Immune complexome analysis reveals the presence of immune complexes and identifies disease-specific immune complex antigens in saliva samples from patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease that mainly damages the salivary and lacrimal glands. Immune complex (IC) formation triggers local inflammation through IC deposition and decreased antigen function. Some ICs can leak from the lesion and into the saliva, but no salivary ICs have been reported to date. We used immune complexome analysis to comprehensively identify antigens incorporated into IC (IC-antigens) in saliva samples from patients with SS (n = 9) or with xerostomia (n = 7). Neutrophil defensin 1 (67%), small proline-rich protein 2D (67%), myeloperoxidase (44%), neutrophil elastase (44%), cathepsin G (33%), nuclear mitotic apparatus 1 (33%) and phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit gamma (33%) were identified as new IC-antigens specifically and frequently detected in the saliva of SS patients. Of these, neutrophil defensin 1, myeloperoxidase, neutrophil elastase and cathepsin G are neutrophil intracellular proteins, which suggests that repeated destruction of neutrophils due to abnormal autoimmunity may be involved in the pathogenesis of SS. We also analyzed serum samples from three SS patients. There was little overlap of IC-antigens between two of the samples (fewer than 30% of the IC-antigens in the saliva samples), suggesting that many ICs are formed locally and independently of the circulation. In addition, we found that four SS-specific salivary antigens show sequence homology with several proteins of oral microbiomes but no antigen has homology with Epstein-Barr virus proteins. The homology between some IC-antigens and oral microbiome proteins may indicate the impact of oral infection on local autoimmunity through molecular mimicry theory.

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts.

BACKGROUND: Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts. METHODS: CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays. RESULTS: Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells. CONCLUSION: This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.

Expression of laminin 5-γ2 chain in cutaneous squamous cell carcinoma and its role in tumour invasion.

BACKGROUND: Laminin-5 (Ln5), a heterotrimer composed of three chains (α3, ß3, and γ2), is a major component of the basement membrane in most adult tissues. One of the chains, Ln5-γ2, is a marker of invasive tumours because it is frequently expressed as a monomer in malignant tumours. Recent studies from our laboratories detected higher levels of Ln5-γ2 expression in basal cell carcinoma (BCC) than in trichoblastoma. Furthermore, Ln5-γ2 overexpression tended to correlate with aggressiveness in BCC. METHODS: In this study, we compared the expression of Ln5-γ2 in invasive squamous cell carcinoma (SCC, n = 62) of the skin to that in preinvasive Bowen's disease (BD, n = 51), followed by analysis of the role of Ln5-γ2 in cancer invasion in vitro. RESULTS: Immunohistochemically, the proportion of SCC cases (86%) strongly positive for Ln5-γ2 expression was higher than that of BD (16%). Real-time RT-PCR showed Ln5-γ2 overexpression in SCC cell line, A431, compared with normal keratinocyte cell line, HaCaT. Ln5-γ2 monomer and proteolytically cleaved, biologically active fragments of Ln5-γ2 were identified in SCC tumour extracts. In in vitro raft cultures, which simulate in vivo conditions, Ln5-γ2 siRNA significantly suppressed epidermal growth factor (EGF)-stimulated A431 cell invasion. CONCLUSION: Our results indicate that Ln5-γ2 has a role in cutaneous SCC invasion.

Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion.

Double membrane structure, autophagosome, is formed de novo in the process of autophagy in the yeast Saccharomyces cerevisiae, and many Apg proteins participate in this process. To further understand autophagy, we analyzed the involvement of factors engaged in the secretory pathway. First, we showed that Sec18p (N-ethylmaleimide-sensitive fusion protein, NSF) and Vti1p (soluble N-ethylmaleimide-sensitive fusion protein attachment protein, SNARE), and soluble N-ethylmaleimide-sensitive fusion protein receptor are required for fusion of the autophagosome to the vacuole but are not involved in autophagosome formation. Second, Sec12p was shown to be essential for autophagy but not for the cytoplasm to vacuole-targeting (Cvt) (pathway, which shares mostly the same machinery with autophagy. Subcellular fractionation and electron microscopic analyses showed that Cvt vesicles, but not autophagosomes, can be formed in sec12 cells. Three other coatmer protein (COPII) mutants, sec16, sec23, and sec24, were also defective in autophagy. The blockage of autophagy in these mutants was not dependent on transport from endoplasmic reticulum-to-Golgi, because mutations in two other COPII genes, SEC13 and SEC31, did not affect autophagy. These results demonstrate the requirement for subgroup of COPII proteins in autophagy. This evidence demonstrating the involvement of Sec proteins in the mechanism of autophagosome formation is crucial for understanding membrane flow during the process.

