Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan

Background  The clinical course of chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and obesity. The K121Q polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 gene and the rs7566605 genotype located near insulin-induced gene 2 have been shown to be associated with insulin resistance and obesity. This study examined whether the K121Q polymorphism in ENPP1 or the rs7566605 genotype is associated with the clinical course of HCV infection. Methods  The relationships between the clinical characteristics of 469 anti-HCV antibody-seropositive subjects (353 were positive for HCV core antigen or RNA, whereas 116 were negative for HCV RNA) and the polymorphisms were analyzed. Results  No significant differences in body mass index, plasma glucose level, serum insulin level, and other biochemical markers were observed between subgroups of subjects with different genotypes at the K121Q polymorphism or rs7566605. The frequency of the homozygous wild-type genotype at K121Q in HCV carriers, however, was significantly higher than that in subjects who were negative for HCV RNA (84.5% vs. 75.9%; P < 0.05). Moreover, in HCV carriers, HCV core antigen levels in subjects homozygous for the wild-type genotype at K121Q were significantly higher than in heterozygous carriers of K121Q (5358 fmol/l vs. 4002 fmol/l; P = 0.04). In contrast, the rs7566605 genotype was not associated with hepatitis C viremia or with the HCV core antigen level. Conclusions  The K121Q variant of ENPP1 may be associated with hepatitis C viremia and core antigen levels in HCV carriers.     

A case of primary small cell carcinoma of the liver that was treated with chemotherapy

Primary small cell carcinoma (SSC) of the liver is very rare in Japan and only ten cases have been reported worldwide. We report herein the case of a 77-year-old man with primary SCC of the liver. He had a tumor over 10 cm in diameter which was localized in the right lobe of the liver and had invaded the right diaphragm. In laboratory tests, high serum levels of lactate dehydrase and neuron-specific enolase were observed. A biopsy specimen showed that the tumor cells were similar in cytology to a pulmonary SCC. The patient was first treated with carboplatin and etoposide according to the therapy protocol for pulmonary SCC and then with a regimen using etoposid and cisplatinum, resulting in an unfavorable outcome. We discuss the clinical course and therapy of extra-pulmonary SCC and review the literature of the cases previously reported.     

A case of squamous cell carcinoma of the lung with a high titer of proteinase 3 antineutrophil cytoplasmic antibody]

A 57-year-old man who had a history of sinusitis was admitted to Ryugasaki-Saiseikai hospital in April 2002 because of productive cough and bloody sputum. Chest radiographs and CT scans showed mediastinal lymphadenopathy and a solitary mass lesion with an irregular margin and cavity in the left lower lung field. Proteinase 3 antineutrophil cytoplasmic antibody (PR3 ANCA) was positive, and this is a sensitive and specific indicator of Wegener's granulomatosis. The pathological findings from transbronchial biopsy revealed squamous cell carcinoma of the lung, without the presence of vasculitis, accompanied by Wegener's granulomatosis. A partial response was finally obtained after three courses of paclitaxel and carboplatin. The serum level of PR3 ANCA decreased from 142 EU to 16 EU. This case appears to have had parallel time courses of progression of squamous cell carcinoma of the lung and changes in serum PR3 ANCA level. This is of importance in considering the relationship of lung cancer and paraneoplastic vasculitis.     

Radioimmunoimaging of tumors with radioactive antibody against a glycoprotein (GP68) found in developing mouse brain

Summary The in vivo localization of a polyclonal antibody (pAb) against a glycoprotein with a molecular mass of 68 kDa (GP68), which was found in developing mouse brain, was studied in murine tumor models to evaluate potential applications of this antibody for in vivo radioimmunodetection and/or therapy of cancer. The tissue distribution of¹²⁵I-labeled GP68 pAb 3 days after i.V. injection into mice bearing four different kinds of solid tumor revealed a high uptake ratio by adenocarcinoma 755 and Lewis 3LL lung cancer. In contrast, the uptake ratio was low in mice bearing Ehrlich solid tumor and sarcoma-180 (S-180). These uptake ratios accorded well with the in vitro binding activity of this antibody with the tumor cells. In an immunoscintigraphic study, adenocarcinoma 755 was successfully visualized with⁶⁷Ga-labeled GP68 pAb. The results of these biodistribution and in vivo radioimmunoscintigraphic studies suggest that GP68 antibody may be applicable to the diagnosis and/or therapy of cancer.Abbreviations pAb polyclonal antibody - AFP -fetoprotein - GP68 68-kDa glycoprotein     

A case of the limited from of Wegener's granulomatosis without c-ANCA]

A 46-year-old woman was admitted to our hospital because of fever, cough and headache in December 2001. Although she had been treated for nasal obstruction and epistaxis by an otorhinolaryngologist in our hospital since 1996, no accurate diagnosis had been made despite repeated biopsies of the nasal mucosa. A chest CT taken in 1999 showed ground-glass opacities in both upper lobes. On admission, chest radiography and CT showed mass shadows without cavitation, corresponding to the lesions causing the ground-glass opacities. In addition, paranasal sinus MRI showed a deformity of the nasal septum accompanied by a space-occupying lesion, suggesting Wegener's granulomatosis. However, the cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA) test was negative. To achieve a definitive diagnosis, we performed an open lung biopsy. The specimen, obtained from the right upper lobe, showed the typical findings of a Wegener's granulomatosis including necrotizing vasculitis. Oral prednisolone treatment initiated at 20 mg daily, combined with oral cyclophosphamide at 50 mg daily markedly improved not only the clinical symptoms, but also the mass shadows in the left upper lobe. Patients with the limited form of Wegener's granulomatosis are occasionally seronegative and respond well to therapy. However, the natural course and the changes in chest radiographs are not understood well in such cases. In this paper, we report a case of the limited form of Wegener's granulomatosis that progressed slowly over a period of 6 years.     

Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation

Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KIT(Val814)) are not fully understood. To examine the oncogenic signal transduction of KIT(Val814), we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KIT(Val814) or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KIT(Val814)- derived mutants, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) severely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3'-kinase (p85 (PI3-K)). Moreover, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85(PI3-K), and the C-terminal region are indispensable for factor-independent growth by KIT(Val814). Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KIT(WT)), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KIT(WT). Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KIT(Val814). These results demonstrate that Tyr719 is crucial for constitutive activation of KIT(Val814), but not for the ligand-induced activation of KIT(WT), and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KIT(Val814), thereby suggesting that KIT(Val814) is a unique activating mutation that leads to a distinguishable function from the effects of KIT(WT).