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IntroductionMultidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL.Methods and analysisForty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to Ethics and disseminationThis study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registrationjRCTs061180093.

Introduction: The objective of the study was to investigate the correlation between differences between imaging modalities and histological heterogeneity in minimally enhancing glioma. Methods: A prospective study was performed in 11 patients with minimally enhancing glioma (10%. The correlation between the imaging discrepancy and histological heterogeneity was investigated. Results: The average T/N ratio for the T2/FL+/MET+ area in grade II glioma (2.08 ± 0.4) was smaller than that in grade III (4.19 ± 2.4), whereas that for the T2/FL+/MET− area was similar in grade II (1.07 ± 0.2) and III (1.07 ± 0.1). The average T/N ratio for the T2/FL+/MET+ area in grade II and III was higher than that for the T2/FL+/MET− area (p

The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients.Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients.Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P0.001), and incidence of acute subdural hematoma (OR, 1.89; P0.001) were associated with in-hospital mortality in elderly patients with TBI.Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients.

The objective of this study was to investigate the distribution of 11C-methionine (MET) and F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) imaging and the hyperintense area in T2 weighted imaging (T2WI) in glioma with no or poor gadolinium enhancement in magnetic resonance imaging (GdMRI). Cases were also analyzed pathologically. We prospectively investigated 16 patients with non- or minimally enhancing ( 10% volume) glioma. All patients underwent MET-PET and FDG-PET scans preoperatively. After delineating the tumor based on MET uptake, integrated 3D images from FDG-PET and MRI (GdMRI, T2WI or FLAIR) were generated and the final resection plane was planned. This resection plane was determined intraoperatively using the navigation-guided fencepost method. The delineation obtained by MET-PET imaging was larger than that with GdMRI in all cases with an enhanced effect. In contrast, the T2WI-abnormal signal area (T2WI+) tended to be larger than the MET uptake area (MET+). Tumor resection was 95% in the non-eloquent area in 4/5 cases (80%), whereas 10 of 11 cases (90.9%) had partial resection in the eloquent area. In a case including the language area, 92% resection was achieved based on the MET-uptake area, in contrast to T2WI-based partial resection (65%), because the T2WI+/MET- area defined the language area. Pathological findings showed that the T2WI+/MET+ area is glioma, whereas 6 of 9 T2WI+/MET- lesions included normal tissues. Tissue from T2W1+/MET+/FDG+/GdMRI+ lesions gave an accurate diagnosis of grade in six cases. Non- or minimally enhancing gliomas were classified as having a MET uptake area that totally or partially overlapped with the T2WI hyperintense area. Resection planning with or without a metabolically active area in non- or minimally enhancing gliomas may be useful for accurate diagnosis, malignancy grading, and particularly for eloquent area although further study is needed to analyze the T2WI+/MET- area.

Objective: Use of an epidural self-blood patch (EBP) is the most effective form of therapy for patients with cerebrospinal fluid (CSF) hypovolemia. However, even if the symptoms are resolved, other clinical aspects of this condition frequently prevent patients resuming social activity. In the present study, we investigated the clinical course of patients with CSF hypovolemia after treatment with an EBP to assess the factors affecting return to work or school, and considered the treatment of patients with progressive chronic subdural hematoma. Patients and Results: We investigated a group of 10 patients with CSF hypovolemia. After initial application of an EBP, 8 of these patients were completely relieved of postural headache and associated symptoms, and the other 2 recovered after a second application. However, 3 patients who had cervical spondylosis or psychosis were still unable to return to work or school. Two patients who were forced to retire have potential for rehabilitation after EBP. One patient has recovered from the illness, but could not return to school due to persistent medical history of psychosis. These patients had suffered symptoms for a long period before EBP (mean, 17.8 months; range 7 months to 3 years) relative to those who were able to resume social activity (mean, 2.0 months; range 7 days to 5 months) (P < 0.05). Three had progressive bilateral chronic subdural hematoma. One of these patients required emergency burr-hole drainage to resolve the neurological deterioration. Conclusions: Both physicians and patients need to be aware of CSF hypovolemia, and the fact that it requires appropriate treatment without delay. While application of an EBP is a fundamentally important therapy even for patients with hematoma, careful follow-up is required for patients showing marked neurological deterioration or an increasing hematoma volume with a brain midline shift, and burr-hole drainage must sometimes be considered in combination with EBP.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

