A case of idiopathic hypereosinophilic syndrome with leptomeningeal dissemination and intraventricular mass lesion: an autopsy report.

A 43-year-old female presented with idiopathic hypereosinophilic syndrome (HES) manifesting as an intraventricular mass lesion and leptomeningeal and cerebral parenchymal infiltration by eosinophils, lymphocytes and macrophages. She had no history of either malignancy or allergic disorder. She complained of hearing disturbance caused by eosinophilic otitis media. Eosinophilia was detected in the peripheral blood. Hearing disturbance and eosinophilia improved with corticosteroid treatment. Six months later, she was admitted with disturbances of consciousness. Magnetic resonance imaging revealed a mass lesion in the right lateral ventricle and leptomeningeal involvement around the brain stem. Her symptoms deteriorated rapidly, and she died of brain stem malfunction. Autopsy demonstrated significant infiltration by eosinophils and lymphocytes into the mass lesion in the ventricle, subarachnoid space, perivascular space and parenchyma of the medulla oblongata. Histological examination of the bone marrow and other organs did not detect any evidence of parasites, malignancies, or systemic disorders in any organ. The final diagnosis was idiopathic HES. The present case shows that leptomeningeal dissemination and infiltration by eosinophils into the cerebral ventricles and brain stem should be considered in the course of idiopathic HES.

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy.

OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.

In vitro interleukin 12 activation of peripheral blood CD3(+)CD56(+) and CD3(+)CD56(-) gammadelta T cells from glioblastoma patients.

Interleukin (IL)-12 has recently been shown to be directly involved in the activation of natural killer and alphabeta T cells via an IL-2-independent pathway. We show here that another type of human cytotoxic cell, gammadelta T cells activated by solid-phase anti-CD3 antibody and expanded using IL-2, obtained, in this case, from the peripheral blood of glioblastoma patients, displays significant tumoricidal activity. In addition, its cytotoxic activity against K562 or Daudi cells or against autologous glioblastoma targets (but not lymphocytes) is significantly enhanced when costimulated with IL-2 and IL-12. To study this synergistic activation by the two interleukins of the patients' gammadelta T cells, we screened the cells for the presence of the IL-2 receptor (IL-2R) and IL-12 receptor (IL-12R) using both flow cytometric analysis and PCR. The patients' gammadelta T cells constitutively expressed the high-affinity IL-2R; when stimulated with IL-12 plus IL-2, the levels of IL-2Ralpha and IL-2Rbeta increased, whereas that of IL-2gamma did not. They also expressed marginal levels of low-affinity IL-12R both immediately after IL-2 expansion and after 24-h incubation, and significantly higher levels after 72-h incubation, consistent with the level of gammadelta T-cell activation. IL-12 alone induced little proliferation of patients' gammadelta T cells in a 24-h assay and none in a 72-h assay; however, it caused a marked inhibition of the IL-2-induced proliferative response in the 72-h assay. The synergistic action of IL-2 and IL-12 was completely abolished by combined pretreatment with anti-IL-2alpha, beta, and gamma mAbs. IL-12-mediated enhancement of gammadelta T cell cytotoxic activity was inhibited by anti-IL-2Rbeta mAb in a dose-dependent manner but not by anti-IL-2Ralpha or anti-IL-2Rgamma mAbs. Thus, the increased expression of the IL-2Rbeta is critical for the synergistic activation of gammadelta T cells by IL-12 plus IL-2; it is also probable that at least the low-affinity IL-12R contributes to the activation of gammadelta T cells mediated by either IL-12 alone or IL-12 plus IL-2. We have, therefore, demonstrated that IL-12 can stimulate the cytotoxic activity of gammadelta T cells from glioblastoma patients, acting via the IL-2Rbeta component of the IL-2R and low-affinity IL-12R. IL-12 activation of patients' gammadelta T cells could possibly be of potential use in the treatment of glioblastoma patients.

Methylated cytosine level in human liver DNA does not decline in aging process.

