Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma.

Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.

Extraocular Pressure Measurements to Avoid Orbital Compartment Syndrome in Aneurysm Surgery.

BACKGROUND: Orbital compartment syndrome (OCS) is a rare but devastating complication following pterional craniotomy. Although the causes of OCS are unclear, external compression of the orbit by a myocutaneous flap is commonly mentioned as a major factor. We evaluated the ocular influence of external compression using an extraocular pressure monitor. METHODS: We measured extraocular pressure in 86 patients who underwent surgery for cerebral aneurysm via a pterional approach. Clinical information and radiologic parameters, including the area of the medial rectus muscle (MRM) and the craniotomy height from the bottom of the anterior skull base, were collected. As a control group, 117 patients who underwent surgery without pressure monitoring were also evaluated. RESULTS: Extraocular pressure reached a maximum during craniotomy (mean, 22.0 mm Hg; range, 18.4-51.0 mm Hg) and decreased after myocutaneous flap adjustment (mean, 7.9 mm Hg; range, 5.4-17.5 mm Hg). Pressure before myocutaneous flap manipulation differed between patients with anterior communicating artery (Acomm) aneurysms and other patients (mean, 16.5 mm Hg vs. 9.4 mm Hg; P = 0.003). Among Acomm aneurysm cases, the monitored group showed a significantly lower MRM swelling ratio (postoperative MRM area/preoperative MRM area) compared with the control group (1.03 ± 0.10 vs. 1.17 ± 0.15; P = 0.036). CONCLUSIONS: Myocutaneous flaps can produce unnoticed overpressure on the orbit, resulting in OCS-related blindness during aneurysm clipping surgery, especially in cases involving mandatory lower craniotomy. The continuous extraocular compressive pressure monitoring technique is a simple and effective approach to prevent such a serious complication.

Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea.

PURPOSE: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. EXPERIMENTAL DESIGN: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. RESULTS: Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy (n = 91) or control group (n = 89). In the intention-to-treat analysis set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. CONCLUSIONS: The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

World Health Organization Grade II Oligodendroglioma Occurring after Successful Treatment for Childhood Acute Lymphoblastic Leukemia.

When treating childhood acute lymphoblastic leukemia (ALL), secondary neoplasms are a significant long term problem. Radiation is generally accepted to be a major cause of the development of secondary neoplasms. Following treatment for ALL, a variety of secondary tumors, including brain tumors, hematologic malignancies, sarcomas, thyroid cancers, and skin cancers have been reported. However, oligodendroglioma as a secondary neoplasm is extremely rare. Herein we present a case of secondary oligodendroglioma occurring 13 years after the end of ALL treatment.

Role of vincristine in the inhibition of angiogenesis in glioblastoma.

OBJECTIVE: Vincristine, a microtubule-destabilizing drug, was found to exhibit anti-angiogenic effects and anti-tumoral activity. However, the precise mechanism by which vincristine inhibits angiogenesis in glioblastomas is not well understood. Our aim was to investigate whether vincristine affects vascular endothelial growth factor (VEGF) expression in glioblastoma cells and determine whether it is mediated by the downregulation of hypoxia-inducible factor-1α (HIF-1α). METHODS: We investigated the expression of HIF-1α in glioblastoma tissues resected from patients and in human glioblastoma cell lines using immunohistochemistry, Western blot analysis, and immunocytochemistry. In addition to an MTT assay assessing the effect of vincristine on cell proliferation and viability, the effects of vincristine on VEGF mRNA expression and HIF-1α protein were examined using real-time RT-PCR and Western blot analysis under 1% O2 (hypoxia). RESULTS: HIF-1α was expressed in the majority of glioblastoma tissues and was detected mainly in the nucleus. Strong immunoreactivity for HIF- 1 α was found often in the hypercellular zones. Under hypoxic conditions, HIF-1α protein levels in the glioblastoma cell lines increased, primarily localizing into the nucleus similar to glioblastoma tissues. Exposure of glioblastoma cells to vincristine resulted in enrichment of the G2-M fraction of the cell cycle, which suggests that vincristine-mediated growth inhibition of glioblastoma is correlated with mitotic inhibition. Using doses lower than those found to reduce the viability and proliferation of cells by 50% (IC50), vincristine decreased both the expression of VEGF mRNA and the level of HIF-1α protein in hypoxic glioblastoma cells. In addition, following exposure to vincristine, the expression of VEGF mRNA was correlated with HIF-1α protein levels. CONCLUSIONS: Our results suggest that the mechanism by which vincristine elicits an anti-angiogenic effect in glioblastomas under hypoxic conditions might be mediated, in part, by HIF-1α inhibition.

Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: A human trial.

CONTEXT: Spinal cord injury (SCI) can cause irreversible damage to neural tissues. However, there is currently no effective treatment for SCI. The therapeutic potential of adipose-derived mesenchymal stem cells (ADMSCs) has been emerged. OBJECTIVE: We evaluated the effects and safety of the intrathecal transplantation of autologous ADMSCs in patients with SCI. Participants/Interventions: Fourteen patients with SCI were enrolled (12 for ASIA A, 1 for B, and 1 for D; duration of impairments 3-28 months). Six patients were injured at cervical, 1 at cervico-thoracic, 6 at thoracic, and 1 at lumbar level. Autologous ADMSCs were isolated from lipoaspirates of patients' subcutaneous fat tissue and 9 × 107 ADMSCs per patient were administered intrathecally through lumbar tapping. MRI, hematological parameters, electrophysiology studies, and ASIA motor/sensory scores were assessed before and after transplantation. RESULTS: ASIA motor scores were improved in 5 patients at 8 months follow-up (1-2 grades at some myotomes). Voluntary anal contraction improvement was seen in 2 patients. ASIA sensory score recovery was seen in 10, although degeneration was seen in 1. In somatosensory evoked potential test, one patient showed median nerve improvement. There was no interval change of MRI between baseline and 8 months post-transplantation. Four adverse events were observed in three patients: urinary tract infection, headache, nausea, and vomiting. CONCLUSIONS: Over the 8 months of follow-up, intrathecal transplantation of autologous ADMSCs for SCI was free of serious adverse events, and several patients showed mild improvements in neurological function. Patient selection, dosage, and delivery method of ADMSCs should be investigated further.

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma.

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-L-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells' ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

Quantitative analysis of tumor volume reduction after three-dimensional conformal radiation therapy for intracranial meningiomas.

To provide radiobiological information on the inherent response of intracranial meningiomas after three-dimensional conformal radiation therapy. Quantitative tumor volume measurements were generated from 120 magnetic resonance images of a total of 24 patients. Gross tumor volumes were delineated on a series of contrast-enhanced T1-weighted magnetic resonance images by using commercial software. The percentage of tumor volume reduction at each follow-up was determined and compared to the baseline tumor volume. The median follow-up time was 103.5 months (range 30-137 months). The mean pre-radiation therapy tumor volume was 30.0 cm(3) (range 1.3-167.4 cm(3)). Tumor volume reduction was observed in 96 % of the study population. The mean absolute and relative tumor volume reduction were 14.0 cm(3) (range -0.6-84.5 cm(3)) and 40.8 % (range -6.8-82.9 %), respectively. The mean relative tumor volume reduction was 15.9, 28.9, 40.5, 50.3, and 52.6 % at 2, 4, 6, 8, and 10 years after irradiation. The quantitative volumetric analysis of the pattern of tumor volume reduction in response to irradiation gives an insight into the radiobiological nature of intracranial meningiomas after conventionally fractionated radiation therapy.

Romo1 is associated with ROS production and cellular growth in human gliomas.