The optimal method for diagnosing cochleovestibular neurovascular compression syndrome(CNVC)remains controversial, and the aim of this study is to develop a standard diagnostic instrument for the condition. The clinical features of 53 sides of 50 patients with a combination of vertigo, tinnitus, and/or hearing loss were retrospectively evaluated. The following five clinical features were evaluated and given a score of 1 or 0:1)a long history of recurrent vertigo, tinnitus, or hearing loss;2)neurological findings related to positional vertigo, nystagmus, tinnitus, or hearing loss;3)neuro-otological findings involving tinnitus, audiometry, or vestibular testing;4)auditory brainstem response(ABR)evaluation with the detection of a low 25-75% II wave amplitude on the contralateral side and delayed interpeak latency in the I-III or I-V waves(usually low II wave amplitude combined with double peaks and a wide-based form)during ABR evaluation using 80 and 90dB clicks;and 5)the detection of vascular contact with the eighth cranial nerve on magnetic resonance imaging-constructive interference in steady state or air computed tomography imaging. Finally, the sum of these scores was evaluated. For cases in which more than one of the features of the items 1), 2), or 3) were present, the score was evaluated based on the most representative of the items.The patients were divided into those with scores of 4-5 and those with scores of 2-3. All the patients with scores of 4-5 exhibited CNVC, while those with scores of 2-3 had other diseases. Therefore, CNVC should be suspected in patients with scores of 4-5, but can be ruled out in those with scores of 2-3.

Objective: Optimal surgical indications for cochleovestibular neurovascular compression syndrome (CNVC) remain controversial. We examined the surgical indications and timing of surgery for CNVC. Methods: The surgical outcomes of 30 patients (32 sides) with vertigo, tinnitus and hearing loss were evaluated. CNVC was diagnosed according to five items for clinical features with a scoring system of 1 or 0 based on the following features: a history, neurological and otological findings, an ABR evaluation, and vascular contact with the eighth cranial nerve on MR or air CT imaging. Patients with scores of 4-5 were diagnosed with CNVC. In addition, three modulation types of tinnitus using median nerve stimulation were evaluated in CNVC (28 sides) and other diseases (12 sides), and classified as suppression (S-type), no change (N-type), and excitation (E-type). Results: At early time, results of 16 sides evaluated using the modulation test before surgery for CNVC, the relationship between modulation of tinnitus and surgical results was evaluated. The ratio of the tinnitus intensity early after the surgery to that before the surgery was significantly lower for the S-type than for the other two types (P

Background We present a case of tentorial dural arteriovenous fistula (TDAVF) causing subarachnoid hemorrhage with mass effect of large venous pouches, which was struggling to diagnosis and management due to complex vasculature and severe general condition. Case description A 43-year-old man was transferred to our hospital due to sudden consciousness disturbance. A neurological examination revealed tetraparesis and pupil dilatation with no light reflex. Imaging findings showed a large lesion in the brainstem with subarachnoid and intraventricular hemorrhage. Since there were multiple feeding arteries and large and multiple venous pouches on vascular imaging, we diagnosed the patient with TDAVF. Because of a high-flow arteriovenous shunt and the presence of large venous pouches, it appeared to be very difficult to approach the shunting point by direct surgery. Therefore, we first performed transarterial endovascular treatment with 25% n-butyl-2-cyanoacrylate to shrink the venous pouches and to reduce the pressure of the posterior fossa, followed by direct radical interruption of the shunting point using the craniotomy maneuver. Postoperative vascular imaging revealed disappearance of abnormal feeding arteries, draining veins, and venous pouches. The patient was discharged and transferred to a rehabilitation hospital with a modified Rankin Scale Score of 3. Accurate interpretation of the detailed vasculature preoperatively and an appropriate treatment strategy using endovascular and direct surgical technique are required to achieve a satisfactory outcome for difficult-to-treat dural arteriovenous fistulas. Conclusions This combined maneuver with endovascular embolism as complementary pretreatment for radical surgery is useful for a case with high-flow shunting and large venous pouches.

Introduction Well-differentiated papillary thyroid carcinoma generally (PTC) have a favorable prognosis. This metastasis is rare in the central nervous system. Brain metastasis has a relatively poor prognosis. We present a rare case of cerebellar metastasis, one that mimics a solid type cerebellar hemangioblastoma and because of which it was very hard to reach accurate preoperative diagnosis. Accurate diagnosis was challenging because of the similar imaging and histopathological findings for these two tumors. Case description A brain lesion was detected by routine medical checkup of the brain with MRI in a 49-year-old woman 2 years after thyroidectomy for well-differentiated PTC. Gadolinium-enhanced MRI showed a homogeneous prominently enhanced lesion with surrounding enhanced dilated vessels in the left cerebellar hemisphere. Digital subtraction angiography showed a strongly stained lesion fed by the peripheral branch of the left posterior inferior cerebellar artery with drainage into the inferior vermian vein, revealing arteriovenous shunting. The most like likely preoperative diagnosis was felt to be that of a solid cerebellar hemangioblastoma. Gross total resection of the tumor was achieved by bilateral suboccipital craniotomy, and intraoperative pathological analysis suggested hemangioblastoma. Histopathological findings showed proliferation of vacuolated sheeted tumor cells with clear and eosinophilic cytoplasm and numerous thin-walled microvessels, consistent with hemangioblastoma. However, the final diagnosis was brain metastasis of the follicular variant of PTC due to a partial thyroid follicle-like pattern including eosinophilic fluid pathologically and positive TTF-1 immunostaining. Discussion and evaluation Since presented rare case of cerebellar metastasis of PTC was very similar to solid type cerebellar hemangioblastoma on imaging and histopathological findings, accurate diagnosis was challenging. Moreover, it is extremely rare for a cerebellar metastasis to occur as an initial distant metastasis of PTC, and hemangioblastoma is the most common primary cerebellar neoplasm in adults. This epidemiological data was also one of the reason of difficulty to reach preoperative accurate diagnosis. Conclusions To the best of our knowledge, there are no other reports of challenging diagnosis case of these two tumors in the literature. Brain metastasis of a well-differentiated PTC could be a relatively poor prognostic factor, and accurate diagnosis and suitable surgical therapy or radiotherapy are needed.

