Carcinogen-induced inflammation and immunosuppression are enhanced in xeroderma pigmentosum group A model mice associated with hyperproduction of prostaglandin E2.

Xeroderma pigmentosum group A (XPA) gene-deficient mice easily developed skin cancers by the application of topical chemical carcinogens as well as by UV irradiation. As certain chemical carcinogens have been shown to be immunosuppressive, we examined the inflammatory and immunosuppressive effects of dimethylbenz(a)anthracene (DMBA) on XPA mice. Compared with wild-type mice, XPA mice showed greater ear swelling and reduction of epidermal Langerhans cells after DMBA application. Topical application of DMBA impaired the induction of contact hypersensitivity, initiated either locally or at distant sites. These DMBA-induced local and systemic immunosuppressions were more greatly enhanced in XPA mice than in wild-type mice. DMBA application induced pronounced production of PGE(2), IL-10, and TNF-alpha in the skin of XPA mice. Treatment with indomethacin, a potent inhibitor of PG biosynthesis, inhibited DMBA-induced inflammation and local immunosuppression. In XPA mice, increased serum IL-10 was detected after DMBA treatment. Excess production of PGE(2), TNF-alpha, and IL-10 after DMBA application may be involved in the enhanced local and systemic immunosuppression in DMBA-treated XPA mice. Susceptibility to DMBA-induced skin tumors in XPA mice may be due to easy impairment of the immune system by DMBA in addition to a defect in the repair of DMBA-DNA adduct. Enhanced immunosuppression by chemical carcinogens as well as the mutagenicity of these mutagens might be associated with the high incidence of internal malignancies seen in XP patients. Moreover, these results supported the hypothesis that persistent DNA damage is a trigger for the production of immunoregulatory cytokines.

Photobiologic and photoimmunologic characteristics of XPA gene-deficient mice.

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced DNA damage and easily develop skin cancers by UV irradiation. Just like human XP patients, homozygous (-/-) mice developed stronger longer-lasting acute inflammation than did wild-type mice after a single irradiation with UVB. Moreover, the model mice showed more severe UV-induced damage of keratinocytes and Langerhans cells than did the control mice. UVB-induced local and systemic immunosuppression was greatly enhanced in the (-/-) mice. Treatment with indomethacin, an inhibitor of prostaglandin (PG) synthesis, inhibited UV-induced inflammation and abrogated immunosuppression. In XPA-deficient mice, the amount of PGE2 and the expression level of COX-2 mRNA greatly increased after UVB irradiation compared with wild-type mice. These results suggest that the excess DNA photoproducts remaining in XPA-deficient cells after UV radiation induce COX-2 expression and subsequently produce a high amount of PGE2, which causes the enhancement of inflammation and immunosuppression. In XPA-deficient mice, the natural killer cell activity significantly decreased after repeated exposures to UVB. Our experimental data indicate that cancer development in XP patients involves not only mutagenesis due to the defect in DNA repair, but also the enhanced UV-immunosuppression and intensified impairment of natural killer function.

[Malignant peripheral nerve sheath tumor with divergent cartilage differentiation from the acoustic nerve: case report].

Malignant peripheral nerve sheath tumors(MPNSTs) of the acoustic nerve are very rare. Only seven cases of MPNST arising from the acoustic nerve have been reported. The authors present a case of MPNST with divergent cartilage and melanotic differentiation of the acoustic nerve. The patient was a 69 year old man admitted to our neurosurgical service in January 1999 complaining of left facial nerve palsy and hearing difficulty of his left ear. The initial CT showed a tumor at the left cerebellopontine angle region. On MRI the tumor was depicted as low intensity on T 1-weighted image and high intensity on T 2-weighted image, the mass was heterogeneously enhanced after administration of Gd-DTPA. The partial removal of the tumor was performed in January 1999. He was discharged February 1999. But he was admitted again because of progressive cerebellar ataxia. MRI showed the rapid regrowth of the residual tumor. In March 1999, complete removal of the tumor was performed. Histopathological analysis revealed a malignant spindle cell neoplasm with divergent cartilage and melanotic differentiation. We review the relevant literature concerning MPNST of the acoustic nerve and discuss the clinical features of malignant eighth cranial nerve tumor.

[Myelopathy caused by tentorial dural arteriovenous fistula: a rare case report].

