Our results indicate that an early diagnosis and active intervention before establishment of irreversible hemodynamic change are essential to achieve a favorable clinical outcome in children with MMD.
There were distinctive expression patterns of matrixins, cytokines and angiogenic factors in MMD patients, which seemed to correlate with disease pathogenesis. The balance between MMPs and TIMPs was disrupted in MMD and correlated with disease pathogenesis. Increased plasma levels of MCP-1 and VEGF in MMD patients may play a role in the recruitment of vascular progenitor cells and in the formation of collateral vessels.
Purpose: Brainstem gliomas are usually inoperable and have a dismal prognosis.Based on the robust tropisms of neural stem cells (NSC) and mesenchymal stem cells (MSC) to brain tumors, we compared the tumor-tropic migratory capacities of these stem cells and evaluated the therapeutic potential of genetically engineered human NSCs encoding cytosine deaminase (CD) and IFNβ against brainstem gliomas. Experimental Design: The directed migratory capacities of NSCs and MSCs to brainstem glioma (F98) were evaluated both in vitro and in vivo. The human NSCs (HB1. F3) and various human MSCs, such as bone marrow-derived MSCs (HM3.B10), adipose tissue-derived MSCs, and umbilical cord blood-derived MSCs, were tested. Human fibroblast cells (HFF-1) were used as the negative control. As a proof of concept, the bioactivity of HB1.F3-CD-IFNβ was analyzed with a cell viability assay, and animals with brainstem gliomas were injected with HB1.F3-CD-IFNβ cells followed by systemic 5-fluorocytosine treatment.Results: In an in vitro modified Transwell migration assay and in vivo stem cell injection into established brainstem gliomas in rats, all the stem cells showed a significant migratory capacity compared with that of the control (P < 0.01). Histologic analysis showed a 59% reduction in tumor volume in the HB1.F3-CD-IFNβ-treated group (P < 0.05). Apoptotic cells were increased 2.33-fold in animals treated with HB1.F3-CD-IFNβ compared with the respective control groups (P < 0.01). Conclusion: The brainstem glioma-tropic migratory capacities of MSCs from various sources were similar to those of NSCs. Genetically engineered NSCs show therapeutic efficacy against brainstem gliomas.
The major aims of this study were to estimate the infection rate and recognize the risk factor for ventriculoperitoneal (VP) shunt infections in children. To analyze shunt infection rate and identify risk factors, a retrospective cohort analysis of 333 consecutive VP shunt series was performed at Seoul National University Children's Hospital in Korea between January 2005 and February 2011. Overall, 35 shunts (10.5%) were infected, which represented an infection rate of 0.075 infection cases per shunt per year. VP shunt infection occurred at a median of 1 month (range, 6 days to 8 months) after insertion. An independent risk factor for shunt infection was undergoing an operation before the first year of life (relative risk 2.31; 95% confidence interval, 1.19-4.48). The most common causative microorganism was coagulase-negative staphylococci in 16 (45.7%) followed by Staphylococcus aureus in 8 (22.9%). Methicillin resistance rate was 83.3% among coagulase-negative staphylococci and S. aureus. In this study, cerebrospinal fluid shunt infection rate was 10.5%. Infection was frequently caused by methicillin-resistant coagulase-negative staphylococci and S. aureus within two months after shunt surgery. Vancomycin may be considered as the preoperative prophylaxis for shunt surgery in a situation where methicillin resistance rate is very high.
