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A 45‐year‐old woman with neurofibromatosis type 1 (NF1) developed a tumor in the left frontal lobe that showed features of giant cell glioblastoma (GC‐GB). In addition to the typical GC‐GB features, the tumor showed lipogenic differentiation, with many atypical lipoblasts and mature adipocytes. Tumor cells, including the lipogenic cells, were immunoreactive for GFAP, S‐100 protein, ATRX, and p53. They were negative for IDH1‐R132H, BRAF V600E, synaptophysin, NeuN, p16, mismatch repair proteins, and CD34. The patient is free from recurrence at approximately two years postoperatively. This is the fifth reported case of NF1‐associated GC‐GB (the second adult case). NF1 gene mutation might have played a role in the pathogenesis of lipogenic differentiation of GC‐GB. The differential diagnosis of lipidized GC‐GB from gliosarcoma or anaplastic pleomorphic xanthoastrocytoma is briefly discussed. [ABSTRACT FROM AUTHOR]

Background: Little is known about the real-world status of neurosurgical treatment of myelomeningocele patients. Objective: To investigate the real-world status of neurosurgical treatment of myelomeningocele patients, medical claims data provided by the Japan Medical Data Center (JMDC) were analyzed. Methods: The health claims data of 556 patients with myelomeningoceles from January 2005 to March 2020 were examined. The number of neurosurgical procedures, including myelomeningocele repair, tethered cord release, cerebrospinal fluid (CSF) shunt, CSF drainage, and endoscopic third ventriculostomy (ETV), was determined. Results: A total of 313 neurosurgical procedures were performed for 135 patients in 74 institutions during the study period. The shunt survival rate was most affected by shunts that were revised when the patient was less than 1 year old, which had a significantly lower survival rate than all of the initial shunts performed when the patient was less than on1 year old; the 1-year shunt survival rate was 35 vs 64% (P = 0.0102). The survival rate was significantly lower in patients younger than 1 year who had CSF drainage before shunting compared to those younger than 1 year who did not have CSF drainage before shunting; the 1-year shunt survival rate was 27 vs 59% (P = 0.0196), and 81% of patients remained free of tethered cord release 10 years later. Conclusions: In this study, a revised shunt of less than 1 year of age and CSF drainage before shunting were the factors that lowered the shunt survival rate in the real world for CSF shunts for hydrocephalus associated with myelomeningocele. [ABSTRACT FROM AUTHOR]

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup. [ABSTRACT FROM AUTHOR]

Background: Stable intraoperative neurophysiology monitoring of infants, especially very young infants, is challenging. In this study, motor evoked potentials (MEPs), the bulbocavernosus reflex (BCR), and somatosensory evoked potentials (SEPs) were simultaneously monitored in infants with lumbosacral lipomas, and these methods were compared retrospectively. Methods: A total of 21 surgeries performed for lumbosacral lipoma in patients less than 1 year old were studied. The mean age at surgery was 133.8 days (range 21–287 days; ≤ 120 days: 9 cases, > 120 days: 12 cases). Transcranial MEPs were measured in the anal sphincter and gastrocnemius, and tibialis anterior and other muscles were added as needed. The BCR was measured by the electromyogram of the anal sphincter muscle with stimulation of the pubic region, and SEPs were measured from the waveforms of stimulation of the posterior tibial nerves. Results: For the BCR, stable potentials could be recorded for all 9 cases at ≤ 120 days of age. In contrast, for MEPs, stable potentials could be recorded in only 4 of 9 cases (p < 0.05). For all patients > 120 days of age, MEPs and the BCR were measurable. SEPs were undetectable in some patients regardless of age. Conclusion: The BCR could be more consistently measured than MEPs in infant patients with lumbosacral lipoma at ≤ 120 days of age. [ABSTRACT FROM AUTHOR]

Background: Although there have been reports investigating the quality of life of patients who underwent ventriculoperitoneal shunting or endoscopic third ventriculostomy (ETV) for congenital hydrocephalus, there have been no studies of the quality of life of patients after ventriculoperitoneal shunt (VPS) removal. In the present study, a survey of pediatric and congenital hydrocephalus patients was conducted to compare the quality of life of patients with a remaining VPS with that of patients who had the shunt removed. Methods: Between February 2020 and November 2021, an outpatient survey was administered to patients 8 years of age and older who had undergone VPS due to a diagnosis of congenital hydrocephalus. The Hydrocephalus Outcome Questionnaire (HOQ) was used to assess the quality of life for this study. The HOQ scores (overall health score, physical health score, cognitive health score, and social-emotional health score) were compared among three groups: a VPS-remaining group, VPS-removed with endoscopic third ventriculostomy (ETV) group, and VPS-removed without ETV group. Results: The total number of patients who underwent VPS for hydrocephalus was 71, with 47 in the VPS-remaining group, 14 in the shunt-removed with ETV group, and 10 in the shunt-removed without ETV group. The HOQ overall health score was 0.68 for the VPS-remaining group, 0.74 for the shunt-removed with ETV group, and 0.74 for the shunt-removed without ETV. There were no significant differences between the VPS-remaining group and the VPS-removed with or without ETV groups (p = 0.3255, 0.4178, respectively). Conclusion: There was no significant difference in the quality of life between patients with a remaining VPS and those who had their VPS removed with or without ETV. [ABSTRACT FROM AUTHOR]