A 51-year-old man with myelopathy due to intracranial dural arteriovenous fistula (dural AVF) is reported. At age 46, the patient experienced subarachnoid hemorrhage caused by rupture of the dural AVF and underwent embolization of the lesion at another hospital. At this time, the patient complained of numbness in his legs and showed paraplegic gait disturbance. MRI scan revealed swelling of the cervical spinal cord. Cerebral angiograms demonstrated the recurrence of tentorial dural AVF fed by bilateral meningohypopheseal trunks and the right posterior inferior cerebellar artery. Arteriovenous shunt (AV shunt) flow was drained into the anterior spinal vein. It seemed that the swelling of the spinal cord and myelopathy was caused by venous hypertension of spinal veins. After surgical interruption of the right petrosal vein which connected dAVF with cerebellar veins, AV shunt was obliterated successfully. Postoperative cerebral angiograms showed disappearance of dural AVF. The patient became ambulant and his cervical spinal cord appeared normal on the postoperative MRI scan. Surgical interruption of the draining vein was simple, effective and essential treatment.

Possible involvement of enhanced prostaglandin E2 production in the photosensitivity in xeroderma pigmentosum group A model mice.

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced DNA damage and easily develop skin cancers by UV irradiation. Therefore, XPA-deficient mice are a useful model of human XP and represent a promising tool for photobiologic studies of the disorder. Exposure to ultraviolet (UV) B (280-320 nm) radiation greatly enhanced inflammation and immunosuppression in these mice. To investigate the molecular mechanisms of enhanced UV inflammation and immunosuppression, we determined the amount of prostaglandin (PG) E2, an inflammatory mediator and immunomodulator, and analysed the expression of cyclooxygenase (COX) mRNA in the ear skin of XPA-deficient mice after UV irradiation. In XPA-deficient mice, the amount of PGE2 significantly increased at 48 and 72 h after UVB irradiation to the level that was 8- and 16-fold higher than those in wild-type mice, respectively. The expression level of COX-2 mRNA increased in a time-dependent manner, although COX-1 mRNA was constantly expressed. Treatment with indomethacin, a potent inhibitor of PG biosynthesis, inhibited UV-induced ear swelling, abrogated local immunosuppression, and decreased the amount of PGE2 in the ear skin of XPA-deficient mice. These results indicate that the excess DNA photoproducts remaining in XPA-deficient cells after UV radiation may induce COX-2 expression. The induced production of PGE2 may be involved in the enhanced inflammation and immunosuppression caused by UV radiation in XPA-deficient mice and XP patients.

Xeroderma pigmentosum variant associated with multiple cancers.

A 62-year-old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun-exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies.

3,4:9,10-Perylenetetracarboxylic dianhydride (PTCDA) by electron crystallography.

The crystal structures of the alpha and beta modifications of PTCDA were analyzed as projected structures along the a axes by electron crystallography using an imaging plate. The results for the alpha modification agree well with the sheet-and-stack structure obtained by X-ray diffraction by M. L. Kaplan et al. (private communication, full set of crystal structure data). Projected onto the (102) plane, which is parallel to the molecular sheets, the long molecular axis makes an angle of 42 degrees with the b axis and the hexagonal benzene rings appear slightly elongated, indicating a slight inclination of the molecular plane from the (102) lattice plane. For the beta modification, it was concluded that the molecules are aligned in a herringbone packing scheme on the (102) plane similar to that of the alpha modification, but with a slightly different angle of the long molecular axis with the b axis (38 degrees ).

[Supratentorial ectopic ependymoma: a case report].

Ependymomas usually arise from the ventricular surface and approximately two-thirds of them are infratentorial. We present an unusual case of supratentorial ependymoma located in the parietal parenchyma and exhibiting no continuity with the ventricular system. On March 30, 1998, a 63-year-old woman was admitted to our neurosurgical service because of a sudden consciousness loss attack two weeks before. On admission, neurological examination revealed no abnormal findings. Computerized tomography (CT) revealed a mass lesion of the parietal lobe which was enhanced homogeneously. Magnetic resonance imaging (MRI) also showed the mass of the parietal lobe which was iso-intense on T1-weighted images, iso and high intense on T2-weighted images and homogeneously enhanced by administration of Gd-DTPA. In the angiography, left carotid angiograms showed a tumor stain. On February 26, 1998, total removal of the tumor was performed using stereotactic craniotomy with neuronavigator and intraoperative echography. After surgery, focal radiation therapy (56Gy) was carried out. The pathological diagnosis was cellular ependymoma with partial clear cell components. Several kinds of tumor may occur in the cerebral parenchyma. We conclude, however, that ependymoma has to be included in the differential diagnosis when the tumor location is distant from the ventricles.