Correlation of LLT-1 and NLRC4 inflammasome and its effect on glioblastoma prognosis.

PURPOSE: LLT-1 is a well-known ligand for the natural killer (NK) cell inhibitory receptor NKRP1A. Here, we examined NLRC4 inflammasome components and LLT-1 expression in glioblastoma (GBM) tissues to elucidate potential associations and interactions between these factors. METHODS: GBM tissues were collected for RNA sequencing (RNA-seq) and Immunofluorescent experiments. Colocalization of LLT-1 and other proteins was assessed by immunofluorescence. Computational analyses utilized RNA-seq data from 296 to 52 patients from the Chinese Glioma Genome Atlas and CHA medical records, respectively. These data were subjected to survival, non-negative matrix factorization clustering, Gene Ontology enrichment, and protein-protein interaction analyses. Receptor-ligand interactions between tumor and immune cells were confirmed by single-cell RNA-seq analysis. RESULTS: In GBM tissues, LLT-1 was predominantly colocalized with glial fibrillary acidic protein (GFAP)-expressing astrocytes, but not with microglial markers like Iba-1. Additionally, LLT-1 and activated NLRC4 inflammasomes were mainly co-expressed in intratumoral astrocytes, suggesting an association between LLT-1, NLRC4, and glioma malignancy. High LLT-1 expression correlates with poor prognosis, particularly in the mesenchymal subtype, and is associated with TNF and NOD-like receptor signaling pathway enrichment, indicating a potential role in tumor inflammation and progression. At the single-cell level, mesenchymal-like malignant cells showed high NF, NLR, and IL-1 signaling pathway enrichment compared to other malignant cell types. CONCLUSION: We revealed an association between NLRC4 inflammasome activity and LLT-1 expression, suggesting a novel regulatory pathway involving TNF, inflammasomes, and IL-1, potentially offering new NK-cell-mediated anti-glioma approaches.

Non-canonical NLRC4 inflammasomes in astrocytes contribute to glioma malignancy.

BACKGROUND: The present study was designed to explore the pathological role of non-canonical NLRC4 inflammasome in glioma. METHODS: This retrospective study included bioinformatical analysis, including survival, gene ontology, ssGSEA, cox regression, IPA and drug repositioning with TCGA and DepMap database. Experimental validations were conducted in glioma patient's sample and evaluated with histological or cellular functional analysis. RESULT: Clinical dataset analysis revealed that non-canonical NLRC4 inflammasomes significantly contribute to glioma progression and poor survival rates. Experimental validation was revealed that the expression of non-canonical NLRC4 inflammasomes were co-localized with astrocytes in malignant gliomas, with a sustained clinical correlation observed between astrocytes and inflammasome signatures. Indeed, the formation of an inflammatory microenvironment increased in malignant gliomas, leading to pyroptosis, known as inflammatory cell death. Molecular interaction analysis revealed that NF-κB pathways potentially serve as the connecting point between the canonical and noncanonical pathways of the NLRC4 inflammasome. Finally, drug repositioning analysis of non-canonical NLRC4 inflammasome-associated molecules revealed that MK-5108, PF4981517, and CTEP may represent effective options for glioma therapy. CONCLUSION: The findings of this study suggest that non-canonical NLRC4 inflammasomes contribute to poor prognosis in patients with glioma and induce an inflammatory microenvironment. We propose the pathological phenomenon of non-canonical NLRC4 inflammasomes and several therapeutic strategies based on the modulation of the inflammatory tumor microenvironment.

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1ß secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein-protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.

The modified lateral supraorbital approach for tumors of the petroclival junction extending into the anterior cerebellopontine area.