Romo1 is a mitochondrial protein whose elevated expression is commonly observed in various types of human cancers. However, the expression status of Romo1 and its implication in the pathogenesis of human glioblastoma (GBM) remain largely undefined. To understand the role of Romo1 in the progression of GBM, we explored its expression in a series of GBM tissues and cell lines and determined its effect on ROS production, cell proliferation, and tumor growth. Romo1 was frequently overexpressed at the mRNA level in both primary tumors and cell lines and its elevation was more commonly observed in high grade tumors versus low grade tumors. Romo1 expression was associated with ROS production and its knockdown led to a marked reduction of in vitro cellular growth and anchorage-independent growth of GBM. Consistently, Romo1 depletion induced a G2/M arrest of the cell cycle that was accompanied with accumulation of phospho-cdc2. Furthermore, a mouse xenograft assay revealed that Romo1 depletion significantly decreased tumor formation and growth. Therefore, our data demonstrate that Romo1 upregulation is a common event in human GBMs and contributes to the malignant tumor progression, suggesting that Romo1 could be a new therapeutic target for human GBM.

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival.

Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

Risk factors of delayed surgical evacuation for initially nonoperative acute subdural hematomas following mild head injury.

BACKGROUND: Although the majority of patients with minimal acute subdural hematomas (aSDHs) can be managed conservatively, some require delayed aSDH evacuation due to hematoma enlargement. This study was designed to determine the risk factors associated with delayed hematoma enlargement leading to surgery in patients with aSDHs who did not initially require surgical intervention. METHODS: From 2002 to 2012, 98 patients were treated for nonoperative aSDHs following mild head injury (Glasgow Coma Scale scores of 13-15). The outcome variables were radiographic evidence of SDH enlargement on serially obtained computed tomography (CT) images and later surgical evacuation. Univariate and multivariate analyses were applied to both the demographic and initial radiographic features to identify risk factors for SDH progression and surgery. RESULTS: Overall, 64 patients (65 %) revealed minimal SDH or spontaneous hematoma resolution (conservative group) with conservative management at their last follow-up CT scan. The remaining 34 patients (35 %) received delayed hematoma evacuation (delayed surgery group) a median of 17 days after the head trauma. There were no significant differences between the two groups for baseline characteristics, including age, injury type, degree of brain atrophy, prior history of antithrombotic drugs, and coagulopathy. The presence of cerebral contusions and subarachnoid hemorrhages was more common in the conservative group (p = 0.003 and p = 0.003, respectively). On multivariate analysis, hematoma volume (p = 0.01, odds ratio [OR] = 1.094, 95 % confidence interval [CI] = 1.021-1.173) and degree of midline shift (p = 0.01, OR = 1.433, 95 % CI = 1.088-1.888) on the initial CT scan were independently associated with delayed hematoma evacuation. CONCLUSIONS: A critical proportion of patients with minimal aSDHs occurring after mild head injury can progress over several weeks and require hematoma evacuation. Especially patients with a large initial SDH volume and accompanying midline shift require careful monitoring of hematoma progression.

Glioma mimicking a hypertensive intracerebral hemorrhage.

Here, we report a rare case of an anaplastic astrocytoma masquerading as a hypertensive basal ganglia hemorrhage. A 69-year-old woman who had been under medical management for hypertension during the past 3 years suddenly developed right hemiparesis with dysarthria. Brain computed tomography (CT) scans with contrast and CT angiograms revealed an intracerebral hemorrhage (ICH) in the left basal ganglia, without an underlying lesion. She was treated conservatively, but underwent a ventriculoperitoneal shunt operation 3 months after the initial attack due to deteriorated mental status and chronic hydrocephalus. Three months later, her mental status deteriorated further. Magnetic resonance imaging (MRI) with gadolinium demonstrated an irregular enhanced mass in which the previous hemorrhage occurred. The final histological diagnosis which made by stereotactic biopsy was an anaplastic astrocytoma. In the present case, the diagnosis of a high grade glioma was delayed due to tumor bleeding mimicking hypertensive ICH. Thus, a careful review of neuroradiological images including MRI with a suspicion of tumor bleeding is needed even in the patients with past medical history of hypertension.