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs.

Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.

Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of T-lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered as the causative virus of ATLL. The karyotypes of ATLL are very complex in both number and structure, although no specific karyotype abnormalities have been identified. HTLV-I is thought to integrate its provirus into random sites in host chromosomal DNA and induces chromosomal instability. The BUB gene is a component of the mitotic checkpoint in budding yeast. Recently, human homologues of the BUB were identified and mutant alleles of hBUB1 and hBUBR1 were detected in two colorectal tumor cell lines, which showed microsatellite instability (MIN). In vitro, BUB proteins form a complex of monomers. These proteins interact with the human MAD1 gene product, a target of the HTLV-1 tax oncogene. We examined the role of checkpoint gene in the chromosomal abnormalities of ATLL by investigating mutations of hBUB1 and hBUBR1, and MIN of replication errors of BAX, insulin-like growth factor, and transforming growth factor beta type II. We analyzed ten cases with ATLL and eight B-cell lymphomas (five diffuse large cell lymphomas, three follicular lymphomas). Complex chromosomal abnormalities were detected in ATLL, while B-cell lymphomas showed only simple or minimal chromosomal abnormalities. Significant mutations/deletion of hBUB1 or hBUBR1 were detected in four of ten cases with ATLL, including two heterozygous point mutations, one homozygous point mutation, and one with a 47 bp deletion. In contrast, only one of eight B-cell lymphomas showed nonsense mutation of hBUBR1. None of the ATLL and B-cell lymphomas showed MIN. In the multistage process of leukemogenesis of ATLL, our findings indicate that mutations of mitotic checkpoint genes may play an important role in the induction of complex chromosomal abnormalities.

Imbalance between apoptosis and telomerase activity in myelodysplastic syndromes: possible role in ineffective hemopoiesis.

The myelodysplastic syndromes (MDS) are a group of disorders characterized by peripheral pancytopenia despite normo- or hyper-cellular bone marrow. This is thought to be due to apoptosis of hematopoietic bone marrow cells, resulting in ineffective hematopoiesis. The heterogeneous nuclear ribonucleoprotein (hnRNP) B1 is involved in pre-mRNA processing and binds to telomeric cDNA repeats. The hnRNP B1 is a marker for early cancer. The aim of our study was to clarify the relationships between prognosis and apoptosis, telomerase activity (TA) and hnRNP expression in the bone marrow. The subjects were 51 patients with MDS, including patients with refractory anemia (RA) (n = 32), refractory anemia with ringed sideroblasts (RARS) (n = 1), refractory anemia with excess blasts (RAEB) (n = 7), refractory anemia with excess blasts in transformation (RAEB-t) (n = 8) and chronic myelomonocytic leukemia (CMMoL) (n = 3). We also studied 6 cases with acute myelogenous leukemia (AML) arising from MDS (AML-MDS) and 10 control subjects. Bone marrow biopsies were stained immunohistochemically for caspase-3 (marker of apoptotic activity) and human telomerase reverse transcriptase (hTERT), and hnRNP B1. Fatal pancytopenia was the cause of death in 19 of the 51 patients. The caspase-3 positive cell rate was higher in MDS (16.3%) than in controls (4.4%) and AML-MDS (0.5%). The percentage of hnRNP B1-positive cells was higher in MDS (15.3%) and AML-MDS (56.3%) than in controls (5.6%). In MDS, hnRNP B1 levels were higher in RAEB and RAEB-t subtypes than in RA and RARS. The percentage of hTERT-positive cells was higher in AML-MDS (50.0%) than in controls (20.2%) and MDS (23.6%). Our findings suggest that activation of apoptosis occurs in MDS in the absence of hTERT expression, implicating high apoptosis in the absence of high TA with ineffective hematopoiesis. Poor prognosis correlated with higher caspase-3 and lower hTERT rates. In MDS, hnRNP B1 activity may be associated with leukemic transformation.

Spontaneous dissecting aneurysms of the basilar artery presenting with a subarachnoid hemorrhage. Report of two cases.

