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Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM.

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups&mdash, group A (n = 13, stereotactically injected pure PLGA microparticles), group B (n = 12, stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13, stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.

Chemotherapy is ineffective for treating malignant glioma (MG) because of the low therapeutic levels of pharmaceuticals in tumour tissues and the well-known tumour resistance. The resistance to alkylators is modulated by the DNA repair protein O

Background To study a case of para-Bombay phenotype caused by compound heterozygous mutation of the FUT1 gene. Methods We performed an agglutination examination to anti-H serum. Secretor status was determined in order to assess the presence of soluble blood group substances. Genotyping of ABO and FUT1 genes were also performed. Results Our results showed the presence of A and H antigens in the saliva. Based on these results, the patient in the present case was diagnosed to have a para-Bombay A phenotype. Direct DNA sequencing of the patient's ABO gene indicated A1v/O1vgenotype. FUT1 gene sequence analysis revealed that the patient harbored the compound heterozygous mutations c.881_882delTT (p.Phe294Cysfs) and c.551_552delAG (p.Glu184Valfs). Conclusions In summary, our findings support that the occurrence of a heterozygous mutation in FUT1, 547delAG/880delTT, is the most common mutation in Taiwanese.

Yuan-Yun Tseng,1,2 Tao-Chieh Yang,3 Yi-Chuan Wang,4 Wei-Hwa Lee,5 Tzu-Min Chang,4 Yi-Chuan Kau,6 Shih-Jung Liu4,7 1Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, 2Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 3Department of Neurosurgery, Asia University Hospital, Taichung, 4Department of Mechanical Engineering, Chang Gung University, Taoyuan, 5Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, 6Department of Anesthesiology, 7Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan Abstract: Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromato­graphy. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day3, followed by the release of high concentrations of the antiangiogenic combretastatin from day21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and antiangiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration. Keywords: nanofibrous membrane, poly(d,l)-lactide-co-glycolide (PLGA), glioblastoma multiforme (GBM), chemotherapy, targeted therapy, antiangiogenesis

Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan- and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026) and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P

Background In this report, we present the results of using upfront Gamma Knife surgery (GKS) in the management of giant central neurocytoma (CNC) (volume >50 mL) without the initial removal of the tumor mass. Case Descriptions Two patients underwent GKS for histologically proven CNC. Clinical and imaging studies were performed to evaluate the response to treatment. GKS involved delivery doses of 12 or 13 Gy to the tumor margin at the isodose line of 50%. Tumor response to GKS appeared as early as 4–6 months after GKS, at which point a dramatic reduction in volume was observed. No adverse effects of radiation or new neurologic deficits were observed in either of the cases. In case 1, we observed a reduction in tumor volume from 69 to 20 mL at 6 months and a further reduction to 10.3 mL at 86 months. In case 2, we observed a reduction in tumor volume from 62 to 31 mL at 4 months with a further reduction to 22.5 mL at 30 months. The female patient (case 1) showed mild weakness in the right lower limb after the minimal surgical removal of tumor using the cortical approach. No additional neurologic deficits were observed after GKS. The young male patient (case 2) presented a complete recovery without any signs of headache at 3 months after GKS. Conclusions Based on this initial experience, it appears that GKS is an effective treatment for CNC and may be used for upfront management in cases of indolent clinical symptoms, even when the tumor is very large.

Decompressive hemicraniectomy (DC) can save the lives of patients with malignant middle cerebral artery (MCA) infarction. We proposed that postoperative midline shift is important for the long-term outcome of patients with MCA infarction. We conducted a retrospective study of DC in 38 patients with malignant MCA infarction. The long-term outcome was assessed one year after surgery using the modified Rankin Scale (mRS) score. Patients who had midline shift less than the optimal diagnostic cut-off point on the fourth postoperative day were classified as having a successful decompression and the remaining patients were classified in the failed decompression group. The successful decompression group mRS score was 4.20±0.89 one year after surgery and the failed decompression group mRS score was 5.11±0.76 (p