Objective: A case of low-grade glioma in which 5-aminolevulinic acid (5-ALA) fluorescence was visualized by a digital exoscope is presented. Case presentation: A 14-year-old girl with recurrent paroxysmal episodes of a strange smell and nausea underwent magnetic resonance imaging (MRI) for further investigation. The MRI showed a tumor with an enhanced nodule in the right temporal lobe. The patient received 5-ALA preoperatively, and intraoperative observation using a 4 K-3-dimension digital exoscope (Olympus ORBEYE) showed that the tumor was fluorescent, which was useful in determining the extent of tumor removal. Postoperative MRI showed that the tumor was completely removed. The histopathological diagnosis was pleomorphic xanthoastrocytoma. She was discharged without any complications. Conclusions: 5-ALA-fluorescence-guided resection of low-grade glioma using the ORBEYE was useful for determining the extent of removal. [ABSTRACT FROM AUTHOR]

A 75-year-old man presented with bilateral lower limb weakness to our hospital from another clinic. Radiological examinations implied the possibilities of idiopathic normal pressure hydrocephalus (iNPH) and a suprasellar cyst, but both were observed conservatively at that time. Due to the progressive gait disturbance, a lumboperitoneal shunt was implanted 1 year later. The clinical symptoms improved, but the cyst had grown after another year, causing visual impairment. Transsphenoidal drainage of the cyst was performed, but delayed pneumocephalus occurred. Repair surgery was performed with temporary suspension of shunt function, but pneumocephalus relapsed two and a half months after the resumption of shunt flow. In the second repair surgery, the shunt was removed because it was assumed that it would prevent closure of the fistula by lowering intracranial pressure. Two and a half months later, after confirming involution of the cyst and no pneumocephalus, a ventriculoperitoneal shunt was implanted, and cerebrospinal fluid (CSF) leakage has not relapsed since then. The coexistence of idiopathic normal pressure hydrocephalus (iNPH) and Rathke's cleft cyst (RCC) is rare, but it can occur. RCC can be cured by simple drainage, but delayed pneumocephalus can occur in cases whose intracranial pressure decreases due to CSF shunting. When simple drainage without sellar reconstruction for RCC is attempted after CSF shunting for coexistent iNPH, attention should be paid to changes in intracranial pressure, and it is desirable to stop the flow of the shunt for a certain period. [ABSTRACT FROM AUTHOR]

Purpose: A rare case of a newborn girl born by a normal vaginal delivery who developed a severe supratentorial subdural hematoma due to a laceration in the tentorium cerebelli is presented. Methods and results: The girl, born by normal vaginal delivery at 39 weeks and 4 days of gestation, showed an intermittent decrease in oxygen saturation and bulging of the anterior fontanelle. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a subdural hematoma centered in the left occipital region with a midline shift. Hematoma evacuation with craniotomy was performed, and the source of bleeding was a laceration of the tentorium cerebelli. Conclusion: Severe supratentorial subdural hematomas can occur due to laceration of the tentorium cerebelli even in a normal vaginal delivery. [ABSTRACT FROM AUTHOR]

Objective When small unruptured aneurysms (SUA) are embolized by coils, manipulation of the microcatheter and coil is limited because of their small size. Previous studies suggested that the morphology of the artery and aneurysm is important. In the present study, we clarified the morphological factors affecting coil-only embolization of SUA. Patients and Methods We retrospectively identified 17 patients who underwent embolization for unruptured aneurysm with a maximum diameter less than 5 mm. We investigated the following: (1) the relationships among dome/neck ratio (D/N), height/neck ratio (H/N), height/dome ratio (H/D), projection of aneurysm-parent artery, and adverse events, (2) immediate and late occlusion, and (3) number of coils. Results (1) Adverse events developed in three cases in which the H/D was smaller than 1 (p < 0.02). There was a significant difference in the rate of adverse events by projection of the aneurysm-parent artery (p < 0.03), (2) Occlusion rate: Immediately after coil embolization, 71% (12/17) were neck remnant; however, 88% (15/17) of SUA became complete occlusion in the follow-up term, and (3) 1.5 ± 0.6 coils were used. Conclusion To achieve successful coil-only embolization in SUAs, it is important to select aneurysms for which the projection of the parent artery is suitable for embolizing and the H/D ratio is larger than 1. In SUAs, occlusion develops naturally after coil embolization. [ABSTRACT FROM AUTHOR]