Various surgical approaches for the removal of meningioma and trigeminal schwannoma in the petroclival junction (PCJ) and anterior cerebellopontine area (CPA) have been described previously. In this study, we compared the surgical outcomes of the combined petrosal approach and a modified lateral supraorbital (MLSO) approach and evaluated the reliability and safety of the MLSO approach. Fifty patients underwent surgical treatment using the combined petrosal or MLSO approach between 1996 and 2011. We retrospectively analyzed the clinical data and compared the two approaches. Among 50 patients, 27 patients underwent operation through the combined petrosal approach and 23 underwent operation through the MLSO approach. The operation time of the MLSO approach was significantly shorter than that of the combined petrosal approach (p = 0.03). There was no significant difference in the gross total resection rate between the two approaches (p = 0.67). After the operation, the improvement in Karnofsky performance score and Mean Glasgow outcomes scales were better in the MLSO approach, but without statistical significance (p = 0.723, p = 0.20 respectively). Complications occurred more often with the combined petrosal approach than with MLSO. Facial nerve palsy was the most common complication, followed by hearing difficulty. The frequency of these two complications was higher in the combined petrosal approach. Various tumors occurring in the PCJ and anterior CPA remain a challenging problem for neurosurgeons. The new modified approach of MLSO yielded good surgical results for these tumors compared to the combined petrosal approach. Therefore, the MLSO approach might be a good option for removal of tumors in the PCJ including anterior CPA.

Epidermoid cyst with unusual magnetic resonance characteristics and spinal extension.

Intracranial epidermoid cysts are generally located in the cerebellopontine and parasellar areas and appear hypo-dense on computed tomography and hypo-intense on T1-weighted magnetic resonance imaging. We report a case of an unusual epidermoid cyst of the cerebellopontine angle extending into the upper cervical canal that appeared hyper-dense on computed tomography scanning, hyper-intense on T1-weighted magnetic resonance (MR) images, and hypo-intense on T2-weighted MR images.

Predictive biomarkers for the responsiveness of recurrent glioblastomas to activated killer cell immunotherapy.

BACKGROUND: Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM. METHODS: To identify biomarkers that predict responsiveness to NK cell therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and a NK cell migration assay to assess the function of these genes. RESULTS: Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI 73.5-100%) for predicting the response to NK cell therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearson's correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)); their prediction performance also showed 100% accuracy (95% CI 73.54-100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment. CONCLUSION: We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor.

Comparing the Expression of Canonical and Non-Canonical Inflammasomes Across Glioma Grades: Evaluating Their Potential as an Aggressiveness Marker.

BACKGROUND: Inflammasomes are key in the initiation of inflammatory responses and serve to defend the organism. However, when the immune system is imbalanced, these complexes contribute to tumor progression. The purpose of this study was to investigate the effect of non-canonical inflammasomes on glioma malignancy. METHODS: We performed bioinformatics analysis to confirm the expression of canonical and non-canonical inflammasome-related molecules according to the degree of malignancy through immunohistochemical examination of glioma tissues obtained with patient consent from our institution. RESULTS: Bioinformatics analysis confirmed that the expression levels of non-canonical inflammasome-related molecules were significantly higher in tumor tissues than in normal tissues, and they also increased according to malignancy, which adversely affected the survival rate. Furthermore, in gliomas, positive correlations were found between N-form gasdermin-D, a key molecule associated with the non-canonical inflammasome, and other related molecules, including NLRP3, caspase-1, caspase-4, and caspase-5. These results were verified by immunohistochemical examination of glioma tissues, and the expression levels of these molecules also increased significantly with increasing grade. In addition, the features of pyroptosis were confirmed. CONCLUSION: This study identified the potential of non-canonical inflammasomes as aggressiveness markers for gliomas and presented a perspective for improving glioma treatment.

Molecular characteristics of incidental lower-grade glioma for treatment decision-making.

