Problems entailed in the definition and pathology of anaplastic astrocytoma

Three-tiered system dividing supratentorial astrocytic neoplasms into the astrocytoma, anaplastic (malignant) astrocytoma and the glioblastoma multiforme has been widely used. However, the pathology of anaplastic astrocytoma is defined in different ways according to different classifications. A total of 42 biopsy specimens from 35 cases diagnosed as anaplastic astrocytoma were reviewed pathologically and their features were correlated with a follow-up clinical study to discuss the prognostic usefulness of the subdivision of anaplastic astrocytoma. In WHO classification, anaplastic astrocytoma is defined as "astrocytoma containing areas of anaplasia". Follow-up study of 7 cases with the histology as such revealed that 5 cases had survived more than one year and seven months. The other 28 cases showed a varied histology and were subclassified into an astrocytoma in which moderately anaplastic cells are found throughout the tumor, an astrocytoma formed by anaplastic fusiform cells, an astrocytoma composed of predominantly rounded anaplastic cells, and a pleomorphic astrocytoma with or without intracytoplasmic hyaline inclusions. A follow-up study of cases with these types of astrocytoma disclosed death in 15 cases within one year and 7 months following the first surgery and that three cases displayed typical histological features of glioblastoma at autopsy. It is considered that there would be a considerable overlap between the group of anaplastic astrocytoma and that of glioblastoma, if we use the term "anaplastic astrocytoma" in a broader category.     

A Case Report of an Adult With Severe Hyperlipidemia During Acute Lymphocytic Leukemia Induction Therapy Successfully Treated With Plasmapheresis

Plasmapheresis for the treatment of hypertriglyceridemia has previously been performed in patients with sudden onset severe hypertriglyceridemia and acute pancreatitis; however, only a few reports of this procedure have been published. We report here on a case showing severe hypertriglyceridemia during asparaginase (Asp) treatment for acute lymphocytic leukemia (ALL), and give an overview of a lipid‐lowering apheresis therapy. To prevent the complication of pancreatitis due to hypertriglyceridemia, we performed plasma exchange (PE) three times using fresh frozen plasma. PE remarkably reduced both serum triglyceride and total cholesterol levels from 5430 mg/dL to 403 mg/dL and from 623 mg/dL to 204 mg/dL, respectively. The causes of severe hyperlipidemia in this patient were considered to include: the Asp treatment for ALL, and a genetic background with a heterozygote of familial lipoprotein lipase (LPL) defect syndrome, because the patient's plasma LPL level after intravenous heparin injection was low at 137 ng/mL. Hence, PE using fresh frozen plasma may be useful not only to remove lipoproteins, but also to supply defective factors, such as LPL, in similar cases.     

Long-lasting change in 5-HT2A receptor-mediated behavior in rats after a single footshock

To investigate the long-term functional change in the 5-HT(2A) receptor after acute stress, we examined the effect of single footshock on head shake behavior induced by the 5-HT(2A) receptor agent (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in rats. Head shakes were evoked in a dose-dependent manner by 0.1-10 mg/kg of DOI, and the maximal response was attenuated by a single footshock given 24 h before. This suggests that there is a decrease in the number of functionally effective 5-HT(2A) receptors. The single footshock-induced reduction in head shakes evoked by DOI was observed immediately and 24 h after footshock, and lasted until 1 and 2 weeks after footshock. Because there were no changes in the [3H]ketanserin binding of the frontal cortex 1 week after footshock, decreases in head shakes were not due to the down-regulation of 5-HT(2A) receptors evoked by footshock.     