Purpose: Lipoma of the filum terminale (FL) is an abnormality in which fat is deposited in the filum terminale. This lipoma is often detected by skin abnormalities in the lumbosacral area such as a sacrococcygeal dimple. Some cases may develop tethered cord and become symptomatic. However, the genetic basis of FL is still unclear. Methods: This study aimed to determine whether there was a family history of FL or other forms of spina bifida among 54 families of 56 patients with FL and to examine whether there is a familial predisposition in FL. In addition, sex, age at diagnosis, presence of symptoms, presence of sacrococcygeal dimple, and the level of conus medullaris between familial and spontaneous cases were evaluated. Results: Of the 54 families of FL patients, there were 48 siblings. Among the 48 siblings, 2 had "occult" FL. The frequency of FL among siblings was estimated to be 4.2% (2/48), which was significantly higher than the sum of previously reported cases of spontaneous FL (0.91%; p = 0.017). However, there was no significant difference in sex, age at diagnosis, presence of symptoms, presence of sacrococcygeal dimple, diameter of filum terminale, or level of conus medullaris between familial and spontaneous cases. Conclusion: To our knowledge, this is the first report on familial FL and examination of the frequency of FL among siblings. The high probability of FL among siblings of FL patients suggests that genetic factors may play a role in FL development. [ABSTRACT FROM AUTHOR]

Medulloblastoma is the second-most common malignant tumor in children. Medulloblastoma has been categorized into four distinct molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. We report on a male child with medulloblastoma, in whom an enlarged ventricle was diagnosed in utero. Magnetic resonance imaging showed cyst formation in the cerebellar hemisphere initially, with tumor growth being indicated later. Tumor resection was performed when the boy was 12 months old. The histological findings showed extensive nodularity. Further genetic analysis revealed the tumor to be SHH type. This is the first description of a medulloblastoma observed from the fetal stage. Our findings in this case indicate that cyst formation may be the pre-neoplastic lesion of SHH-subtype medulloblastomas. [ABSTRACT FROM AUTHOR]

Resection or biopsy of intraventricular brain tumors using an endoscope has become common, but the limitations of these procedures are not clear. Manipulation to access a tumor that arises from the blind angle of the rigid endoscope, such as the anterior part of the aqueduct, is limited. We report here that we successfully resected a recurrent medulloblastoma in the anterior part of the aqueduct using only a flexible endoscope. This method appears to be suitable for poorly vascularized and suctionable tumors that arise in the blind angle of a rigid endoscope. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors are rare, and little is known about the existence of cancer stem cells in this disease. Identification of the tumorigenic population will contribute to the development of effective therapies targeting neuroendocrine tumors. Surgically resected brain metastases from a primary neuroendocrine tumor of unknown origin were dissociated and cultured in serum-free neurosphere medium. Stem cell properties, including self-renewal, differentiation potential, and stem cell marker expression, were examined. Tumor formation was evaluated using intracranial xenograft models. The effect of temozolomide was measured in vitro by cell viability assays. We established the neuroendocrine tumor sphere cell line ANI-27S, which displayed stable exponential growth, virtually unlimited expansion in vitro, and expression of stem-cell markers such as CD133, nestin, Sox2, and aldehyde dehydrogenase. FBS-induced differentiation decreased Sox2 and nestin expression. On the basis of real-time PCR, ANI-27S cells expressed the neuroendocrine markers synaptophysin and chromogranin A. Intracranial xenotransplanted brain tumors recapitulated the original patient tumor and temozolomide exhibited cytotoxic effects on tumor sphere cells. For the first time, we demonstrated the presence of a sphere-forming, stem cell-like population in brain metastases from a primary neuroendocrine tumor. We also demonstrated the potential therapeutic effects of temozolomide for this disease. [ABSTRACT FROM AUTHOR]