Sox2 is a key transcription factor that maintains the proliferation of neuroglial stem cells and inhibits neuronal fate commitment. Moreover, it was recently found that brain tumors contain stem cells that resemble normal neuroglial stem cells in many respects. This study was undertaken to describe Sox2 expression in various brain tumors, and to determine whether Sox2 expression is a universal feature of brain tumors, or whether its expression is limited to a specific lineage of brain tumors. Sox2 immunohistochemistry was performed on 194 brain tumor tissues of various kinds. Fetal and adult normal brain tissues obtained by autopsy and brain tissues of epilepsy patients with cortical dysplasia were used as controls. Semiquantitative reverse transcription polymerase chain reaction was used to confirm the immunohistochemical results. Double immunofluorescence was performed to characterize the lineage of Sox2-positive cells. Sox2 was found to be expressed in various glial tumors, including those with astroglial, oligodendroglial, and ependymal lineages, and in the glial components of mixed neuroglial tumors, regardless of pathologic grade. In brain tumors of embryonal origin, supratentorial primitive neuroectodermal tumors showed robust Sox2 expression, whereas medulloblastomas and pineoblastomas did not. The majority of Sox2-positive tumor cells coexpressed glial fibrillary acidic protein, and most Sox2-negative cells in medulloblastomas and pineoblastomas showed neuronal differentiation. This study suggest that Sox2 may be a tumor marker of glial lineages rather than a universal brain tumor stem cell marker, because its expression pattern was found to correspond to differentiation pathways. On the other hand, the aberrant coexpressions of Sox2 and of a neuronal marker were widely observed in glioblastomas, which reflects a disorganized differentiation pattern that characterizes highly malignant tumors.
The prognosis of glioblastoma is better in children than in adults. Radical resection followed by concurrent chemoradiation therapy may be the initial treatment of choice.
Germinoma in the basal ganglia (BG) is notorious for its diagnostic difficulty. Clinical and radiological features of this disease are quite diverse, but have not been well characterized with respect to prognosis. We retrospectively reviewed the clinical course and treatment outcomes of 17 patients with a BG germinoma. The initial magnetic resonance imaging (MRI) features were classified. Clinical features and treatment outcomes were then analyzed with this classification scheme. A Type 1 lesion was defined as a subtle lesion with faint or no contrast enhancement (six patients). Type 2, 3, and 4 lesions were defined as contrast-enhancing lesions and were differentiated by the lesion size and the presence of subependymal seeding (11 patients). Type 1 lesions were distinct from the other lesions. Patients with a Type 1 lesion had a significantly longer time from the initial MRI to diagnosis than patients with Type 2, 3, and 4 lesions (P = 0.012). The actuarial progression-free survival and overall survival of patients 5 years after diagnosis were 66 and 77%, respectively. The presence of a Type 1 lesion (P = 0.004), a longer time delay in the diagnosis (P = 0.038), and radiation therapy without complete ventricular coverage (P = 0.010) were significantly associated with tumor progression. Profound motor deficits at diagnosis were associated with deterioration in motor function after tumor remission (P = 0.035). Early diagnosis of BG germinomas could affect the ability to control a tumor and neurological outcomes. In particular, high clinical suspicion and active diagnostic procedures are recommended. For optimal treatment, radiation fields should include entire ventricles even if there is no subependymal seeding.
Mesenchymal stem cells (MSCs) have an extensive migratory capacity for gliomas, which is comparable to that of neural stem cells. Among the various types of MSCs, human adipose tissue-derived MSCs (hAT-MSC) emerge as one of the most attractive vehicles for gene therapy because of their high throughput, lack of ethical concerns, and availability and ease of isolation. We evaluated the therapeutic potential and safety of genetically engineered hAT-MSCs encoding the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against brainstem gliomas. Human AT-MSCs were isolated from human fat tissue, characterized, and transfected with TRAIL using nucleofector. The therapeutic potential of TRAIL-producing hAT-MSCs (hAT-MSC.TRAIL) was confirmed using in vitro and in vivo studies. The final fate of injected hAT-MSCs was traced in long-survival animals. The characterization of hAT-MSCs revealed the expression of MSC-specific cell-type markers and their differentiation potential into mesenchymal lineage. Short-term outcomes included a 56.3% reduction of tumor volume (P < .001) with increased apoptosis (3.03-fold, P < .05) in animals treated with hAT-MSC.TRAIL compared with the control groups. Long-term outcomes included a significant survival benefit in the hAT-MSC.TRAIL-treated group (26 days of median survival in the control group vs 84 days in the hAT-MSC.TRAIL-treated group, P < .0001), without any evidence of mesenchymal differentiation in vivo. Our study demonstrated the therapeutic efficacy and safety of nonvirally engineered hAT-MSCs against brainstem gliomas and showed the possibility of stem-cell-based targeted gene therapy for clinical application.
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