BACKGROUND Mandibular bone fracture associated with traumatic cervical subluxation is a rare injury. The diagnosis of a traumatic cervical subluxation is more easily delayed than other conditions in patients with mandibular bone fractures. The aim of this study is to investigate the incidence of traumatic cervical subluxation associated with mandibular bone fractures. METHODS This is a retrospective cohort study of 653 consecutive emergency department patients with mandibular bone fractures investigated for evidence of concomitant traumatic cervical subluxation. RESULTS This study reports on 7 patients (1.07%) with a diagnosis of traumatic cervical subluxation from a cohort of 653 with mandibular bone fractures as a result of motor vehicle accidents. Two of seven patients had their diagnosis made while in the emergency room, thus, 71.43% of these injuries were discovered on studies done up to 10 days after the trauma, including after surgical correction of the mandibular bone fracture. CONCLUSION The importance of a thorough initial examination (both physical and radiologic) and suspicion of traumatic cervical subluxation in patients with mandibular bone fractures is worth emphasizing as delayed diagnosis and management could result in permanent neurologic injury. We suggest dynamic flexion-extension cervical radiographs and thin-slice computerized tomography scans in patients with mandibular fractures routine as an important and routine practice protocol.

Purpose To measure wall shear stress (WSS) in the common carotid arteries (CCA) of a spontaneously hypertensive rat (SHR) model and a normotensive Wistar Kyoto rat (WKY) model by 2D phase-contrast magnetic resonance imaging (PC-MRI). Materials and methods PC-MRI was performed on 7 SHR and 7 WKY at ages of 4 and 7 months at a 7 T scanner. Images in the middle CCA (CCA mid ) and in the bifurcation of CCA (CCA bifur ) were acquired. The WSS values for differentiating characteristics between two models were calculated. Further, its location-specific change, regional distribution along the CCA circumference, and the reproducibility were evaluated. Results In the 4-month-old rats, SHR showed lower temporal averaged WSS (WSS avg ) and peak systolic WSS (WSS s ) in the CCA bifur in comparison with WKY (WSS avg : 0.95 ± 0.18 vs. 1.30 ± 0.36 N/m 2 ( P s : 1.68 ± 0.70 vs. 3.22 ± 2.49 N/m 2 ( P avg was lower in the CCA bifur than in the CCA mid . The regional distribution of WSS avg along the circumference of CCA showed lower values in WKY, particularly in posterior segments of CCA bifur . The intra-observer, intra-scan and inter-scan reproducibility was acceptable and the disagreements were ranged from − 0.05 to 0.06 N/m 2 . Conclusion This study evaluated WSS in SHR and WKY models by 2D PC-MRI. High reproducibility analyses further indicated the reliability of measurements of WSS in the CCA of SHR and WKY models using PC-MRI at 7 T.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and the prognosis of patients afflicted with GBM has been dismal, exhibiting progressive neurologic impairment and imminent death. Even with the most active regimens currently available, chemotherapy achieves only modest improvement in the overall survival. New chemotherapeutic agents and novel approaches to therapy are required for improving clinical outcomes. In this study, we used an electrospinning technique and developed biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes that facilitated a sustained release of carmustine (or bis-chloroethylnitrosourea, BCNU), irinotecan, and cisplatin. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the nanofibrous membranes. The experimental results showed that the biodegradable, nanofibrous membranes released high concentrations of BCNU, irinotecan, and cisplatin for more than 8 weeks in the cerebral cavity of rats. A histological examination revealed progressive atrophy of the brain tissues without inflammatory reactions. Biodegradable drug-eluting nanofibrous membranes may facilitate sustained delivery of various and concurrent chemotherapeutic agents in the cerebral cavity, enhancing the therapeutic efficacy of GBM treatment and preventing toxic effects resulting from the systemic administration of chemotherapeutic agents.