5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is widely used for detection and planning of resection of malignant gliomas and other brain tumors. However, no reports have described 5-ALA fluorescence-guided surgery or direct visualization of germ cell tumors. Here, we report two cases of germ cell tumors in which a positive 5-ALA fluorescent signal was visualized with a neuroendoscope. Both cases had a tumor in the pineal region that was associated with hydrocephalus. The patients underwent surgery after administration of 5-ALA. After ventricular puncture of the anterior horn, we could observe the ventricular wall and tumor using the Karl Storz Photodynamic diagnosis system endoscope. Then, biopsy of the pineal tumor and endoscopic third ventriculostomy were performed in both cases. In case 1, a 22-year-old man, part of the ventricular wall and tumor tissue showed red fluorescence. In case 2, a 16-year-old man, part of the fornix and infundibular recess showed red fluorescence, and the tumor showed relatively weak red fluorescence. The histopathological diagnosis of both cases was pure germinoma. This is the first report of direct visualization of mixed germinomas with 5-ALA fluorescence-guided endoscopic surgery. This method not only allows visualization of the tumor mass, but may also be useful for detailed observation in the ventricular wall. [ABSTRACT FROM AUTHOR]

The patient was a 72-year-old woman who had previously undergone treatment for femoral chondrosarcoma (histologically rated as myxofibrosarcoma). She suddenly developed left homonymous hemianopsia and was diagnosed with cerebral embolism. Because she had atrial fibrillation, we treated her for cardiogenic cerebral embolism. About 3 months later, however, she developed left hemiplegia, and head magnetic resonance imaging revealed multiple tumorous lesions affecting the previously detected infracted area and several new areas. We assumed that a tumor embolus had caused cerebral embolism, which resulted in growth of the tumor from the embolus and formation of a metastatic brain tumor. The metastatic foci formed from the tumor embolus were visualized by diagnostic imaging, and histological examination of the resected tumor confirmed that the brain tumor had occluded the brain vessel (tumorigenic cerebral embolism). No such case has been reported to date, and this case seems to be important. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small noncoding RNAs that take part in diverse biological processes by suppressing target gene expression. Elevated expression of miR-21 has been reported in many types of human cancers. Radiotherapy is a standard adjuvant treatment for patients with glioblastoma. However, the resistance of glioblastoma cells to radiation limits the success of this treatment. In this study, we found that miR-21 expression was upregulated in response to ionizing radiation (IR) in U251 cells, which suggested that miR-21 could be involved in the response of U251 cells to radiation. We showed that a miR-21 inhibitor enhanced IR-induced glioblastoma cell growth arrest and increased the level of apoptosis, which was probably caused by abrogation of the G-M arrest induced by IR. Further research demonstrated that the miR-21 inhibitor induced the upregulation of Cdc25A. Taken together, these findings suggest that miR-21 inhibitor can increase IR-induced growth arrest and apoptosis in U251 glioblastoma cells, at least in part by abrogating G-M arrest, and that Cdc25A is a potential target of miR-21. [ABSTRACT FROM AUTHOR]

Even when we successfully perform a total extirpation of glioblastoma macroscopically, we often encounter tumor recurrence. We examined seven autopsy brains, focusing on tumor cell infiltration in the peripheral zone of a tumor, and compared our findings with the MR images. There has so far been no report regarding mapping of tumor cell infiltration and DNA histogram by flow cytometry, comparing the neuroimaging findings with the autopsy brain findings. The autopsy brain was cut in 10-mm-thick slices, in parallel with the OM line. Tissue samples were obtained from several parts in the peripheral zone (the outer area adjacent to the tumor edge as defined by postcontrast MRI) and then were examined by H&E, GFAP, and VEGF staining. We defined three infiltrating patterns based on number of infiltrated cells as follows: A zone, 100%-60% of the cells infiltrated tumor cells compared with tumor cell density of the tumor mass; B zone, 60%-20%; C zone, 20%-0%. In the autopsy brain, the tumor was easily identified macroscopically. We found that (1) the tumor cells infiltrated the peritumoral area; and (2) tumor cell infiltration was detected over an area measuring from 6 to 14 mm from the tumor border in the A zone. When performing surgery on glioblastoma, a macroscopic total extirpation of the tumor as defined by the contrast-enhanced area in MRI is therefore considered to be insufficient for successfully reducing tumor recurrence. [ABSTRACT FROM AUTHOR]

We report two infant cases with atypical teratoid/rhabdoid tumor (AT/RT) located in the cerebellar vermis and spinal cord. MRI showed the tumors were isointense on T1-weighted images and mixed intensity of isointense and slight high intensity on T2-weighted images. Postcontrast MRI demonstrated clear margin of tumor and heterogeneous strong enhancement. It was difficult to differentiate the tumor from medulloblastoma by hematoxylin and eosin staining. However, immunohistochemical staining showed that these tumor cells react positively for cytokeratin, smooth muscle actin (SMA), and epithelial membrane antigen (EMA) and helped us with the differentiation. Electron microscopic study has confirmed the presence of mesenchymal components, such as filaments and desmosome junctions in the rhabdoid cells, but no neuronal components. The tumors rapidly increased in size, showing high MIB-1 index, and the prognosis was gave. [ABSTRACT FROM AUTHOR]