Complete response in an elderly patient with advanced gastric scirrhous cancer treated with combined chemotherapy of TS-1 and CDDP

A 79-year-old male was diagnosed as having a scirrhous cancer of the stomach. Carcinomatous peritonitis was suspected on abdominal CT examination and the CA19-9 showed a high level of 95 U/ml. The patient was treated with combined chemotherapy of TS-1 and CDDP. TS-1 (100 mg/day) was administered for 14 days followed by 14 days rest as one course. CDDP was administered in 24-h continuous intravenous infusion on day 8. This treatment was done every 4 weeks regularly. After 5 courses, X-ray and endoscopy examinations revealed disappearance of cancerous lesions in the stomach with an improvement in the extensibility. No cancer cell were confirmed by endoscopic biopsy, nor did a CT-scan detect carcinomatous peritonitis. The CA19-9 decreased within the normal limit. Ten months after chemotherapy was started, the patient was very healthy without a recurrence of cancer. This combined chemotherapy has administered in 8 courses, and during this period no high grade toxicities (WHO grade 3 or 4) occurred. This TS-1/CDDP chemotherapy was effective for scirrhous gastric cancer and might be administered safely even for aged patients.     

Proliferation and cell death of human glioblastoma cells after carbon‐ion beam exposure: Morphologic and morphometric analyses

Histological analyses of glioblastoma cells after carbon‐ion exposure are still limited and ultrastructural characteristics have not been investigated in detail. Here we report the results of morphological and morphometric analyses of a human glioblastoma cell line, CGNH‐89, after ionizing radiation to characterize the effect of a carbon‐beam on glioblastoma cells. Using CGNH‐89 cells exposed to 0–10 Gy of X‐ray (140 kVp) or carbon‐ions (18.3 MeV/nucleon, LET = 108 keV/μm), we performed conventional histology and immunocytochemistry with MIB‐1 antibody, transmission electron microscopy, and computer‐assisted, nuclear size measurements. CGNH‐89 cells with a G to A transition in codon 280 in exon 8 of the TP53 gene had nuclei with pleomorphism, marked nuclear atypia and brisk mitotic activity. After carbon‐ion and X‐ray exposure, living cells showed decreased cell number, nuclear condensation, increased atypical mitotic figures, and a tendency of cytoplasmic enlargement at the level of light microscopy. The deviation of the nuclear area size increased during 48 h after irradiation, while the small cell fraction increased in 336 h. In glioblastoma cells of the control, 5 Gy carbon‐beam, and 10 Gy carbon‐beam, and MIB‐1 labeling index decreased in 24 h (12%, 11%, 7%, respectively) but increased in 48 h (10%, 20%, 21%, respectively). Ultrastructurally, cellular enlargement seemed to depend on vacuolation, swelling of mitochondria, and increase of cellular organelles, such as the cytoskeleton and secondary lysosome. We could not observe apoptotic bodies in the CGNH‐89 cells under any conditions. We conclude that carbon‐ion irradiation induced cell death and senescence in a glioblastoma cell line with mutant TP53. Our results indicated that the increase of large cells with enlarged and bizarre nuclei, swollen mitochondria, and secondary lysosome occurred in glioblastoma cells after carbon‐beam exposure.     

CAMSAP3 orients the apical-to-basal polarity of microtubule arrays in epithelial cells