Objectives and Importance: Although pontine hemorrhage is very often fatal, the clinical manifestations vary accord-ing to the location and extent of the hematoma. We investigated the prognostic factors of pontine hemorrhage by assessing clinical manifestation and CT findings in relation to outcome. Materials and Methods: The outcome and clinical features of 19 patients with pontine hemorrhage without surgical intervention were analyzed. The CT features of the hematoma were classified into four types: massive, tegmento-basilar, transverse oval, and small unilateral. The Glasgow Outcome Scale (GOS) was used to assess patient outcome (G, good recovery; MD, moderate disability; SD, severe disability, V, vegetative state, D, death) at discharge. Results: The outcome was MD in 7 cases, SD in 3, and D in 9. Eight of 9 patients with acute hydrocephalus died, whereas only one of 10 patients without hydrocephalus died (p 12, tetraparesis, or respiratory failure (p < 0.01, 0.05, 0.01, respectively). Four of 5 patients with CT evidence of massive hemorrhage died, and another patient became vegetative. The outcome in 6 patients with tegmento-basilar-type hematoma included D in 3, V in 2, and MD in 1, and that in 7 patients with transverse oval hematoma included D in 2, V in 1, SD in 1, and MD in 3. Five (65%) of the 8 patients with transverse oval or small unilateral hematomas were able to walk (MD) with or without assistance, whereas only 2 (18%) of 11 patients with tegmento-basilar-type and massive hematoma were ambulatory at discharge (p < 0.05). Conclu-sion: On the basis of CT classification, the functional prognosis of transverse oval pontine hemorrhage is as favorable as that of the small unilateral type.

The optimal surgical approach for a trigone meningioma is still controversial. Here, we report two patients with trigone meningioma treated successfully via an occipital inter-hemispheric and trans-cortical approach in the lateral semi-prone position. A 53-year-old woman was admitted to a local hospital with sudden transient dizziness and vomiting. The CT brain scan demonstrated a right intra-ventricular tumour. She was therefore transferred to our hospital for surgical treatment. The other patient was a 67-year-old woman who was admitted to a local hospital after a traffic accident and a CT brain scan revealed an incidental right intra-ventricular tumour. After referral to our hospital, periodic MRI examinations revealed gradual tumour enlargement within a one-year period. Neither of the patients had any neurological deficits, including in the visual fields. The head of each patient was positioned so that the tumour-containing right ventricle was oriented downwards and laterally. An occipital inter-hemispheric approach was performed and using a navigation system, the tumour was identified about 1 cm in depth from the cortical surface. After the medial part of the tumour was debulked, the posterior and then the anterior choroidal blood supplies to the tumour were identified. Occlusion of these vessels achieved tumour haemostasis. The tumours were totally removed via a 1.5-cm cortical incision. Brain retraction was minimal because the right hemisphere was pulled down by gravity. Therefore, the para-splenial cisterns were easily accessed, resulting in early release of cerebrospinal fluid. Post-operative MRI showed complete removal of the tumour and the patients had no neurological deficits. Anti-epileptic medication was withdrawn one week after the operation. The occipital inter-hemispheric fissure lacks important bridging veins. The approach used and patient positioning minimized damage to the lateral aspect of the optic radiation and the corpus callosum. Except in patients with very large trigone meningiomas, this approach is useful for decreasing the risk of post-operative hemianopsia or epilepsy, and possibly speech disturbance, even in patients with a tumour in the dominant hemisphere.