Although p53 controls cell death after various stresses, its role in neuronal death after brain ischemia is poorly understood. To address this issue, we subjected p53-deficient (p53−/− and p53+/–) mice (backcrossed for 12 generations with C57BL/6 mice) and wild-type mice (p53+/+) to transient global ischemia by the three-vessel occlusion method. Despite similar severity of ischemia, as shown by anoxic depolarization and cortical blood flow, neuronal death in the hippocampal cornus ammonis (CA)1 region was much more extensive in p53+/+ than in p53−/− mice (surviving neuronal count, 9.3%±3.0% versus 61.3%±34.0% of nonischemic p53+/+controls, respectively, P<0.0037). In p53+/− mice, a similar trend was also observed, though not statistically significant (43.5% of nonischemic p53+/+controls). In p53+/+ mice, p53-like immunoreactivity in hippocampal CA1 neurons was enhanced at 12 h after ischemia, and messenger ribonucleic acid for Bax, a direct downstream target of p53, was also increased. These results indicate that p53 potentiates ischemic neuronal death in vivo and suggest that this molecule could be a therapeutic target in neuronal death after cerebral ischemia.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 1332–1340. doi:10.1038/sj.jcbfm.9600293; published online 15 March 2006 [ABSTRACT FROM AUTHOR]

We have characterised the blood vessels found in normal cerebral vasculature and in arteriovenous malformations (AVMs), based on the expression of smooth muscle cell (SMC)-specific proteins. The marker proteins used were smooth muscle α-actin and four myosin heavy chain isoforms (SM1, SM2, SMemb and NMHC-A). Specimens of AVM obtained during surgery, and normal cerebral vessels from autopsy cases were studied immunohistochemically and compared. The arterial components of AVM contained an abundance of SMCs of the contractile phenotype, which were positive for α-actin, SM1 and SM2, but not for SMemb and NMHC-A. These components showed the same staining pattern as mature normal arteries. Two different types of abnormal veins were found in the AVM specimens: large veins with a thick and fibrous wall (so-called 'arterialised' veins) and intraparenchymal thin-walled sinusoidal veins. The former expressed α-actin, SM1, SM2, and SMemb, the latter expressed α-actin, SM1, and SM2. These marker expression patterns resembled those of normal cerebral arteries, and the results were compatible with arterialisation of the cerebral veins caused by arteriovenous shunting. However, the expression of SMemb was found only in the arterialised type of veins, not in the sinusoidal type or the arteries that had sustained abnormal blood flow in the AVMs. The thick-walled veins in the AVMs showed the same staining pattern as normal veins of dural plexus origin (large subarachnoid veins and dural sinuses). It is therefore possible to assume that they originated from the dural plexus, and extended into the brain during the formation of AVMs. [ABSTRACT FROM AUTHOR]

Provides information on a study which examined comprehensive gene expression profiles of oligodendroglial tumors using the oligonucleotide microarray. Composition of oligodendrogliomas; Discovery in neuro-oncology; Marker separating oligodendrogliomas into subgroups; Keys to investigate the molecular biologic features of tumor cells.

Cavernous malformations (CVMs) and arteriovenous malformations (AVMs) were immunostained for three smooth muscle cell (SMC)-specific protein markers (smooth muscle α-actin, SM1 and SM2). Smooth muscle α-actin, a widely used marker of SMCs, is reportedly one of the earliest proteins expressed during differentiation of SMCs and expressed in some kinds of mesoderm-derived cells. In contrast, SM1, an isoform of myosin heavy chain (MHC), is detected only in SMCs. SM2 is another MHC isoform and expressed in the contractile phenotype of SMC. All 14 intraaxial CVMs were positive for smooth muscle α-actin, but SM1 was detected in only three of them and SM2 was not found. Their staining pattern resembled that of normal intraparenchymal and pial veins. All 15 cerebral AVMs and 5 out of 6 extraaxial CVMs from the cavernous sinus, orbit and scalp were positive for all three markers, as were the normal cerebral arteries. The venous components of AVMs, as well as the arterial components, expressed SM2, and were different from normal veins in the brain and intraaxial CVMs. This study shows that the histological analysis using the three markers for SMC is useful to differentiate intraaxial CVM from AVM and extraaxial CVMs. [ABSTRACT FROM AUTHOR]