In order to ascertain a generality of the age-dependent decrease in DNA methylation level among different mammalian species, methylated cytosine contents in human liver and spleen DNA at different ages have been determined using high performance liquid chromatography (HPLC). Unexpectedly, the liver DNA revealed no appreciable decline with age while the spleen DNA showed a slight reduction. It indicates that a decrease of methylation level in genomic DNA is not a common denominator of age-related changes in mammals.

A simple method for the propagation and purification of gamma delta T cells from the peripheral blood of glioblastoma patients using solid-phase anti-CD3 antibody and soluble IL-2.

Although gamma delta T cells make up no more than 10% of the peripheral blood mononuclear (PBM) cells, they appear to play an important role in host defense against tumor growth. In order to evaluate their functional activity against tumors and their response to various cytokines, large numbers of cells are required. Here, we describe a newly-devised method for the isolation and expansion of gamma delta T cells from the peripheral blood of cancer patients, in particular those with glioblastoma. Using this approach, a 1000-1500-fold increase in total cell numbers was achieved in two weeks, the proportion of gamma delta T cells in the expanded population being, on average, approximately 30% after 14 days of culture. The method therefore gives a yield of approximately 10-15 x 10(8) gamma delta T cells from only 5 ml of peripheral blood from glioblastoma patients and normal controls. The highly purified gamma delta T cells of glioblastoma patients were shown to bear both a high-affinity interleukin-2 receptor (IL-2R) and a low-affinity IL-12 receptor (IL-12R). They also displayed significant cytotoxicity against autologous tumor cells, but not against autologous fresh or IL-2-treated lymphocytes, and proliferated in response to IL-2, both effects being dependent on the dose of IL-2 used for activation. In addition, overnight incubation with 700 U/ml of IL-2 or 50 ng/ml of IL-12 resulted in significant cytotoxic activity of patients' gamma delta T cells against K562 target cells, the level of activity being almost the same as with similarly-treated gamma delta T cells from normal controls (P > 0.05). These results demonstrate that the patients' gamma delta T cells obtained using this method are intact in terms of cytotoxic function. Thus, this method not only makes it possible to produce large numbers of purified gamma delta T cells but also to produce populations containing both gamma delta T cells and NK cells, both active against tumor targets which might be suitable for clinical trials of adoptive-immunotherapy, especially in cancer patients for whom no effective therapy is available.

Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the tumor-specific cytotoxicity of gammadeltaT cells from glioblastoma patients.

Adoptive immunotherapy using tumor-specific killer cells can be beneficial in inducing regression of advanced cancer. The roles of cytokines on effector cells in inducing maximal killing activity and the accompanying side-effects should be investigated in vitro and fully understood prior to their clinical use. The present study indicates that the gammadeltaT cells involved in autologous tumor-specific killing consist of several populations in terms of their T cell receptor (TCR) repertoire, but predominantly express the products of the Vgamma9/Vdelta2 gene locus of the TCR. We then examined the effect of TNF-alpha and IFN-gamma on these tumor-specific gammadeltaT cells for possible clinical use in cancer patients. TNF-alpha alone, at concentrations of 0.01-1.0 microg/ml, caused increased gammadeltaT cell cytotoxicity against autologous glioblastoma cells, whereas IFN-gamma alone had no effect. The combination of TNF-alpha (1 microg/ml) with IL-2 (50 units/ml) resulted in further enhancement of cytotoxicity. TNF-alpha, but not IFN-gamma, marginally inhibited the proliferative response of gammadeltaT cells; a similar result was seen when the cytokines were combined. TNF-alpha may, therefore, be one cytokine capable of inducing increased autologous tumor-specific activity in gammadeltaT cells, bearing mainly Vgamma9/Vdelta2 chains, which can be enhanced when combined with other cytokines.

Diffuse form of primary leptomeningeal gliomatosis. Case report.

Primary leptomeningeal gliomatosis is rare, and the diffuse form is even rarer with only three cases reported in the literature. A fourth case is described in this report. Computerized tomography (CT) findings showed hydrocephalus with enhancement of the cerebral cisterns, and analysis of cerebrospinal fluid obtained by lumbar puncture showed many atypical cells. Based on these findings, a diagnosis of leptomeningeal tumor was made. There was some improvement in neurological and CT findings following radiotherapy and chemotherapy.