In the neurosurgery of brain tumor, patients' life after surgery crucially depends on completeness of malignant glioma resection. For decades, Photo-Dynamic Diagnosis using some oncotropic dyes (sensitizers) has been being improved as a surgical navigation system. In another field of medical diagnosis, a ratio metric technique, e.g. fluorescence ratio imaging, was applied to tumor detection, in which not only fluorescence from sensitizer, but also intrinsic auto-fluorescence were used to diagnose tumor lesions. However, it has never developed exhaustively in terms of signal noise ratio and resolution with system configuration, especially when applied to brain tumor boundary detection. In this study, in order to demarcate the brain tumor, “2-Color Photo-Dynamic Diagnosis System”, based on fluorescence ratio imaging, was constructed with higher sensitivity and resolution. This real time surgery navigating system, consisted of two CCDs and spectroscopic adaptor, can take better account of fluorescence spectroscopic characteristics. This was experimentally applied to brain tumor detection. Consequently, it was quantitatively confirmed that the contrast between tumor lesions and normal tissue could be enhanced. The present system was clarified to be effective to brain tumor monitoring and surgical delimitation.

We studied regional cerebral blood flow (r-CBF) by the Patlak plot method with 99mTc-SPECT in 5 adult patients with moyamoya disease presenting with ischemic symptoms. The mean values of r-CBF at rest of ACA, MCA and PCA territories were 38.0±1.9 (SD), 38.5±3.7 and 38.0±1.9 ml/100 g/min, respectively. The increase in r-CBF after administration of acetazolamide was 4.8, 5.8 and 12.3 ml/100 g/min, respectively. After bilateral double STA-MCA anastomosis with encephalo-myo-arterio-synangiosis, the r-CBFs at rest markedly improved, whereas those after administration of acetazolamide showed no significant change.

We report neurological changes and circulatory and pulmonary symptoms after surgical intervention in cases of brainstem cavernous angioma. Eight patients who underwent surgical intervention for brainstem cavernous angiomas were retrospectively reviewed. Two of 4 patients who underwent total removal of the mass showed marked resolution of the preoperative signs including IX nerve palsy, MLF syndrome, cerebellar sign and homonymous hemianopsia, and two patients who underwent partial removal of the lesions had permanent neurological deficits. Inadequate excision results in not only recurrence of hemorrhage, but also postoperative neurological deterioration. Bradycardia can occur during the surgical intervention, and careful monitoring is mandatory for a couple of days after operation to detect circulatory and pulmonary failure such as atrial flutter.

A 29-year-old man and a 46-year-old woman presented with calcified brain metastasis from pulmonary adenocarcinoma. Both patients had a relatively benign clinical course and prolonged survival after total removal of the tumors. The male patient was still alive 2 years 3 months after surgical resection of the metastatic and primary tumors. The female patient had had brain metastasis 8 years after surgical resection of lung cancer, and survived for 3 years 3 months after removal of the brain metastasis. The MIB-1 indexes of the two cases were relatively low compared with other cases of brain metastases. Calcification and low MIB-1 index may indicate longer survival in patients with metastatic tumors if the primary tumor is controlled.

A 50-year-old man presented with neuro-Behcet's disease (NBD) manifesting as a large neoplasm-like lesion affecting the brainstem, basal ganglia, and white matter of the cerebral hemisphere. He had no history of disease except for psychoneurosis. On admission, neurological examination found left hemiparesis and dysarthria. Magnetic resonance (MR) imaging showed multiple small ring-like enhancement in the basal ganglia, brainstem, and deep white matter. Biopsy of the mass was performed. Histological examination revealed invasion of inflammatory cells in the white matter, especially around the blood vessels. After the brain biopsy, the patient developed oral aphthae, genital ulcers, and skin eruptions, which are indicative of Behcet's disease. MR imaging after three courses of steroid pulse therapy revealed that the edematous lesion had become smaller with minimum midline shift. NBD should be considered in the differential diagnosis of lesions with multiple ring-like enhancement extending from the basal ganglia to the brainstem, because dermatological manifestations are sometimes obscured during periods of remission.

頭蓋内ナビゲーションは、術中に、脳神経外科医に病変部位を表示し、手術を補助する装置である。このためには、手術前に、MR画像を撮像する必要があり、頭蓋内電極留置後の皮質焦点切除には応用しにくかった。我々は、多少の工夫により、難治性てんかん患者に対し、頭蓋内電極留置によるモニタリングに引き続き行なう皮質焦点切除術の際に、ナビゲーションを併用しているので症例を提示し報告する。ナビゲーションは、頭皮上にマーカーを置き、MRを施行し、ナビゲーションのワークステーションコンピュータ上で、リファレンスを設定し、画像と術野該当構造を空間座標上に合致させる作業が必要である。頭蓋内電極留置前から、頭皮上にマーカーを置き、MR画像を撮像する。マーカー部位を、モニタリング期間中に維持し、手術操作による頭皮の腫脹などの影響を受けないように留意する必要がある。これにより、硬膜下電極によりマッピングされた皮質切除予定部位と、ナビゲーションにより表示される病変部との関係を確認しながら手術可能であった。髄液の流出と硬膜下電極による圧排による脳の偏位がナビゲーションの正確性に影響することに注意しなければならない。