Background Mouse imprinted gene Peg3 encodes a large C2H2 type zinc finger protein with unique characteristics. Peg3 knockout mice were found to show an impairment in maternal behaviour of the adult female. Mouse Peg3 is located on the proximal region of chromosome 7 which is syntenic to the long arm of human chromosome 19. It has been reported that a loss of heterozygosity (LOH) of chromosome 19q occurs frequently in several glioma types. Results We isolated human PEG3 cDNA. Both human and mouse PEG3 were strongly expressed in the adult brain and the Peg3 protein was localized in the nuclei of both neurones and glial cells. A significant decrease in PEG3 expression was more commonly observed in glioma cell lines as compared with that in primary cultures of astrocytes. Transfection of PEG3 cDNA in a glioma cell line resulted in a loss of tumorigenicity in nude mice. Conclusions The human PEG3 gene is a paternally expressed imprinted gene. Introduction of PEG3 cDNA into the glioma cells suggests that human PEG3 protein functions as a tumour suppressor. Human PEG3 is located on 19q13.4 and is one of the candidates for tumour suppressor genes that are predicted to be sited in gliomas. [ABSTRACT FROM AUTHOR]

Studies the progression of beta-human chorionic gonadotrophin in the serum and cerebrospinal fluid of patients with germ cell tumors. Prognosis of the disease using combination chemotherapy; Function of serum markes in the detection of tumor recurrence.

Various therapeutic approaches toward killing glioma cells by inducing apoptosis have been developed, but these approaches are often hampered by anti-apoptotic mechanisms. In this study, we attempted to develop a technique that overrides the resistance toward apoptosis in glioma cells. To date, p53- and Fas-mediated apoptotic pathways have been shown to be different. Therefore, we carried out a gene therapy that combines the pro-apoptotic effect of these two different pathways. The recombinant adenoviruses (Advs) for p53 and Fas ligand (FL) (Adv-p53 and Adv-FL, respectively) were constructed. Transfecting the p53 gene into glioma cell lines (A-172 and U251 glioma cells) led to overexpression of Bax, a protein that induces permeability transition; at the same time, this transfection brought about an overexpression of Fas. To intensify Fas-mediated apoptosis, we transferred the FL gene together with the p53 gene by Adv-mediated gene transduction into A-172 and U251 cells. Coinfecting Adv-p53 and Adv-FL into A-172 cells, which are relatively resistant to apoptosis by infection with Adv-p53 or Adv-FL alone (Adv-p53, multiplicity of infection (MOI) of 100: 8.5 ± 0.7%; Adv-FL, MOI of 100: 3.0 ± 0.1%) resulted in a drastic enhancement of the percentage of apoptotic cells (Adv-p53 and Adv-FL, each at an MOI of 30: 24.2 ± 0.9%). Coinfection with Adv-p53 and Adv-FL in U251 cells resulted in a similar enhancement of the percentage of apoptotic cells (Adv-p53 and Adv-FL, each at an MOI of 30: 59.0 ± 2.3%) compared with that seen in U251 cells transfected with Adv-p53 or Adv-FL alone (Adv-p53, MOI of 30: 3.1 ± 0.3%; Adv-FL, MOI of 30: 18.1 ± 0.3%). Regardless of whether a cell line is resistant or sensitive to FL- and p53-mediated apoptosis, coinfection with Adv-p53 and Adv-FL dramatically enhanced the degree of apoptosis of glioma cells. Our results indicate that the coinfection approach can be used as a modality for the gene therapy of... [ABSTRACT FROM AUTHOR]

The transduction of Bax protein, which is up-regulated in radiation- and chemotherapy-induced apoptosis, augments the cytotoxicity of radiotherapy and chemotherapy for cancers. The cytotoxicity of Bax overexpression is caused primarily by mitochondrial dysfunction, which is also involved in the apoptosis triggered by caspase-8. In this study, we transduced the Bax gene in combination with caspase-8 gene to evaluate whether or not this approach induces effective cytotoxicity in glioma cells. In terms of cancer gene therapy, it is critically important to induce cytotoxic genes in a cancer-specific manner. Therefore, we used the myelin basic protein promoter to drive cytotoxic genes. The expression level controlled by the myelin basic protein promoter was relatively low in gliomas. In U251 and U-373 MG glioma cells, adenovirus-mediated transduction of the Bax gene combined with caspase-8 gene induced enhanced apoptosis and cell death as determined by morphological analysis and assay for dead cells, hypodiploid cells, and DNA fragmentation (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling method). This therapeutic modality would be useful to induce a specific and enhanced cytotoxic effect for gliomas. [ABSTRACT FROM AUTHOR]