OBJECTIVE: Several limitations are associated with the early diagnosis and treatment of incidental lower-grade glioma (iLGG), and due to its unknown molecular features, its management is categorized as either the "wait-and-see" strategy or immediate treatment. Therefore, in this study the authors explored iLGG's clinical and molecular landscape to improve its management. METHODS: The authors retrospectively assessed the differences between the molecular and clinical characteristics of iLGG and symptomatic lower-grade glioma (sLGG) samples filtered based on symptom data corresponding to The Cancer Genome Atlas cohort with mutations. Thereafter, genomic and transcriptomic analysis was performed. RESULTS: There was no significant difference between iLGG and sLGG with respect to mutation status; however, there was an increase in the interaction between major mutations in sLGG, depending on the histological subtype and the IDH1 mutation status. Furthermore, the IDH1 mutation characteristics corresponding to wild-type glioma were much more obvious in sLGG than in iLGG. Additionally, in sLGG, genes associated with malignancy, including cell proliferation-related, cell migration-related, epithelial-to-mesenchymal transition-related, and negative regulation of cell death-related genes, were significantly upregulated, and groups showing higher expression levels of these genes were associated with worse prognosis. Also, 8 of the 75 identified upregulated genes showed positive correlation with resistance to the drugs that are normally used for glioma treatment, including procarbazine, carmustine, vincristine, and temozolomide. CONCLUSIONS: The new insights regarding the different molecular features of iLGG and sLGG indicated that the immediate management of iLGG could result in better prognosis than the wait-and-see strategy.

NOX2-Induced High Glycolytic Activity Contributes to the Gain of COL5A1-Mediated Mesenchymal Phenotype in GBM.

The alteration of the cellular metabolism is a hallmark of glioma. The high glycolytic phenotype is a critical factor in the pathogenesis of high-grade glioma, including glioblastoma multiforme (GBM). GBM has been stratified into three subtypes as the proneural, mesenchymal, and classical subtypes. High glycolytic activity was found in mesenchymal GBM relative to proneural GBM. NADPH oxidase 2 (NOX2) has been linked to cellular metabolism and epithelial-mesenchymal transition (EMT) in tumors. The role of NOX2 in the regulation of the high glycolytic phenotype and the gain of the mesenchymal subtype in glioma remain unclear. Here, our results show that the levels of NOX2 were elevated in patients with GBM. NOX2 induces hexokinase 2 (HK2)-dependent high glycolytic activity in U87MG glioma cells. High levels of NOX2 are correlated with high levels of HK2 and glucose uptake in patients with GBM relative to benign glioma. Moreover, NOX2 increases the expression of mesenchymal-subtype-related genes, including COL5A1 and FN1 in U87MG glioma cells. High levels of NOX2 are correlated with high levels of COL5A1 and the accumulation of extracellular matrix (ECM) in patients with GBM relative to benign glioma. Furthermore, high levels of HK2 are correlated with high levels of COL5A1 in patients with GBM relative to benign glioma. Our results suggest that NOX2-induced high glycolytic activity contributes to the gain of the COL5A1-mediated mesenchymal phenotype in GBM.

Maximal surgical resection and adjuvant surgical technique to prolong the survival of adult patients with thalamic glioblastoma.

The importance of maximal resection in the treatment of glioblastoma (GBM) has been reported in many studies, but maximal resection of thalamic GBM is rarely attempted due to high rate of morbidity and mortality. The purpose of this study was to investigate the role of surgical resection in adult thalamic glioblastoma (GBM) treatment and to identify the surgical technique of maximal safety resection. In case of suspected thalamic GBM, surgical resection is the treatment of choice in our hospital. Biopsy was considered when there was ventricle wall enhancement or multiple enhancement lesion in a distant location. Navigation magnetic resonance imaging, diffuse tensor tractography imaging, tailed bullets, and intraoperative computed tomography and neurophysiologic monitoring (transcranial motor evoked potential and direct subcortical stimulation) were used in all surgical resection cases. The surgical approach was selected on the basis of the location of the tumor epicenter and the adjacent corticospinal tract. Among the 42 patients, 19 and 23 patients underwent surgical resection and biopsy, respectively, according to treatment strategy criteria. As a result, the surgical resection group exhibited a good response with overall survival (OS) (median: 676 days, p < 0.001) and progression-free survival (PFS) (median: 328 days, p < 0.001) compared with each biopsy groups (doctor selecting biopsy group, median OS: 240 days and median PFS: 134 days; patient selecting biopsy group, median OS: 212 days and median PFS: 118 days). The surgical resection groups displayed a better prognosis compared to that of the biopsy groups for both the O6-methylguanine-DNA methyltransferase unmethylated (log-rank p = 0.0035) or methylated groups (log-rank p = 0.021). Surgical resection was significantly associated with better prognosis (hazard ratio: 0.214, p = 0.006). In case of thalamic GBM without ventricle wall-enhancing lesion or multiple lesions, maximal surgical resection above 80% showed good clinical outcomes with prolonged the overall survival compared to biopsy. It is helpful to use adjuvant surgical techniques of checking intraoperative changes and select the appropriate surgical approach for reducing the surgical morbidity.

