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This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low doses both in experiments and in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD(50) > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA repair potential in wild-type mice and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53 deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML prone, with Trp53 deficiency to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing benzene exposure dose, including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences.

These results suggest that pituitary involvement of GPA should be taken into account for the differential diagnosis of IgG4-related hypophysitis.

Fifty-five patients with intracranial germ-cell tumors were treated in Kobe University Hospital between 1972 and 1989. Thirty-four patients were male and 21 were female, and all patients were between 0 and 39 years of age. There was a peak incidence between 16 and 20 years in male patients and 11 and 15 years in female patients. The tumors occurred most frequently in the pineal region (25 cases), followed by the suprasellar (17), both pineal and suprasellar (6), basal ganglia (5), and frontal and temporal lobe (2) regions. There was a male predominance in the incidence of germ-cell tumors except for the patients with suprasellar tumors. Initial symptoms and neurological signs differed according to the location of the tumor. The symptoms of increased intracranial pressure and Parinaud's sign were most frequently seen in patients with a pineal tumor, while diabetes insipidus and visual disturbance were most common in patients with suprasellar tumors. Human chorionic gonadotropin were positive in the serum, cerebrospinal fluid and/or tumor cyst in 14/26 patients, and alpha-fetoprotein in 6/22 patients examined. There were 45 patients with pure germinoma both histologically verified and clinically diagnosed. The 5-year survival rate of the patients with germinoma was 69% in cases in which tumor marker was negative and unknown cases, and 86% in cases where the tumor marker was positive. The authors discuss management of the patients with intracranial germ-cell tumors.