Gliomas express a higher amount of Fas than normal brain tissue. It is of interest to know whether expression of the Fas receptor is unfavorable to the antiapoptotic pathways in gliomas. In this study, we introduced the Fas gene via an adenovirus vector (Adeno-Fas) into the A-172, U251, and U-373 MG glioma cell lines, each of which expresses Fas on the cell surface. Infection of Adeno-Fas induced apoptosis in each glioma cell line. In U251 cells and A-172 cells that express the same level of Fas as a result of infection with Adeno-Fas, a much higher percentage of U251 cells underwent apoptosis than did A-172 cells. This suggests that each glioma cell line has its own threshold of Fas expression, above which apoptosis is induced, and that the constitutive expression of Fas is below the level of this threshold. It was found that the constitutive expression of the anti-apoptotic gene Bcl-XL is higher in A-172 cells than in U251 cells. Adenovirus-mediated transduction of the Bcl-XL gene into U251 cells effectively suppressed Adeno-Fas-mediated apoptosis. These data indicate that the Bcl-XL gene is one of the important determinants of the threshold for Fas-mediated apoptosis. When U251 and U-373 MG cells were transduced with the Fas gene controlled by the myelin basic protein promoter, which had been shown to be active in gliomas but not in neural tissues, the cells underwent markedly enhanced apoptosis. Taken together, these results indicate that the overexpression of Fas alone induced apoptosis in each glioma cell line. The degree of Fas-mediated apoptosis was attenuated by the expression of an anti-apoptotic gene, Bcl-XL. The adenovirus-mediated induction of Fas gene controlled by a tissue-specific promoter (e.g., myelin basic protein promoter) would be a promising therapeutic approach for malignant glioma. [ABSTRACT FROM AUTHOR]

Purpose: Although chemotherapeutic protocols that include chloroethylnitrosoureas (CENUs), such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), have been a mainstay of treatment for glioblastomas, the clinical outcomes have been unsatisfactory. More effective chemotherapeutic protocols for these tumors will require clear delineation of more cytocidal and cytostatic chemotherapeutic drugs. Methods and Results: In this study, we measured the cytocidal effects of ACNU, cisplatin, actinomycin D, and staurosporine, administered within their therapeutic dose ranges, in the treatment of glioblastoma cells. As assessed by WST-1 colorimetric assay, the number of viable cells decreased markedly in T98G cultures treated with actinomycin D or staurosporine, to less than 20% of the level in control cultures at 72 h, but did not decrease or even increased after 6 days of treatment with ACNU. After treatment with cisplatin for 5 days, cell viability decreased to 30% of control. As assessed by fluorescence microscopic examination of nuclear staining by Hoechst 33258 and by electron microscopy, the majority of dead cells treated with actinomycin D, staurosporine, or cisplatin had morphologic features of apoptosis. Caspase-3 activity increased more than 20-fold in cells treated with actinomycin D, staurosporine, or cisplatin but increased less than fivefold in ACNU-treated cells. In addition to caspase-3 activation, western blot analysis demonstrated cleavage of caspase-2 during the apoptotic process. These findings indicate that actinomycin D and staurosporine potently induce apoptosis, whereas ACNU exerts mainly a cytostatic rather than a cytocidal effect. Conclusion: Actinomycin D and staurosporine and their derivatives are potentially effective chemotherapeutic agents against glioblastoma cells at least in vitro. [ABSTRACT FROM AUTHOR]

A case of multiple intracranial germ cell tumor in which a pineal tumor regressed spontaneously after resection of the cerebellar mass is reported. Immunohistochemical staining of the cerebellar mass showed that most of the infiltrating lymphocytes were positive for CD3 and CD8. The anti-Ki-67 monoclonal antibody MIB-1 staining of the resected tumor revealed a high MIB-1 positivity ratio (36.1%) among the large tumor cells, and TUNEL staining demonstrated that positivity in up to 6% of the tumor cells. Possible mechanisms responsible for this spontaneous regression including immunological responses and apoptosis induced by T lymphocytes are discussed. [ABSTRACT FROM AUTHOR]

The Bax protein plays a critical role in the apoptosis of cancers induced by radiotherapy or chemotherapy, which induce both apoptosis and necrosis. We transduced various glioblastoma cells with the Bax gene via an adenoviral vector and found that A-172 cells led to necrotic cell death, while U251 cells apoptotic cell death, even though a similar level of Bax protein was introduced. A-172 cells displayed a much higher constitutive expression of the Bcl-XL protein compared with that of U251 cells. Upon simultaneous overexpression of the Bcl-XL and Bax proteins in the U251 cells, Bax-induced apoptosis of U251 cells was suppressed and an increase in the number of necrotic cells was seen. Moreover, induction of a higher amount of Bax protein in A-172 cells increased the percentage of apoptotic cells. In conclusion, if a cancerous cell expresses a high enough amount of Bax to undergo death, apoptosis will be induced. If a cancerous cell expresses a level of Bcl-XL which prevents Bax-induced apoptosis, the overexpression of Bax leads to necrotic cell death. [ABSTRACT FROM AUTHOR]