A spontaneous dissecting aneurysm of the basilar artery is a rare disorder, usually presenting with ischemia rather than a subarachnoid hemorrhage (SAH). Two cases are described of a dissecting aneurysm of the basilar artery presenting with an SAH. Vertebral angiography revealed a double lumen to the basilar artery. Magnetic resonance (MR) imaging detected the intramural hematoma. One patient was treated conservatively, and the other underwent operative intervention with wrapping of the aneurysm. The usefulness of MR imaging in the diagnosis and the treatment options are discussed.

Subsidence of seizure induced by stereotactic radiation in a patient with hypothalamic hamartoma. Case report.

The authors report on a patient who exhibited intractable epilepsy due to an inaccessible hypothalamic hamartoma and subsequently underwent stereotactic radiosurgery. This 25-year-old man had a 24-year history of intractable gelastic and tonic-clonic seizures. Magnetic resonance (MR) imaging performed at examination as well as that performed 30 months earlier demonstrated a nonenhancing and nonprogressive spherical mass, approximately 10 mm in diameter, located on the patient's right side at the floor of the third ventricle. Focal radiation treatment performed with a gamma knife unit administered 36 Gy to the center and 18 Gy to the periphery of the lesion. This treatment resulted in an improvement in seizure control. Before the patient underwent radiosurgery, he suffered from three to six generalized seizures per month in spite of attentive compliance with an anticonvulsant medication regimen. After irradiation of the harmatoma, the frequency of the seizures transiently increased and then subsided 3 months posttreatment. The patient has been free of seizures for the last 21 months, with no neurological or endocrinological complications. Magnetic resonance imaging performed 12 months posttreatment demonstrated complete disappearance of the lesion.

Expression of hnRNP B1 in four major histological types of lung cancers.

Heterogeneous nuclear ribonucleoprotein B1 is one of the nuclear pre-mRNA binding proteins involved in RNA metabolism. Recently, over-expression of B1 has been reported to be useful in the early detection of squamous cell carcinomas of the lung. To elucidate its significance in other histological types of lung cancers, we carried out a comparative study, four major types of lung cancers and normal lung tissues. 37 surgical specimens were examined using a B1-specific monoclonal antibody (2B2). Immunohistochemically, 2B2 demonstrated B1 protein in the nuclei not only of squamous cell carcinoma (10/10) but also of adenocarcinoma (17/18), small cell carcinoma (5/5) and large cell carcinoma (3/4). A lesser amount of B1 protein was also detected in normal cells. Quantitative immunoblotting revealed that B1 expression was markedly higher in cancer tissues than normal tissues and it varied among the four histological types. To establish the usefulness of B1, a threshold should be set for over-expression.

Closed-Wedge osteotomy for osteochondritis dissecans of the capitellum. A 7- to 12-year follow-up.

This article details a 7- to 12-year follow-up of seven young male baseball players with osteochondritis dissecans of the capitellum that we treated using closed-wedge osteotomy. This procedure was established by Yoshizu in 1986 for the treatment of "Little League elbow." The bone of the capitellum was revascularized and remodeled within 6 months in all seven patients. Six of the patients were able to return to full athletic activity and continued to play baseball. Radiographic assessment during the follow-up study revealed minimal osteoarthritic change and suggests that the treatment is useful for such an injury.

Treatment selection for cerebral arteriovenous malformations: radiosurgery or microsurgery.

The clinical results and patient characteristics of 318 cases of cerebral arteriovenous malformations (AVMs) were analyzed: 138 patients were treated by surgery including 98 cases of total removal and 17 cases of subtotal removal; 37 patients were treated conservatively; 139 patients were treated by gamma-knife and 6 patients were treated by linac-knife radiosurgery using stereotactic multi-converging arcs systems. Clinical data analysis was performed using the same protocol in both of the surgery and the radiosurgery groups. Operative mortality for total removal was one out of 98 cases (1%). There was one death by hemorrhage, one case of symptomatic rebleeding and two cases of asymptomatic bleeding in patients treated by radiosurgery. Thus, mortality was 1 out of 145 (0.7%). Patients with total resection of AVMs had the best clinical results in comparison with subtotal resection or with conservative treatment. Morbidity was the lowest in the patients treated by radiosurgery. However, the total obliteration rate was lower than the surgical cure rate. The decision for treatment should be based on an estimation of mortality, morbidity and cure rate for each treatment.

Bone marrow and serum concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1 alpha,25-dihydroxyvitamin D in patients with leukemia and normal subjects.

