the hepatocellular carcinoma cell lines, was shown by Western blot. In vivo, we observed vascular endothelial growth factor expression in both hepatocellular carcinoma and non-hepatocellular carcinoma tissues. However, in 12 of 20 cases, vascular endothelial growth factor mRNA levels were significantly up-regulated in hepatocellular carcinoma tissues. In the majority of cases (10 out of 12 cases) with abundant tumor vascularity, vascular endothelial growth factor mRNA up-regulation in hepatocellular carcinoma tissues was observed. We failed to detect Flt-1 mRNA expression in hepatocellular carcinoma cells. CONCLUSIONS This study suggests that the possibility that hepatocellular carcinoma cells overexpress the vascular endothelial growth factor gene and protein. These findings support the hypothesis that vascular endothelial growth factor is one of the important factors involved in the angiogenesis of hepatocellular carcinoma, and may even be involved in the development and/or progression of hepatocellular carcinoma itself.

Acute onset of nephrotic syndrome during interferon-α retreatment for chronic active hepatitis C

A 57-year-old woman was scheduled to receive recombinant interferon-α retreatment for chronic active hepatitis C. During the course of therapy, the patient showed rapid onset of oliguria, dizziness, edema, and a pre-shock state. She was subsequently admitted to hospital and was diagnosed as having nephrotic syndrome. After admission, albumin-dominant proteinuria persisted despite the discontinuation of interferon therapy. Light microscopy of a renal needle biopsy specimen showed interstitial lymphoid cell infiltration, but no marked changes of the glomeruli and no staining for immunoglobulin or complement. Electron microscopy showed diffuse effacement of the glomerular epithelial foot processes, leading to a diagnosis of minimal change nephrotic syndrome with interstitial nephritis. Proteinuria resolved after the initiation of oral prednisolone therapy (1 mg/kg per day). The number of patients with chronic hepatitis C requiring interferon retreatment is increasing rapidly. We herein report this rare case of acute onset of nephrotic syndrome during interferon-α retreatment.

An autopsy case of autoimmune pancreatitis after a 6-year history of steroid therapy accompanied by malignant dissemination of unknown origin.

Little is known about the long-term outcome of autoimmune pancreatitis (AIP), and whether AIP possesses malignant potential. We report herein a 68-year-old Japanese AIP patient who rapidly developed systemic malignant dissemination of unknown origin, resulting in death. The patient was diagnosed histopathologically as having AIP in 1999. After a 6-year history of 5 mg/day of prednisolone therapy, a sudden onset of abdominal pain and convulsive seizure occurred, and the patient died on the tenth hospital day owing to diffuse peritoneal disseminations and metastases in the bilateral lungs and brain. Autopsy disclosed that the primary site was renal cell carcinoma, detectable only by autopsy, originating in the left kidney. On microscopy, metastatic cells obtained from the brain, lung, and peritoneum were composed of pleomorphic malignant cells identical to those from the renal cell carcinoma. Unexpectedly, abundant IgG4-positive plasma cell infiltration, suggesting high activity of AIP in pancreatic parenchyma and around dilated bile ducts, was still observed.

Fulminant hepatic failure accompanied by fatal rhabdomyolysis following exertional heatstroke

We present a previously healthy 38-year-old Japanese man who developed exertional heatstroke (EHS) following a long-distance run and presented with fulminant hepatic failure (FHF) accompanied by a life-threatening flare-up of rhabdomyolysis. Intensive life-supporting medical procedures, including plasma exchange, hemodiafiltration, steroid pulse therapy, and anticoagulant treatment enabled the patient to survive FHF. Initially, his general condition was thought to be improving; however, smoldering rhabdomyolysis suddenly flared up with a marked increase in creatine kinase levels when the dose of steroids was reduced, subsequent to which his condition deteriorated rapidly, eventually resulting in death. The serum levels of interleukin-6 measured retrospectively were found to be markedly elevated and to have fluctuated synchronously with the disease activity. This case report demonstrates that EHS can cause FHF and severe rhabdomyolysis, the outcome of which was tragic even though FHF was substantially well managed; however, the clinical evidence suggests the possible therapeutic efficacy of steroid therapy for refractory rhabdomyolysis occurring in EHS.

Recognition of Hepatitis C Virus Nucleocapsid Protein-derived Peptides by Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTL) are thought to be involved in the immune clearance of virus-infected cells as well as in the pathogenesis in viral infection. We studied the CTL response to the putative nucleocapsid protein (NP) of hepatitis C virus (HCV) in patients with chronic hepatitis C. Peripheral blood lymphocytes (PBL) were stimulated repeatedly with synthetic HCV-NP peptides. HCV-NP peptide-specific CTL could be induced from PBL in seven of ten HCV-positive patients with chronic hepatitis while they could not be induced from PBL of HCV-negative individuals. The results suggests the existence of HCV-specific CTL in the peripheral blood of patients with chronic hepatitis C, and provide a strategy to study the role of CTL in the viral clearance and the pathogenesis in HCV infection.

Drug-induced MPO-ANCA-positive necrotizing crescentic glomerulonephritis preceded by granulomatous hepatitis

A 67-year-old man being treated with allopurinol, furosemide, digoxin, and tamocapril for congestive heart failure and paroxysmal atrial fibrillation was admitted to our hospital because of intermittent fever, general fatigue, and liver dysfunction. On admission, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, and the titer was high. Discontinuation of all four drugs led to improvement of the symptoms, but the patients renal function deteriorated. Liver biopsy showed granulomatous hepatitis (GH), and renal biopsy findings led to a diagnosis of pauci-immune necrotizing crescentic glomerulonephritis (CGN). The patients renal function spontaneously improved without immunosuppressive therapy, and the MPO-ANCA titer decreased. We speculate that some common pathway induced by the drugs, possibly allopurinol, led to the two different clinical diseases, GH and CGN.

Rat Bite Fever Caused by Streptobacillus moniliformis in a Cirrhotic Patient Initially Presenting with Various Systemic Features Resembling Henoch-Schönlein Purpura

We herein report the case of a 61-year-old Japanese cirrhotic patient who developed rat bite fever (RBF) and whose first presentation was serious clinical features mimicking those of Henoch-Schönlein purpura (HSP). In addition to the critical clinical conditions, since the histopathology from purpuric skin eruptions was not inconsistent with that of HSP, therapy with prednisolone was promptly started in order to prevent his death. However, initial blood culture on admission yielded a small and slow-growing bacterial growth, which was gradually revealed by further subculture to be a peculiar bacterium, Streptobacillus moniliformis, leading to a definitive diagnosis of RBF. After the immediate cessation of prednisolone, the patient was treated with a more appropriate antibiotic and consequently made a full recovery. An immunocompromised condition with seriously decompensated liver cirrhosis together with moderately severe chronic kidney disease (CKD) in this patient probably exacerbated the severity of the disease.