Malignant tumors intrinsically manifest genetic instability, and consequently genetic aberrations successively accumulate in tumor cells as the tumor progresses. However, the relationship of genetic instability and biological behavior still remains to be investigated in malignant tumors. In the present investigation, the relationship between chromosomal instability and patient prognosis was studied in 19 malignant gliomas. Chromosomal instability was estimated by numerical variation in chromosomes 7, 10 and 17 which was measured by fluorescence in situ hybridization (FISH), and DNA ploidy was determined by laser scanning cytometry. The mean number of fractions was significantly higher in cases with DNA aneuploidy than in those with DNA diploidy. The tendency toward higher fractions in glioblastomas existed, although it did not reach statistical significance. Kaplan-Meier survival rate analysis demonstrated significantly lower survival rates in patients with higher fractions of chromosome 7 (>5) than others. Our results suggest that DNA aneuploidy in malignant gliomas reflects an underlying chromosomal instability, and that this instability is associated with clinical behavior.

To elucidate the structural abnormalities and the relationship between chromosome structural disorders and DNA copy number aberrations in tumor cells, we applied the techniques of spectral karyotyping (SKY), comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH), using yeast artificial chromosome (YAC) probes for nine human glioblastoma cell lines. One striking finding was that independently derived cell lines had the same recurrent marker chromosomes. Seven recurrent chromosomes were detected by these cytogenetic methods. In particular, cell lines U251, SNB-19, and U373-MG showed very similar karyotypes. It is also interesting that regions of DNA amplification were found translocated and/or inserted at a high rate (91.7%). In all, there were 12 amplified loci in five of the nine cell lines. These amplified chromosomal bands were scattered on the chromosomes, including the normal chromosome, with one exception (7q32-qter in U373-MG). FISH with YAC clones mapping to these chromosomal regions as DNA probes often showed DNA probe signals not only at original chromosomal sites but also in translocated or inserted segments. This form of DNA amplification was characterized by low-level increases (four- to 10-fold) and by translocation or insertion of the relevant chromosomal locus. These studies shed light on typical derivative chromosomes and the relationship between DNA amplification and chromosomal translocation in glioblastoma. © 2001 Wiley-Liss, Inc.

Nineteen intracranial germ cell tumours treated during the past 11 years were evaluated retrospectively. The tumours were classified into three groups according to the level of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) in serum and cerebrospinal fluid, and the optimal treatment for each group was determined. Group A consisted of patients with normal titres of AFP and HCG, group B of patients with relatively high titres (< 10 times normal), and group C comprised patients with higher titres ( 10 times normal levels). In group A, an appropriate field and dose of irradiation was necessary to prevent craniospinal dissemination. In group B, none of four patients who underwent total or subtotal resection of the tumour had craniospinal disseminatio n or tumour recurrence, whereas dissemination occurred in four further patients, including two who had received radiochemotherapy only, and two who had undergone partial resection of the tumour. While patients in group C had dissemination at the time of initial diagnosis, most patients in group B developed dissemination more than 10 months after initial treatment, suggesting that the type of treatment received as first line therapy is important in patients in this group. The prognosis of patients in group C, however, was unaffected by the priority given to either surgery, radiation or chemotherapy as first line treatment. Craniospinal dissemination can be prevented in patients with germ cell tumours who have a relative increase in levels of AFP and HCG by aggressive removal of the tumours as first line therapy, regardless of the type of adjuvant therapy given.

Deletion of chromosome 10 is one of the most common chromosomal alterations in glioma. At 10p15, the telomeric region of the short arm of chromosome 10, loss of heterozygosity (LOH) has been frequently observed by microsatellite analysis, suggesting the presence of a tumor suppressor gene. We examined LOH in 34 gliomas on chromosome 10, and frequent LOH on 10p was detected on 10p15, in agreement with deletion mapping studies on chromosome 10. We then constructed a bacterial artificial chromosome (BAC) clone contig covering the critical region, which spanned the interval between D10S249 and D10S533 on 10p15. The map contained 68 BAC clones connected by 74 sequenced tag sites (STSs) and covered approximately 2.7 Mb, with one gap. A total of 74 STSs, including 6 microsatellite markers, 29 expressed sequenced tags (ESTs), and 39 BAC end STSs, were physically arranged. Twenty-eight ESTs were mapped in the interval between D10S249 and D10S559 (approximately 1200 kb), and another EST was mapped in the interval between D10S559 and D10S533 (approximately 1300 kb). This sequence-ready BAC clone contig map will be a basic resource for high-quality sequencing and positional cloning of the putative tumor suppressor gene at 10p15 in glioma.