Isolated lateral sinus thrombosis presenting as cerebellar infarction in a patient with iron deficiency anemia.

As a rare cerebrovascular disease, cerebral venous thrombosis (CVT) is caused by various conditions including trauma, infection, oral contraceptive, cancer and hematologic disorders. However, iron deficiency anemia is not a common cause for CVT in adult. Posterior fossa infarction following CVT is not well demonstrated because posterior fossa has abundant collateral vessels. Here, we report a case of a 55-year-old man who was admitted with complaints of headache, nausea, and mild dizziness. The patient was diagnosed with isolated lateral sinus thrombosis presenting as cerebellar infarction. Laboratory findings revealed normocytic normochromic anemia due to iron deficiency, and the patient's symptoms were improved after iron supplementation.

Prediction of outcomes in young adults with aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is rare in young adults and little is known about aneurysms in this subgroup. The effect of clinical and prognostic factors on the outcome based on the Glasgow Outcome Scale (GOS) scores and the predictors of unfavorable outcomes were analyzed in young adults with aneurysmal SAH. A retrospective review of the clinical parameters, including age, sex, hypertension, smoking status, hyperlipidemia, location of the cerebral aneurysm, size of the aneurysm, multiplicity, perioperative complication such as hydrocephalus, vasospasm, and hematoma, and Hunt and Hess and Fisher grading on presentation, was conducted in 108 young adults (mean age 34.8 years) managed at our institute. The outcome was classified based on GOS grading into unfavorable (GOS scores 1-3) or favorable (GOS scores 4 or 5). The overall mortality rate was 3.7% (4/108 patients). Univariate regression analysis for the outcomes at discharge found that age at the time of presentation, male sex, size of aneurysm, multiple aneurysms, hyperlipidemia, and poor Hunt and Hess and Fischer grades were associated with unfavorable outcome. Multivariate regression analysis found independent effects of sex, multiple aneurysms, size of aneurysm, and Hunt and Hess grade on the outcome at discharge. Size of aneurysm, presence of multiple aneurysms, Hunt and Hess grade, and hypertension were the predictors of outcome at mean 2-year follow up based on multivariate exact regression analysis. The multimodal approach with aggressive medical management, early intervention, and surgical treatment might contribute to favorable long-term outcomes in patients with poor expected outcomes.

Comparison of cerebrospinal fluid biomarkers between idiopathic normal pressure hydrocephalus and subarachnoid hemorrhage-induced chronic hydrocephalus: a pilot study.

BACKGROUND: We examined the cerebrospinal fluid (CSF) markers of subarachnoid hemorrhage (SAH)-induced and idiopathic normal pressure hydrocephalus (INPH) to investigate the pathophysiology and mechanism of communicating hydrocephalus compared to obstructive hydrocephalus. MATERIAL/METHODS: We obtained CSF samples from 8 INPH, 10 SAH-induced hydrocephalus, and 6 unmatched patients with non-hemorrhagic obstructive hydrocephalus during their ventriculoperitoneal shunt operations. Transforming growth factor (TGF)-ß1, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and total tau in the CSF were analyzed via enzyme-linked immunosorbent assay. RESULTS: The mean VEGF levels in the CSF of patients with SAH-induced hydrocephalus, INPH, and obstructive hydrocephalus were 239 ± 131, 239 ± 75, and 163 ± 122 pg/mL, respectively. The total tau concentrations in the CSF of the groups were 1139 ± 1900, 325 ± 325, and 1550 ± 2886 pg/mL, respectively. TNF-α values were 114 ± 34, 134 ± 38, and 55 ± 16 pg/mL, respectively. TGF-ß1 values were 953 ± 430, 869 ± 447, and 136 ± 63 pg/mL, respectively. A significant difference in TNF-α and TGF-ß1 levels was observed only between SAH-induced and chronic obstructive hydrocephalus, and between INPH and chronic obstructive hydrocephalus (p<0.01). CONCLUSIONS: No significant differences in the 4 CSF biomarker levels were observed between INPH and SAH-induced hydrocephalus, whereas CSF TNF-α and TGF-ß1 levels were increased compared to those in patients with chronic obstructive hydrocephalus. Post-SAH hydrocephalus and INPH are probably more destructive to neural tissues, and then stimulate the inflammatory reaction and healing process, compared with obstructive hydrocephalus.

Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling.

Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C-C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis.

The Correlation between Insertion Depth of Prodisc-C Artificial Disc and Postoperative Kyphotic Deformity: Clinical Importance of Insertion Depth of Artificial Disc.

OBJECTIVE: This study was designed to investigate the correlation between insertion depth of artificial disc and postoperative kyphotic deformity after Prodisc-C total disc replacement surgery, and the range of artificial disc insertion depth which is effective in preventing postoperative whole cervical or segmental kyphotic deformity. METHODS: A retrospective radiological analysis was performed in 50 patients who had undergone single level total disc replacement surgery. Records were reviewed to obtain demographic data. Preoperative and postoperative radiographs were assessed to determine C2-7 Cobb's angle and segmental angle and to investigate postoperative kyphotic deformity. A formula was introduced to calculate insertion depth of Prodisc-C artificial disc. Statistical analysis was performed to search the correlation between insertion depth of Prodisc-C artificial disc and postoperative kyphotic deformity, and to estimate insertion depth of Prodisc-C artificial disc to prevent postoperative kyphotic deformity. RESULTS: In this study no significant statistical correlation was observed between insertion depth of Prodisc-C artificial disc and postoperative kyphotic deformity regarding C2-7 Cobb's angle. Statistical correlation between insertion depth of Prodisc-C artificial disc and postoperative kyphotic deformity was observed regarding segmental angle (p<0.05). It failed to estimate proper insertion depth of Prodisc-C artificial disc effective in preventing postoperative kyphotic deformity. CONCLUSION: Postoperative segmental kyphotic deformity is associated with insertion depth of Prodisc-C artificial disc. Anterior located artificial disc leads to lordotic segmental angle and posterior located artificial disc leads to kyphotic segmental angle postoperatively. But C2-7 Cobb's angle is not affected by artificial disc location after the surgery.

Usefulness of thallium-201 SPECT for prediction of early progression in low-grade astrocytomas diagnosed by stereotactic biopsy.

OBJECTIVE: To establish the value of thallium-201 single-photon emission computed tomography ((201)Tl-SPECT) as a predictor of early progression in low-grade astrocytomas (LGAs). METHODS: We studied 57 consecutive patients who underwent 201 Tl-SPECT before stereotactic biopsy (n=33) or surgical resection (n=24). The value of radiologic and histopathological variables ((201)Tl index and MIB-1 index) in predicting progression free survival (PFS) was examined in each group of patients. RESULTS: During a median follow up of 55 months (range, 11-101), progression of the primary lesion was identified in 46 patients (80.7%). Based on Cox's proportional hazards model, the increased thallium uptake was associated with a short PFS in both biopsy and resection groups, whereas the MIB-1 index was significant only in the resection group. Considering the cut-off value, (201)Tl index>1.7 was statistically significant for reduced PFS in the biopsy group; however, MIB-1 index was not directly related to the PFS at any level. For the surgical resection group, both a (201)Tl index>1.9 and a MIB-1 index>6% were associated with short PFS. CONCLUSION: (201)Tl SPECT may play a role in prediction of early tumor progression not only in resected LGAs, but also in biopsy-proven LGAs. Therefore, we suggest that patients with LGAs established from biopsy should be considered as high-risk groups for early progression if the tumor shows a high (201)Tl uptake, even if the tumor demonstrates low proliferative activity on histopathologic examination.

Transplantation of umbilical cord blood stem cells for treating spinal cord injury.

Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.

O6-methylguanine DNA methyltransferase status determined by promoter methylation and immunohistochemistry in gliosarcoma and their clinical implications.

O(6)-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3-14.5 months] and 8.3 months (95% CI, 7.4-9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.