Concentrations of 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D [24,25(OH)2D], and 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] in bone marrow and serum of patients with leukemia and normal subjects were assayed. There were highly significant correlations between the bone marrow and serum concentrations of the respective vitamin D metabolites. Especially, the concentrations of 25-OH-D and 1,25(OH)2D in the bone marrow gave very similar values to those in serum. This is a big advantage in controlling the bone marrow levels of vitamin D metabolites in patients with leukemia, because doctors can calculate the bone marrow levels from the serum levels of the respective vitamin D metabolites without bone marrow aspiration. When 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) was administered orally to eight patients with leukemia, clinical conditions were improved in seven patients: four complete remissions (CR), one partial response (PR), and two minor responses (MR) without severe hypercalcemia. The results suggest that the therapy with 1 alpha-OH-D3 is fairly effective for curing human leukemia although it is not dramatic.

Regional difference in fenestration of choroidal capillaries in Japanese monkey eye.

The fenestration of the endothelial cells of the choroidal capillaries in the periphery, posterior pole and macular region of the eyeball was studied comparatively by the freeze-fracture technique and morphometric analysis. Fenestrations in the P face appeared as circular or ovoid, vallate papillae, whereas those in the E face appeared as craters. The central know of the diaphragm, which is composed of a cluster of particles, could be observed in some fenestrations. The average diameter of fenestrations was 95.5 +/- 9.9 nm in the periphy, 73.2 +/- 4.8 nm in the posterior pole and 79.3 +/- 4.5 nm in the macular region. Among these three areas, the difference in diameter of fenestrations was significant (P less than 0.01). The average number of fenestrations per 1 micron2 was 32.0 +/- 4.4 in the periphery 39.3 +/- 2.5 in the posterior pole and 45.0 +/- 2.6 in the macular region. The difference in the density of fenestrations was significant (P less than 0.01) between the periphery and the macular region. The regional difference in the density of fenestration may indicate the functional difference of the relating retinal portion.

Electrophysiological studies and physical examinations in entrapment neuropathy: sensory and motor functions compensation for the central nervous system in cases with peripheral nerve damage.

We performed electrophysiological studies and objective physical examinations in 60 patients with carpal tunnel syndrome and 21 patients with cubital tunnel syndrome. Compared with our normal data, the sensory nerve conduction velocity across the wrist was defined as abnormal in 97% of the carpal tunnel syndrome patients, the corresponding value of the amplitude of the sensory nerve action potential was 58% and the value of the two point discrimination test was 28% while the value of the Semmes-Weinstein monofilament test was defined as abnormal in 64% of the cases. In cubital tunnel syndrome patients, motor nerve conduction velocity across the elbow was defined as abnormal in 91%, the amplitude of the M-wave was 96%, manual muscle testing was 63% and their side pinch strength was defined as abnormal in 24% of the cases. The functions of recognition are preserved in the cases with moderate damage of peripheral nerve due to the cancellation of synaptic occlusion. Motor performance also compensated in the central nervous system. Therefore the sensitivity of the objective physical examination is less than that of electrophysiological study of peripheral nerve itself. For entrapment neuropathy electrophysiological findings are more sensitive than the objective physical examinations.

Structural comparisons of cell organelles and nuclei in rat hepatocytes with three different fixation techniques.

The morphological properties of cell organelles and nuclei in rat hepatocytes were compared, when the hepatocytes were either chemically fixed in glutaraldehyde and osmium (GA-Os), chemically fixed only in osmium (Os-2h) or physically fixed with a microwave-irradiated osmium (Mw-Os) fixative for a short duration. Judging from the fine structure, the mitochondria and rER were best preserved after physical fixation; because of the smooth surfaces and regular open contours, but both organelles shrank in the two chemical fixatives. The Golgi complexes and peroxisomes of the hepatocytes were not markedly changed by any of the fixative procedures. However the lysosomes and sER were changed to some extent after physical fixation. In the nucleus, the two kinds of chromatins and the nucleolus were best preserved with physical fixation. In conclusion, physical fixation is a very simple and fast procedure that is convenient for routine electron microscopy if some attention is paid to the morphological changes.

[Analysis of genome types of adenovirus type 7 isolated in Fukuoka Prefecture in 1996].