A malignant lymphoma developed in the central nervous system (CNS) of a 7-year-old boy 5 years after he had received chemotherapy and cranial irradiation for acute lymphoblastic leukemia (ALL). Bone marrow analysis of the original leukemia showed a pre-B cell phenotype, whereas the resected brain tumor showed a T cell phenotype on immunophenotypic analysis. Because of this difference in immunophenotype, and because the patient had received multiple-drug chemotherapy and 1,800 cGy of cranial irradiation for the original ALL, we consider that the malignant lymphoma was a second neoplasm. This is a very rare case in two respects: it was a malignant lymphoma arising in the CNS as a second neoplasm after ALL and a T cell lymphoma occurring in a child.

Pituitary adenomas are benign monoclonal tumors that are either hormonally functional or nonfunctional. Although their histologic and immunocytologic characteristics have been studied extensively, cytogenetic studies are scarce. We have investigated the cytogenetic alterations and DNA ploidy patterns of 12 sporadic pituitary adenomas, including 2 growth-hormone-secreting tumors, 1 prolactinoma, and 9 nonfunctional adenomas, by comparative genomic hybridization (CGH) and laser scanning cytometry (LSC). CGH revealed that the mean number of sites of copy gain was significantly higher in functioning adenomas than in nonfunctioning tumors (P < 0.01). The most frequent change detected was loss of 13q (5 cases), with a minimal common overlapping region at 13q14. These findings suggest that a putative tumor suppressor gene on 13q14 may play an important role in the development of pituitary adenomas. DNA aneuploidy was detected by LSC in 3 of the 12 cases. The DNA aneuploid adenomas showed cytogenetic changes more frequently than did the DNA diploid tumors (P < 0.02).

Intracranial metastasis without pulmonary involvement of Wilms’ tumor is very rare, and most previously reported metastatic sites have been in the cerebral parenchyma. We experienced a rare case of metastasis of Wilms’ tumor in the tectal plate without pulmonary involvement. A 3-month-old boy was admitted to our hospital due to hydrocephalus. After insertion of a ventriculoperitoneal shunt, there were no neurological deficits. Five months after the operation, a mass 5 cm in diameter extending from the tectal plate into the third ventricle was found. A mass 10 cm in diameter within the retroperitoneal space, which occupied the right kidney, was also found. Both tumors were resected and diagnosed histologically as Wilms’ tumor. Despite every effort including chemotherapy and radiotherapy, the patient died at 14 months old. The majority of children with hydrocephalus showing thickening of the tectal plate would most likely have tectal glioma; however, this unusual case report reminds us that metastasis of Wilms’ tumor can occur in the tectal plate causing hydrocephalus.

Little is known about genetic alterations during malignant progression of meningioma. We used comparative genomic hybridization (CGH) in 20 patients (13 with typical, 4 with atypical and 3 with anaplastic meningiomas) to investigate the genetic pathway underlying the development of meningioma. Typical meningiomas displayed only a few genetic changes such as monosomy 22. Anaplastic meningiomas manifested more aberrations than typical meningiomas, frequently exhibiting losses of 1p, 2p, 6q, chromosome 10 and 14q, and gain of 20q, in addition to monosomy 22. The average number of alteration sites in each patient with typical meningioma was significantly less than those in each patient with atypical (p < 0.01) and with anaplastic meningioma (p < 0.05). Anaplastic meningiomas showed the chromosomal changes seen in atypical meningiomas together with other aberrations. These CGH findings suggest that losses of 1p, 2p, 6q, chromosome 10 and 14q, and gain of 20q are genetic changes implicated in the malignant progression of meningioma.

Prolactin-secreting adenoma, which usually presents with amenorrhea and galactorrhea syndrome, is quite rarely diagnosed in the prepubertal age group. We reported a rare case of a prepubertal prolactin-secreting adenoma and discuss its clinical, radiological and histological features. An 8-year-old girl presented with headache, progressive visual deterioration and precocious puberty. The serum prolactin level was 57.8 ng/ml. Computerized tomography and magnetic resonance imaging revealed an invasive suprasellar tumor. The tumor was partially resected through an interhemispheric approach in a first operation, and residual tumor was resected through the right pterional approach in a second operation. The histological diagnosis was a prolactin-secreting adenoma with high cellular pleomorphism. The Ki-67 labeling index was 5.7%, indicating aggressive biological behavior. Postoperatively, the patient was prescribed bromocriptine as maintenance therapy, and the serum prolactin level became normalized. There is a tendency for diagnosis of a prepubertal prolactin-secreting adenoma to be delayed because there are no endocrinological manifestations. Therefore, the tumor tends to become larger and invasive. Although it is rarely experienced, a prolactin-secreting adenoma should be considered in the differential diagnosis of a large, invasive parasellar lesion in the prepubertal age group.