To prevent neoplasia, cells of multicellular organisms activate cellular disposal programs such as apoptosis in response to deregulated oncogene expression, making the suppression of such programs an essential step for potentially neoplastic cells to become established as clinically relevant tumors. Since the mutation of ras proto-oncogenes, the most frequently mutated proto-oncogenes in human tumors, is very rare in some tumor types such as glioblastomas and gastric cancers, we hypothesized that mutated ras genes might activate a cell death program that cannot be overcome by these tumor types. Here we show that the expression of oncogenically mutated ras gene induces cellular degeneration accompanied by cytoplasmic vacuoles in human glioma and gastric cancer cell lines. Cells dying as a result of oncogenic Ras expression had relatively well-preserved nuclei that were negative for TUNEL staining. An immunocytochemical analysis demonstrated that the cytoplasmic vacuoles are derived mainly from lysosomes. This oncogenic Ras-induced cell death occurred in the absence of caspase activation, and was not inhibited by the overexpression of anti-apoptotic Bcl-2 protein. These observations suggested that oncogenic Ras-induced cell death is most consistent with a type of programmed cell death designated `type 2 physiological cell death' or `autophagic degeneration', and that this cell death is regulated by a molecular mechanism distinct from that of apoptosis. Our findings suggest a possible role for this non-apoptotic cell death in the prevention of neoplasia, and the activation of the non-apoptotic cell death program may become a potential cancer therapy complementing apoptosis-based therapies. In addition, the approach used in this study may be a valuable way to find genetically-regulated cell suicide programs that cannot be overcome by particular tumor types. [ABSTRACT FROM AUTHOR]

The usefulness of histopathological grading in predicting the prognosis of patients with ependymomas is controversial. To clarify the discrepancy between the histological malignancy and the prognosis of these tumors, we estimated the proliferative potential of 32 intracranial and intraspinal ependymomas and correlated the findings with the clinical behavior. Each patient received an intraoperative infusion of bromodeoxyuridine (BUdR, 200 mg/m i.v.) before tumor removal; the BUdR labeling index (LI), or percentage of BUdR-labeled cells, was determined immunohistochemically in excised specimens. The mean BUdR LI (±SD) of intracranial malignant ependymomas was 4.1±2.8%. Nonmalignant intracranial and intraspinal ependymomas and subependymomas had mean LIs of 1.5±0.9%, 1.1±0.3%, and <1%, respectively. Overall, 44% of the tumors recurred. There were no statistically significant differences in the recurrence rates of intracranial and intraspinal ependymomas, including subependymomas (43% and 44%, respectively), or of intracranial ependymomas with LIs greater than 1.0% and less than 1.0% (67% and 44%, respectively). However, the early recurrence rate (within 24 months after treatment) of tumors with LIs greater than 1.0% was higher than that of tumors with LIs of less than 1.0% (100% vs. 25%, P<0.05). The BUdR LI also showed a statistically significant inverse correlation with the time to recurrence. These findings indicate that BUdR LI reflects the proliferative potential of individual ependymomas and can be used to help predict the recurrence and estimate the prognosis of these tumors. [ABSTRACT FROM AUTHOR]

Forty-one infants with histologically verified primary intracranial neoplasms were studied who had been diagnosed and treated during the first year of life at the Hospital for Sick Children during the years 1975-1986. Forty-one percent of tumors were astrocytomas, 22% were primitive neuroectodermal tumors, and 20% were choroid plexus papillomas. Seventy-one percent were located in the supratentorial compartment and 29% in the infratentorial compartment. Thirty percent were in the cerebral hemisphere, 12% in the optic pathway-hypothalamic region, 5% in the thalamus, 17% in the cerebellum, 5% in the brain stem, 12% in the lateral ventricles, 12% in the III ventricle, and 7% in the IV ventricle. The most common presenting features in this series of patients were vomiting and increasing head size. The symptoms and signs before diagnosis were present for 2 months or less in 87% of cases. Forty-four percent of the tumors were totally resected while only a partial resection or biopsy was carried out in 56%. Sixty-six percent of the patients required a CSF diversionary shunt. Twenty-nine percent of patients received radiotherapy. Slightly more than half of these received radiotherapy immediately after surgery, whereas delayed radiation therapy was performed in the remainder. The surgical mortality was 7.3%. Of the entire group, 39% have died, with most dying within 6 months of surgery. Treatment, survival relative to histologic type, psychomotor development, and neurologic function of the survivors are discussed. [ABSTRACT FROM AUTHOR]