Autologous adoptive immune-cell therapy elicited a durable response with enhanced immune reaction signatures in patients with recurrent glioblastoma: An open label, phase I/IIa trial.

Glioblastoma multiforme (GBM) is an aggressive malignancy classified by the World Health Organization as a grade IV glioma. Despite the availability of aggressive standard therapies, most patients experience recurrence, for which there are currently no effective treatments. We aimed to conduct a phase I/IIa clinical trial to investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM. This study was a single-arm, open-label, investigator-initiated trial on 14 patients recruited between 2013 and 2017. The immune cells were administered via intravenous injection 24 times at 2-week intervals after surgical resection or biopsy. The safety and clinical efficacy of this therapy was examined by assessing adverse events and comparing 2-year overall survival (OS). Transcriptomic analysis of tumor tissues was performed using NanoString to identify the mechanism of therapeutic efficacy. No grade 4 or 5 severe adverse events were observed. The most common treatment-related adverse events were grade 1 or 2 in severity. The most severe adverse event was grade 3 fever. Median OS was 22.5 months, and the median progression-free survival was 10 months. Five patients were alive for over 2 years and showed durable response with enhanced immune reaction transcriptomic signatures without clinical decline until the last follow-up after completion of the therapy. In conclusion, autologous adoptive immune-cell therapy was safe and showed durable response in patients with enhanced immune reaction signatures. This therapy may be effective for recurrent GBM patients with high immune response in their tumor microenvironments. Trial registration: The Korea Clinical Research Information Service database: KCT0003815, Registered 18 April 2019, retrospectively registered.

The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase.

Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential ex vivo therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene, cytosine deaminase (CD) to brain tumors. MSCs were engineered to produce CD enzymes at various levels using different promoters. When co-cultured, CD-expressing MSCs had a bystander, anti-cancer effect on neighboring C6 glioma cells in proportion to the levels of CD enzymes that could convert a nontoxic prodrug, 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) in vitro. Consistent with the in vitro results, for early stage brain tumors induced by intracranial inoculation of C6 cells, transplantation of CD-expressing MSCs reduced tumor mass in proportion to 5-FC dosages. However, for later stage, established tumors, a single treatment was insufficient, but only multiple transplantations were able to successfully repress tumor growth. Our findings indicate that the level of total CD enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent glioblastomas through repetitive treatments.

Posttreatment high-grade glioma: usefulness of peak height position with semiquantitative MR perfusion histogram analysis in an entire contrast-enhanced lesion for predicting volume fraction of recurrence.

PURPOSE: To determine whether semiquantitative histogram analysis of the normalized cerebral blood volume (CBV) for an entire contrast material-enhanced lesion could be used to predict the volume fraction of posttreatment high-grade glioma recurrence compared with posttreatment change. MATERIALS AND METHODS: The institutional review board approved this retrospective study. Informed consent was obtained. Thirty-nine patients with pathologically proved predominant tumor recurrence (tumor recurrence group, tumor fraction > or =50% [n = 14]), mixed tumor and posttreatment change (mixed group, tumor fraction > or =20% and <50% [n = 10]), and predominant posttreatment change (treatment change group, tumor fraction <20% [n = 15]) were evaluated. Histogram parameters of normalized CBV-histogram width, peak height position (PHP), and maximum value (MV)-were measured in entire contrast-enhanced lesions and used as discriminative indexes. Ordered logistic regression was used to determine independent factors for predicting the diseases of posttreatment contrast-enhanced lesions. Leave-one-out cross-validation was used to determine diagnostic accuracy. RESULTS: PHP was an independent predictive factor (P = .003) for differentiating contrast-enhanced lesions in patients with posttreatment gliomas. According to receiver operating characteristic curve analyses, PHP provided sensitivity of 90.2% and specificity of 91.1% for differentiating tumor recurrence from mixed and treatment change groups at an optimum threshold of 1.7 by using leave-one-out cross-validation. MV helped distinguish treatment change group from tumor recurrence and mixed groups at an optimum threshold of 2.6 (sensitivity, 96.5%; specificity, 93.1%). CONCLUSION: PHP can be used to predict the volume fraction of posttreatment high-grade glioma recurrence.