18F-fluoro-2'-deoxyuridine as a tracer of nucleic acid metabolism in brain tumors.

The value of 18F-fluoro-2'-deoxyuridine (18F-FUdR) as a tracer for nucleic acid metabolism was studied using an experimental rat brain-tumor model. The 18F activity in the tumor tissue 45 minutes after intravenous injection of 18F-FUdR was about 12 times higher than that in the contralateral cortex. Double-labeled autoradiography with 18F-FUdR and 14C-thymidine revealed similar brain-tumor images. In contrast, an autoradiographic comparison of 18F-FUdR with 14C-aminoisobutyric acid, which reveals the impairment of the blood-brain barrier, showed very different images. Also, the 18F radioactivity in the tumor tissue was at a constant level for 30 to 120 minutes, whereas a notable increase in 18F activity with time was observed in nucleotides and acid-insoluble fractions. These results suggest that the distribution pattern of 18F-FUdR closely correlates with the metabolism of nucleic acid and that this drug could be a useful tracer for positron emission tomography.

Skull metastasis of thyroid carcinoma. Study of 12 cases.

Over the past 33 years the authors have treated 12 cases of skull metastasis from thyroid carcinoma, accounting for 2.5% of a total of 473 cases of thyroid cancer. A study of these 12 cases revealed the following characteristics. The mean age of the patients was 60.4 years and the predominant incidence was in the seventh decade of life. The incidence of skull metastasis from thyroid cancer was higher among women than among men. The primary sign was a soft hemispheric tumor resting on the skull. The tumors were rich in vascularity with osteolytic changes in the skull. The average period from diagnosis of the thyroid tumor until thyroidectomy was 14.3 years, and until discovery of the skull metastasis was 23.3 years. The clinical course was thus very long. The most frequent histopathological presentation was follicular adenocarcinoma. Such lesions were morphologically well differentiated, with little pleomorphism and atypism, but detailed examination showed infiltration into the vascular lumen or capsule. The mean survival time in these patients was 4.5 years from the time of diagnosis. The prognosis in this lesion was relatively poor, considering its long clinical course.

Tumor-specific cytocidal and immunopotentiating effects of relatively low molecular weight products derived from the basidiomycete, Agaricus blazei Murill.

Currently, some natural herbal extracts are believed to have a marked tumoricidal effect and low toxicity for normal tissues. We investigated the effect of relatively low molecular weight products extracted from the basidiomycete, Agaricus blazei Murill, on MethA tumor cell growth with the aim of producing synthetic derivatives based on these products. Inoculation of the low molecule fraction (LM) into the primary tumor of a two-tumor model resulted in the marked inhibition of the tumor, not only in the right flank, but also in the non-injected left flank. Chromatographic purification and physicochemical characterization showed the main tumoricidal activity to be located in a low molecule fraction-3 (LM-3), containing alpha-1,4-glucan-beta-1,6-glucan complex with an average molecular weight of 20 kDa. A11 LM fractions and crude ATF showed in vitro selective cytotoxicity for MethA tumor cells, having no effect on normal cells. Serum levels of immunosuppressive acidic protein (IAP) in mice receiving LM fractions, particularly LM-3, significantly increased, indicating the possible activation of granulocytes. We speculate that the inhibition of the distant tumor might be due to the increased migration of granulocytes, enhanced by the effect of extract injections at the primary tumor site.

Review of incompletely occluded surgically treated cerebral aneurysms.

Among the 837 cases of direct surgical treatment of single saccular aneurysms in our clinic from 1961 until September, 1975, postoperative angiograms were obtained in 578 cases and an investigation showed 41 had residual aneurysms. Of these, 19 were further treated by muscle wrapping or wrapping subsequent to treatment ofhe neck. Postoperative angiograms revealed residual aneurysms in 22 cases (3.8%) in which insufficient surgical treatment was performed.

Third ventricle cavernous angioma: report of two cases.