Comparative genomic hybridization (CGH) is a technique that allows the detection of losses and gains in DNA copy number across the entire genome. We used CGH to study the genetic alterations that occur in primary astrocytomas, including 14 glioblastomas (GBM), 12 anaplastic astrocytomas (AA), and 7 low-grade astrocytomas (LGA). The average numbers of total aberrations in GBM, AA, and LGA were 9.7, 5.4, and 4.0, respectively. The average number of DNA sequence losses in GBM was significantly higher than that in AA or LGA (P eight cases) observed in all grades of astrocytoma were 7p13-p12 (gain), 7q31 (gain), 8q24.1-q24.2 (gain), 9p21 (loss), 10p12-p11 (loss), 10q22-qter (loss), 13q21-q22 (loss), and 20q13.1-q13.2 (gain). Loss of 9p, 10p, or 10q, and the gain or amplification of 7p, were observed frequently in GBM (64%, 57%, 64%, and 50% of cases, respectively). Frequent alterations found in AA were losses of 9p, 10q, and 13q, and gains of 1q, chromosome 7, 11q, and Xq. Whereas 7p13-p11 amplification occurred exclusively in cases with the loss of all or part of chromosome 10, this change never occurred in cases having an increase in copy number of 8q, which was the most frequent change observed in LGA (four of seven cases). These results may indicate that an increase in copy number of 8q is an important event in GBM, with a genetic pathway, which is distinct from that in GBM with 7p amplification. Genes Chromosomes Cancer 21:340–346, 1998. © 1998 Wiley-Liss, Inc.

A 72-year-old male presented with a pilocytic astrocytoma in the velum interpositum manifesting as a 5-day history of dizziness attacks and unstable gait. Computed tomography and T1-weighted magnetic resonance imaging with gadolinium enhancement demonstrated a small, homogeneously enhanced mass in the velum interpositum. The tumor was removed subtotally, and the structure of the splenium was intact. The histological diagnosis was pilocytic astrocytoma. The MIB-1 growth fraction was 5%. The tumor may have originated from the splenium or the thalamus. The aggressive histology indicates the need for close neuroimaging follow-up.

The epidemiology of pediatric brain tumor was studied in a 10-year period from 1986 to 1995 in Yamaguchi prefecture. The total number of pediatric brain tumors was 83, and the incidence was 2.5/100,000/year, which did not change during the period. The sign most frequently seen was intracranial hypertension, whereas focal signs were less frequent. Although asymptomatic cases increased in this period, outcomes did not improve. Significant differences between pediatric and adult cases were the percentage of male patients (70.0 vs. 43.7%), tumor location on the midline (59.0 vs. 20.8%) and tumor location in the posterior fossa (44.6 vs. 26.3%). The midline location of many pediatric brain tumors results in the absence of focal signs, which delays the diagnosis and makes surgery difficult.

Breast tumor development and progression are thought to be driven by an accumulation of genetic alterations, but little is known about the specific changes that occur during the metastatic process. We analyzed pairs of primary breast cancers and their matched lymph node metastases from 11 patients, pairs of primaries and distant metastases from three patients, and pairs of primaries, and local recurrences from two patients by using comparative genomic hybridization (CGH). Simultaneous hybridization analysis of primary versus matched lesion DNAs from 11 patients was also performed (modified CGH). This modified approach was useful not only for confirming CGH results but also for demonstrating quantitative differences between aberrations present at both sites. Frequent chromosomal changes present at both sites (> 35% of 16 cases) were 1q, 8q, and 17q gains and 6q, 8p, 9q, 13q, 16q, 17p, and Xp losses. The total number of aberrations detected exclusively in the lymph nodes or distant metastases was higher than that in the primary tumors (2.5 vs. 0.7, P < 0.05). We found high-level amplifications in four metastases (two lymph nodes and two distant metastases), but none in any primary tumor. These findings suggest that progression from primary breast cancer to metastasis may be associated with the acquisition of further genetic changes. Although further investigations are required, it was of interest that 3 of 11 patients (27%) showed 18q loss solely in their lymph node metastases.

Effects of hyperthermia on the cell kinetics of glioblastoma cells were investigated using flow cytometry. Pulse-labeling with 5-bromodeoxyuridine (BUdR) and chasing of the labeled cells revealed temporary accumulation of the labeled cells in G2M phase and a reduction of DNA synthesis. The level of cyclin B rises rapidly in G2 phase and falls at the end of mitosis in normal cycling cells. Cyclin B binds to p34cdc2, resulting in histone kinase activity which is necessary for the initiation of mitosis. The amount of p34cdc2 remains constant throughout the cell cycle. The level of cyclin B was measured using an anti-cyclin B antibody and flow cytometry in order to investigate the cause of the G2 accumulation induced by hyperthermia. A low level of cyclin B, in comparison with that of normal cycling cells, persisted for more than 3 h after hyperthermia. These results indicate that the temporary accumulation of cells in G2M phase after hyperthermia may be caused, at least in part, by an insufficient level of cyclin B.