Neural induction with neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain.

Mesenchymal stem cells (MSCs) have been shown to ameliorate a variety of neurological dysfunctions. This effect is believed to be mediated by their paracrine functions, since these cells rarely differentiate into neuronal cells. It is of clinical interest whether neural induction of MSCs is beneficial for the replacement therapy of neurological diseases. Here we report that expression of Neurogenin1 (Ngn1), a proneural gene that directs neuronal differentiation of progenitor cells during development, is sufficient to convert the mesodermal cell fate of MSCs into a neuronal one. Ngn1-expressing MSCs expressed neuron-specific proteins, including NeuroD and voltage-gated Ca2+ and Na+ channels that were absent in parental MSCs. Most importantly, transplantation of Ngn1-expressing MSCs in the animal stroke model dramatically improved motor functions compared with the parental MSCs. MSCs with Ngn1 populated the ischemic brain, where they expressed mature neuronal markers, including microtubule associated protein 2, neurofilament 200, and vesicular glutamate transporter 2, and functionally connected to host neurons. MSCs with and without Ngn1 were indistinguishable in reducing the numbers of Iba1+, ED1+ inflammatory cells, and terminal deoxynucleotidyl transferase dUTP nick-end labeling(+) apoptotic cells and in increasing the numbers of proliferating Ki67+ cells. The data indicate that in addition to the intrinsic paracrine functions of MSCs, motor dysfunctions were remarkably improved by MSCs able to transdifferentiate into neuronal cells. Thus, neural induction of MSCs is advantageous for the treatment of neurological dysfunctions.

Associations of miR­146aC>G, miR­149C>T, miR­196a2C>T and miR­499A>G polymorphisms with brain tumors.

MicroRNAs (miRNAs/miRs) are short, non­coding RNAs that are implicated in tumorigenesis, functioning as tumor suppressors and oncogenes. However, the clinical significance of miRNA expression profiles for brain tumors remains unclear. Therefore, the present study was designed to investigate the associations between miRNA genetic variants and brain tumor risk. A total 362 participants were recruited, including 179 who were healthy subjects and 183 who were patients with brain tumors confirmed as gliomas, meningiomas or schwannomas. This study investigated the single nucleotide polymorphisms miR­146aC>G, miR­149T>C, miR­196a2T>C and miR­499A>G by polymerase chain reaction­restriction fragment length polymorphism. It was found that the dominant miR­149 and CC genotypes were significantly more frequent in patients with glioma. The odds ratios for the C­C­C­G, C­T­C­G and G­C­T­G haplotypes (miR­146aC>G­miR­149T>C­miR­196a2T>C­miR­499A>G) were significantly increased in glioma, as were the odds ratios for the GCT haplotype of miR­146aC>G, miR­149T>C and miR­196a2T>C, and for the C­C­G haplotype of miR­149T>C, miR­196a2T>C and miR­499A>G. In meningioma, the odds ratios were increased in the G­T­C­G haplotype of miR­146aC>G, miR­149T>C, miR­196a2T>C and miR­499A>G. The odds ratios were also increased in the G­C­G haplotype of miR­146aC>G, miR­196a2T>C and miR­499A>G, and in the C­C­G haplotype of miR­149T>C, miR­196a2T>C and miR­499A>G. The odds ratios for schwannoma were increased in the G­C­T­G haplotype of miR­146aC>G, miR­149T>C, miR­196a2T>C and miR­499A>G, and in the C­C­G haplotype of miR­149T>C, miR­196a2T>C and miR­499A>G. In conclusion, these results suggested that the miR­149 polymorphism may be involved in the development of gliomas, and the C­C­G haplotype of miR­149T>C, miR­196a2T>C and miR­499A>G showed increased odds ratios for all types of brain tumors.