Cavernous angioma arising in the third ventricle is an extremely rare disease. We have reviewed five cases previously reported, as well as our own two cases, and discuss the clinical characteristics of and surgical approach to cavernous angioma at this site. The bifrontal craniotomy and interhemispheric translamina terminalis approach minimize the damage to the brain and allow for an approach to the third ventricle in a wide operative field with minimal compression of the brain itself. We have found this approach to be suitable for surgery on angiomas of the anterior half of the third ventricle.

Interhemispheric approach through the lamina terminalis to tumors of the anterior part of the third ventricle.

Operative approaches to tumors of the third ventricle, mainly the bifrontal approach through the lamina terminalis, are discussed. The latter approach has several advantages. First, the main arteries can be exposed and the operative field is sufficiently wide to render the operative procedure safe. Second, cortical incision or excision is unnecessary. By cutting the lamina terminalis, which is usually thin and expanded as a result of hydrocephalus, even a large tumor can be removed. In addition, lethal complications are avoided, because this approach has less possibility of damage to the lateral wall of the third ventricle. Seventeen cases of tumor in the third ventricle underwent operation via this approach. The operative technique for the bifrontal approach through the lamina terminalis and three representative cases are reported. This approach can be applied not only to tumors, but to arteriovenous malformations or giant aneurysms adjacent to the third ventricle.

Hemorrhage and abnormal veins in acoustic neurinoma: MR findings.

We reviewed the MR imaging findings of 57 acoustic neurinomas which were verified at surgery or diagnosed on the basis of neuroradiological and neurootological data. Two uncommon MR findings of acoustic neurinoma were found. First, hypointense areas were observed on T2-weighted images in five of the 12 tumors larger than 25 mm in diameter. These hypointense areas represented hemosiderin deposition secondary to occult intratumoral hemorrhage. Second, curvilinear or round signal voids were noted at the periphery of 11 large or medium-sized tumors, and these corresponded to "abnormal veins" seen on angiographic studies.

[Enhancement of the effect of X-irradiation against cultured human glioblastoma cells by pretreatment with ACNU].

Human glioblastoma A-7 (GB A-7) cells can apparently recover from potentially lethal X-irradiation. The authors, using a colony-forming assay, studied the influence of pretreatment with 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) on the effectiveness of X-irradiation against GB A-7 cells grown in monolayers and as multicellular spheroids. Pre-exposure to ACNU inhibited the recovery of irradiated GB A-7 cells. In monolayer cells, the combination treatment was most effective when ACNU was applied 2 to 8 hours prior to irradiation, and the larger the X-ray dose, the more potent the effect. ACNU pretreatment was more effective against large spheroids (enhancement ratio 1.86) than against small ones (1.34). Large spheroids showed necrosis, whereas small ones did not. Isobolographic analysis disclosed that the effect of combining X-irradiation and ACNU is within an additive envelope at the surviving fraction of 10(-2), while supra-additive at the surviving fraction of 10(-3). These results suggest that the potency of X-irradiation is augmented by ACNU pretreatment through an interactive mechanism. Further, suppression of recovery from X-ray induced potentially lethal damage was influenced by the presence of necrosis.

Effects of X-irradiation alone and in combination with ACNU on human glioblastoma cells in vitro.

The combined effects of x-irradiation and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloro-ethyl)-3-nitrosourea (ACNU) on multicellular glioblastoma A-7 spheroids were analyzed by means of cell survival and dose-response curves. The actual dose-response curve for small spheroids was almost identical to that estimated from the cell survival curve. It was strongly suggested that a small number of radiation-resistant cells, which were not detected in the cell survival curve, were present in large spheroids with central necrosis. The enhancing effect of ACNU was greater with large spheroids than with monolayer cells or small spheroids. A possible explanation for this is that ACNU is higher effective against the few radiation-resistant cells that may be present in larger spheroids.

[Stenosis of the internal carotid artery following head injury--a case report (author's transl)].