Polarized epithelial cells exhibit a characteristic array of microtubules that are oriented along the apicobasal axis of the cells. The minus-ends of these microtubules face apically, and the plus-ends face toward the basal side. The mechanisms underlying this epithelial-specific microtubule assembly remain unresolved, however. Here, using mouse intestinal cells and human Caco-2 cells, we show that the microtubule minus-end binding protein CAMSAP3 (calmodulin-regulated–spectrin-associated protein 3) plays a pivotal role in orienting the apical-to-basal polarity of microtubules in epithelial cells. In these cells, CAMSAP3 accumulated at the apical cortices, and tethered the longitudinal microtubules to these sites. Camsap3 mutation or depletion resulted in a random orientation of these microtubules; concomitantly, the stereotypic positioning of the nucleus and Golgi apparatus was perturbed. In contrast, the integrity of the plasma membrane was hardly affected, although its structural stability was decreased. Further analysis revealed that the CC1 domain of CAMSAP3 is crucial for its apical localization, and that forced mislocalization of CAMSAP3 disturbs the epithelial architecture. These findings demonstrate that apically localized CAMSAP3 determines the proper orientation of microtubules, and in turn that of organelles, in mature mammalian epithelial cells.Microtubules play pivotal roles in fundamental cellular functions, including cell division, intracellular transport, and cell morphogenesis. They are dynamic structures with an intrinsic polarity of rapidly growing plus-ends and slowly growing minus-ends (1). In living cells, the microtubule minus-ends are stabilized by binding to specific molecules or structures, such as the γ-tubulin ring complex located at the centrosome (2). In epithelial cells, however, most microtubules do not emanate from the centrosome; instead, they are aligned along the apicobasal axis with their minus ends facing toward the apical domain (3–5). These observations suggest the presence of unidentified mechanisms that stabilize the minus ends of microtubules at apical regions. Such mechanisms have not yet been identified, although the potential involvement of microtubule-binding proteins, such as ninein, has been suggested (6).Although many proteins that modulate plus-end dynamics have been identified (7), how the minus-ends are controlled at noncentrosomal sites remains less well understood (2, 8–10). CAMSAP3 (also known as Nezha) is a member of the calmodulin-regulated–spectrin-associated proteins (CAMSAP)/Nezha/Patronin family proteins, which bind and stabilize the minus-ends of microtubules (11–18). In cultured mammalian cells, CAMSAP proteins have been shown to stabilize noncentrosomal microtubules in the cytoplasm or cell junctions (11, 14, 19, 20), suggesting their possible involvement in the spatial regulation of microtubule assembly in polarized cells, such as epithelial-specific longitudinal microtubule alignment.To date, no study has analyzed CAMSAP function in fully polarized epithelial cells, however. In the present study, we examined whether CAMSAP3 contributes to the epithelial-specific microtubule organization using intestinal epithelial cells. Our results demonstrate that CAMSAP3 plays a key role in tethering microtubules to the apical cortex in epithelial cells, and in turn regulates the positioning of organelles at their cytoplasm.     

The First Cooperative Living-related Donor Liver Transplantation Performed by Two Separate Institution Teams: The Kanagawa Liver Transplantation Program

(Received for publication on Sept. 26, 1996; accepted on May 12, 1997)     

Correlation between glioblastoma cell infiltration and T2 prolongation on magnetic resonance imaging

Tumor cell infiltration around the tumor tissue in glioblastoma was investigated in 13 patients with glioblastoma who underwent gross total tumor removal. Thirty-four glioblastoma cases were operated on between January 1988 and December 1995. T1-weighted magnetic resonance imaging (MRI) with gadolinium enhancement was used to measure tumor size, and T2-weighted MRI to detect perilesional edema. Biopsy samples of surrounding tissue taken after tumor removal were histologically examined. Small tumors (< 3 cm diameter) and moderatesized tumors with mild perilesional edema had no or few infiltrating tumor cells in the surrounding tissue. In contrast, large tumors (> 6 cm diameter) with moderate or high perilesional edema had intensive tumor cell infiltration.     

Cerebellar Contribution to Pattern Separation of Human Hippocampal Memory Circuits

The cerebellum is a crucial structure for cognitive function as well as motor control. Benign brain tumors such as schwannomas, meningiomas, and epidermoids tend to occur in the cerebellopontine angle cisterns and may cause compression of the posterior lateral cerebellum near the superior posterior fissure, where the eloquent area for cognitive function was recently identified. The present study examined cognitive impairment in patients with benign cerebellar tumors before and after surgical intervention in order to clarify the functional implications of this region in humans. Patients with cerebellar tumors showed deficits in psychomotor speed and working memory compared with healthy controls. Moreover, these impairments were more pronounced in patients with right cerebellar tumors. Functional magnetic resonance imaging during performance of a lure task also demonstrated that cerebellar tumors affected pattern separation or the ability to distinguish similar experiences of episodic memory or events with discrete, non-overlapping representations, which is one of the important cognitive functions related to the hippocampus. The present findings indicate that compression of the human posterior lateral cerebellum affects hippocampal memory function.