Pathologic diagnosis of recurrent glioblastoma: morphologic, immunohistochemical, and molecular analysis of 20 paired cases.

To evaluate the prognostic value of the volume of residual viable tumor versus therapy-induced necrosis in resection material and the diagnostic value of ancillary tests in recurrent glioblastoma (GBM), we conducted a retrospective review of 20 patients whose initial and recurrent specimens were available. Recurrent GBMs were graded according to the extent of histopathologic parameters: recurrent tumor with high-grade, non-high-grade, and pure high-grade tumor components and therapy-related necrosis. We also examined MIB-1 labeling, isocitrate dehydrogenase 1 mutation, and epidermal growth factor receptor amplification in primary and recurrent GBMs. To evaluate patient outcomes according to clinical and pathologic parameters, a survival analysis was performed, and correlations between histopathologic parameters and each ancillary test were assessed. Among clinical parameters, age above 60 years was associated with decreased survival (P=0.022), but other clinical parameters showed no significant association with overall survival. Among the 3 histopathologic parameters, the extent of recurrent tumor, including high-grade and non-high-grade components, revealed a significant association with overall survival (P=0.042), but neither the extent of pure high-grade components nor therapy-related necrosis showed any prognostic value. MIB-1 labeling, isocitrate dehydrogenase 1 mutation, and epidermal growth factor receptor amplification were useful for the diagnosis of recurrent GBMs but showed no prognostic value. Our data suggest that histopathologic evaluation on the basis of tumor extent in resected recurrent GBM specimens may provide additional prognostic information on the survival of patients with recurrent GBM.

Stereological analysis on migration of human neural stem cells in the brain of rats bearing glioma.

OBJECTIVE: The objective of this study was to determine the rate and pattern of NSC migration in the brain and its time course after NSC transplantation. METHODS: We investigated the tropism of HB1.F3 (F3) immortalized human NSCs in rats bearing U373 human glioma in the brain. Rats received an injection of human U373MG malignant glioma cells into the striatum followed by an injection of F3 cells into the contralateral hemisphere 7 days later. We analyzed the numbers, distribution, and migration rate of NSCs using unbiased stereology. RESULTS: Approximately 10% of the injected NSCs migrated into the tumor region by 50 minutes after NSC injection. The number of NSCs in the tumor region increased slowly up to 5 days post-injection and increased significantly up to 15 days post-injection. Changes in tumor volume showed similar patterns. The rate of NSC migration was approximately 175 microm/min. NSCs increased in number approximately 1.7-fold during day 1 in the absence of tumor cell inoculation in vivo. However, the proliferation of NSCs began to decline after 5 days after injection. CONCLUSION: We identified for the first time the rate and pattern of NSC migration to the tumor mass in vivo. These findings may provide useful information with respect to preclinical research of gene therapy for malignant gliomas.

Desmoplastic fibroma of the skull in an infant.

CASE REPORT: A 1-year-old girl presented with a 10-month history of progressive protuberance of the left frontal skull. Magnetic resonance imaging and computed tomography demonstrated a large osteolytic interosseous mass extending to the frontal sinus and temporal base without any intracranial invasion. A fronto-temporo-parietal craniectomy of the outer skull table and excision of an interosseous tumor resulted in local dural exposure in the temporal area that was covered by cranioplasty. Pathological examination identified desmoplastic fibroma (DF) of the skull. The patient's cranial asymmetry was improved without recurrence of the tumor up to the 12th month after excision. DISCUSSION: In the literature, 11 cases of DF of the skull have been reported, two of which have involved children (one an infant). We report the second known infantile case of DF of the skull.