This paper reports a rare case in which a development and improvement of post-traumatic stenosis of the internal cartoid artery was documented by angiographical studies. A 31-year-old male suffered from disturbance of consciousness with left hemiparesis following head trauma. On admission, plain craniograms showed fracture of the bilateral vertex and a fracture crossed the right carotid canal. Right carotid angiogram revealed that the internal carotid artery was visualized "striped" and its wall was irregular narrowing. Angiogram taken nine days after the trauma showed an improvement of the stenosis. Consciousness disturbance and neurological signs had gradually improved by the end of the fourth post traumatic month. In the follow-up angiographical study, six months after the injury, the stenosis of internal carotid artery was found greatly improved.

[A device for prolonged releasing of anticancer drug--bleomycin: Second report].

The authors have developed a new dosage-form using a water soluble anticancer drug, Bleomycin (BLM), which had prolonged releasing properties exceeding for 15 days in vivo for intracranial administration. Basic experiments using these tablets have been previously reported. This study evaluates the anti-cancer effect of the tablets and its clinical application. For the evaluation of the anti-cancer effect, glioma cells were transplanted into the peritoneal cavity of Wister rats. The rats were divided into 4 main groups and treated by as follows: 1) BLM tablets (1 mg.P) implantation in the peritoneal cavity, 2) Placebo implantation, 3) Bleomycin solution (total 1 mg. P) injection and 4) physiological saline solution injection (The control). The group treated with BLM tablets showed the best results. Clinical application of BLM tablets was performed in 6 patients of craniopharyngioma. During operation, the tablets were placed into tumor cavity by alon-alpha. In one case, recurrence was greatly prolonged. This tablet is considered to usable for the treatment of cancer in not only the field of neurosurgery but also in other fields.

[Medulloblastoma with intractable ascites treated by carboquone--a complication of a ventriculoperitoneal shunt (author's transl)].

Although complication occasionally occur in the use of ventriculoperitoneal shunts (VP-shunt), the occurrence of intractable ascites and extracranial metastasis through the shunt are uncommon. Recently intractable ascites occurred in a two years old girl in whom a left VP-shunt had been placed before four month for obstructive hydrocephalus secondary to medulloblastoma. Paracentesis was performed with recovery of clear, straw-colored fluid with a specific gravity of 1012, a protein content of 0.3 gm/L and many of mononuclear cell on microscopic examination. Liver-scan and enzyme profile gave normal results. During 3 weeks, 6 times paracentesis were performed and total volumes of ascites were 3850 ml. At 5 and 6 times paracentesis, Carboquone 1 mg was injected into peritoneal cavity and 0.1 mg into ventricle cavity through flashing device. After these injection, intractable ascites were cured, no metastasis can be seen in peritoneal cavity when died 4 month later. No precise explanation can be offered for occurrence of this intractable ascites. It is said that chronic irritation of the visceral and parietal peritoneum or sub-clinical peritonitis may cause peritoneal malabsorption. In our case, antitumor agent was very effective, so this treatment will be recommended to try for intractable ascites.

[A case of glioblastoma in which early diagnosis was difficult by MRI].

The authors report a case of glioblastoma in which MR images with Gd-DTPA enhancement changed rapidly during the early stage. A 61 year-old male presented with sudden right facial spasm and dysarthria. However, both a plain and an enhanced CT failed to demonstrate any abnormal lesions. On the other hand, T2 weighted MR image revealed a well circumscribed high intensity lesion in the left frontal lobe without mass effect. This lesion could not be differentiated from cerebral infarction, since no contrast enhanced lesion was able to be observed in T1 weighted MR image with Gd-DTPA. His symptoms gradually became aggravated and at 3 months from the onset, MR image with Gd-DTPA disclosed a small enhanced lesion in the left frontal lobe near the cortical surface. After 6 months from the onset, he suffered from right hemiparesis and motor aphasia. The MR image with Gd-DTPA at this time showed a large enhanced lesion in the left frontal lobe with mass effect. He was admitted to our hospital, and subtotal removal of the tumor and intraoperative radiation was carried out. The patient did well postoperatively without additional neurological deficit, and then he received additional radiation therapy. It should be noted that Gd-DTPA enhanced MR image might fail to reveal the lesion of glioblastoma in its early stage, while T1 weighted image discloses only the gyral swelling.