We report a rare case of unruptured aneurysms in systemic lupus erythematosus (SLE). A 28-year-old female who had suffered from SLE for 5 years was admitted to our hospital because she noticed diplopia three weeks before. She presented with left abducens palsy on admission. CT scans revealed intracranial multiple calcified lesions. MRA and the cerebral angiography showed multiple saccular aneurysms from the cavernous segment to the petrous segment of the left internal carotid artery (ICA). These findings suggested that left abducens palsy was related to cranial nerve compression due to the aneurysm at the cavernous segment of the left ICA. As balloon occlusion test for 15 minutes of the left ICA with 99mTc-HMPAO SPECT was tolerable, the patient underwent the endovascular trapping of multiple aneurysms from the cavernous segment to the petrous segment of the left ICA with detachable coils. Postoperative course was uneventful and left abducens palsy fully recovered. She was discharged with no neurological deficits. This is the first report presenting left abducens palsy due to unruptured aneurysms in SLE. We summarized the previous reports of cerebral aneurysms in SLE.

Intraventricular meningiomas account for 9.8-14% of all intraventricular tumors and for 20% of lateral ventricle tumors [1,2]. Meningiomas of the lateral ventricle constitute 0.5-4.5% of all intracranial meningiomas [3,4]. Between 60% and 94% of them arise from the choroid plexus at the trigone. The predilection for the trigone may be attributed to the abundance of choroid plexus arachnoidea. The clinical manifestations of lateral ventricular meningiomas depend on the tumor size [5]: A small tumor causes no clinical symptoms because the lateral ventricle has a relatively large compensating space. The most common initial symptoms are headaches, vomiting and consciousness disturbance related to increased intracranial pressure. Sensori-motor deficits, clumsiness, ataxia, and cognitive impairment including dysphasia, dyslexia, dysgraphia, and dyscalcula, are sometimes observed according to the tumor location. Visual field deficits and seizures are present, especially in patients with large tumors. Other unusual symptoms, such as epilepsy, can also occur [6]. Cushing and Eisenhardt grouped the symptoms caused by large ventricular meningiomas into the following types [7]: (a) headache caused by increased intracranial pressure; (b) contralateral spotted homonymous hemianopsia; (c) contralateral sensory disturbance and hemiparesis; (d) symptoms of cerebellar damage; and (e) possible paralexia in patients with tumors located on the left side.

Temporal arteritis is a rare systemic autoimmune disease and the arteritic process in this case of temporal arteritis involved large and medium-size arteries. Temporal arteritis with internal carotid artery (ICA) occlusion is very rare. We report a case of temporal arteritis with ICA occlusion following superficial temporal artery (STA) -middle cerebral artery (MCA) anastomosis, together with steroid therapy. A 73-year-old female presented with a headache, visual disturbance of left side, and suppression of activity. Left STA was inflammatory and overswelling. Magnetic resonance angiography (MRA) and angiography revealed occlusion of the left internal carotid artery (ICA) at the cervical portion and lowering of vascular reserve on PAO SPECT. Diagnosis as temporal arteritis was conclusive due to the clinical presentation, laboratory studies, and left temporal artery biopsy, so steroid pulse therapy was initiated. Inflammation of left STA disappeared after steroid therapy, but left ICA occlusion on angiography and lowering of vascular reserve on SPECT remained for 3 months afterwards. Because of this, STA-MCA anastomosis was performed. There were no complications after the operation and the donor artery has been patent for two years. Temporal arteritis with ICA occlusion that requires extracranial-intracranial bypass (EC-IC bypass) is very rare. STA-MCA anastomosis with steroid therapy is effective for the prevention of cerebral infarction.

Cell suspensions prepared from freshly frozen tissue specimens were used to examine aberrations in the number of chromosome 7 signals in 10 human gliomas. Nuclear DNA was hybridized in vitro with an alpha satellite DNA probe specific for the centromeric regions of chromosome 7, using fluorescence in situ hybridization (FISH). The intensity of the fluorescence signal from the hybridized probe was measured, together with the nuclear DNA content, by flow cytometry. The mean probe fluorescence of all nuclei was compared to the mean copy number per nucleus found with microscopic scoring. Moreover, the mean probe fluorescence ratio of DNA aneuploid nuclei relative to DNA diploid nuclei (FISHa/FISHd) was calculated to determine how the numerical aberration of chromosome 7 signals contributes to the DNA ploidy of the sample. The results from the flow-cytometric analysis and from microscopic evaluation were compatible. One of four tumors with DNA diploidy had a higher average intensity of FISH signal and a broader coefficient of variation in FISH signal than normal brain tissue; this was shown to be due to the gain of chromosome 7 signals. Although FISHa/FISHd correlated with DNA indices (P < 0.01), there were some disparities, probably due to other complex genotypic associations involving several gains or losses of chromosomes. Thus gain of chromosome 7 in gliomas is related to both DNA ploidy change and chromosome specific gain. It is concluded that flow-cytometric quantification of FISH is useful in investigating numerical aberrations of chromosomes and nuclear DNA content simultaneously.