Adenovirus type 7 (Ad7) was rarely isolated in Japan till 1994, but during April 1995 to August 1996, isolations of Ad7 were reported 230 cases. We isolated Ad7 in January and July 1996 in Fukuoka prefecture. We analyzed its genome type by using 14 restriction endonuclease and studied seroepidemiology of Ad7 infection in Fukuoka prefecture. Isolated Ad7 strains were identical by 14 restriction endonuclease. Between new Ad7 isolates and prototype (Gomen; Ad7p), 4 restriction endonuclease patterns were identical but 10 restriction endonuclease patterns were different. From the result of restriction endonuclease pattern analysis, genome type of Ad7 isolated in Fukuoka may be the same to Ad7c reported by Noda et al. (1996). The alterations in the cleavage sites of 10 restriction endonucleases between new Ad7 isolates and Ad7p were revealed at least 12 sites. Ad7 antibody positive rates in serum specimens collected in Fukuoka Prefecture were 3.6% in 1994 and 9.7% in 1996.

[An epidemic of aseptic meningitis caused by echoviruses in Fukuoka Prefecture during April 1997 to August 1998].

An epidemic of aseptic meningitis in Fukuoka Prefecture during April 1997 to August 1998 was studied to determine the serotype of viruses isolated in Fukuoka Prefecture. In Fukuoka Prefecture, bimodal peaks were seen in July and December 1997. Monthly changes of reported aseptic meningitis patients and period of virus isolation revealed that epidemics of the earlier part in 1997 was caused by echovirus 9 (E 9) and the latter part due to echovirus 30 (E 30). E 9 was isolated mainly in Chikugo Area from June to October 1997 but, E 30 was isolated all in areas of Fukuoka Prefecture. Isolation of E 30 continued after January 1998 in Fukuoka Prefecture. Isolation of echovirus 18 started in June 1998. The main serotypes of isolates are changing. The E 30 isolates are serotyped by neutralization with the aid of antiserum pools for enterovirus type differentiation, but serotyping was difficult with commercially available antiserum. The result of neutralization tests with standard serum and an immune albino rabbit serum prepared in our laboratory with the E 30 isolates indicated that the isolates in Fukuoka Prefecture was an antigenic variant.

[Epidemic of influenza in Kyushu-Okinawa District (April 1994-March 1995)].

The prevalence of influenza in Kyushu-Okinawa District in April 1994- March 1995 was studied as the prevalence of influenza virus, to determine the sero-type of influenza viruses isolated in Kyushu- Okinawa District prefectures and cities. As a result, three sero-types of influenza viruses, i.e. type A/H1N1, type H3N2 and type B, were isolated in Kyushu-Okinawa District in this season, but most of the isolates were type A/H3N2 and type B. Weekly changes of reported influenza patients and period of virus isolation at local public health institutes revealed that influenza epidemics of the earlier part in this season was caused by type A/H3N2 and the latter part due to type B. Type A/H3N2 spread all over Kyushu-Okinawa District in a shorter period (about 2 weeks) through the westside of Kyushu and down south, and type B stayed about one month in northern Kyushu and took about 7 weeks to spread all over Kyushu-Okinawa District. Based on these results, the spread of influenza virus in Kyushu-Okinawa District was visualized on the isopleth maps.

[Peritumoral hemorrhage after radiosurgery for metastatic brain tumor: a case report].

An unusual case of peritumoral hemorrhage after radiosurgery for the treatment of metastatic brain tumor is reported. This 64-year-old woman had a history of breast cancer and underwent right mastectomy in 1989. She remained well until January 1993, when she started to have headache, nausea and speech disturbance, and was hospitalized on February 25, 1993. Neurological examination disclosed right hemiparesis and bilateral papilledema. CT scan and MR imaging showed a solitary round mass lesion in the left basal ganglia region. It was a well-demarcated, highly enhanced mass, 37mm in diameter. Cerebral angiography confirmed a highly vascular mass lesion in the same location. She was treated with radiosurgery on March 8 (maximum dose was 20Gy in the center and 10Gy in the peripheral part of the tumor). After radiosurgery, she had an uneventful course and clinical and radiosurgical improvement could be detected. Her neurological symptoms and signs gradually improved and reduction of the tumor size and perifocal edema could be seen one month after radiosurgery. However, 6 weeks after radiosurgery, she suddenly developed semicoma and right hemiplegia. CT scan disclosed a massive peritumoral hemorrhage. Then, emergency craniotomy, evacuation of the hematoma and total removal of the tumor were performed on April 24. Histopathological diagnosis was adenocarcinoma. It was the same finding as that of the previous breast cancer. Histopathological examination revealed necrosis without tumor cells in the center and residual tumor cells in the peripheral part of the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)