Introduction: Chronic hydrocephalus is a common complication that can occur after aneurysmal subarachnoid haemorrhage (SAH). The purpose of this study was to investigate clinical risk factors that could predict the occurrence of shunt-dependent chronic hydrocephalus after aneurysmal SAH. Methods: Eighty-eight consecutive patients who underwent either surgery or transarterial endovascular embolization as a treatment for cerebral aneurysm within 72 h -after experiencing SAH from March 2005 to July 2006 were studied retrospectively to assess the risk factors that might predict shunt-dependent chronic hydrocephalus. Clinical and demographic factors were examined, including age, sex, initial admission mean arterial blood pressure (MABP), blood sugar level at admission, fever frequency, initial external ventricular drainage (EVD), Fisher grade, Hunt and Hess grade, intraventricular haemorrhage (IVH) and treatment methods to define predictors of shunt-dependent hydrocephalus. The length of hospital stay and modified Rankin scale recorded 6 months after SAH were also evaluated; these parameters were compared between the shunt-dependent and non-shunt-dependent groups. Results: Of the 88 patients, 22 (25%) underwent shunt placement to treat their chronic hydrocephalus. The average length of hospital stay was 33.9 days for the shunt-treated group and 14 days for the non-shunt-treated group. The non-shunt-treated group scored an average of 1.05 on the modified Rankin scale compared with 2.77 for the shunt-treated group. A univariate analysis revealed that several admission variables were associated with long-term shunt-dependent hydrocephalus: (1) increased age (p = 0.023); (2) initial admission MABP (p = 0.027); (3) a high Fisher grade (p = 0.031); (4) a poor admission Hunt and Hess grade (p = 0.030); (5) the presence of IVH (p = 0.029), and (6) initial EVD (p < 0.0001). The factor most commonly associated with shunt-dependent hydrocephalus over the course of hospital days was fever frequency (p < 0.0001). Conclusions: Chronic hydrocephalus after aneurysmal SAH has a multifactorial aetiology. Understanding the risk factors that predict the occurrence of chronic hydrocephalus may help neurosurgeons to expedite permanent cerebrospinal fluid diversion, which could decrease both the cost and length of hospital stay and prevent further complications.

Comparing a prospective group of 32 patients, who underwent percutaneous vertebroplasty (PVP) and who were treated with teriparatide for at least 18 months after a new-onset adjacent vertebral compression fracture (VCF), and compared it with a retrospective group of 33 patients, who received antiresorptive agents combined with repeated PVPs for post-PVP new-onset adjacent VCFs.This comparative study aimed to assess the immediate and mid-term efficacy and safety of teriparatide for treating new adjacent VCFs after vertebroplasty.Vertebroplasty may provoke fractures in adjacent, nonaugmented vertebrae. Subsequent VCFs can occur much sooner and more frequently after PVPs. Antiresorptive agents do not effectively prevent new-onset VCFs or prompt pain relief. Treatment with teriparatide is effective and rapid in increasing spinal bone mineral density (BMD) and in decreasing vertebral fracture risk in patients with osteoporosis.Relevant clinical data were compared between a prospective group of patients who received teriparatide and a retrospective group of patients who received antiresorptive agents and repeated PVPs for new-onset adjacent VCFs after PVP.Data in prospective group, including visual analogue scale scores and BMD were compared with those in a retrospective group. In group A, only 1 new-onset VCF occurred during the mean follow-up period of 22.56 months. In group B, 5 patients (6 vertebrae) developed new-onset VCFs after the second PVP, and 2 of these 5 patients had additional new VCFs after the third PVP. Teriparatide significantly reduced the risk of new VCFs after vertebroplasty (odds ratio=0.18; 95% confidence interval, 0.02-1.64). The increase of lumbar spine BMD was 26.32% after 18 months of treatment with teriparatide and 4.62% after 18 months of treatment with antiresorptive agents. In addition, at the 18-month follow-up, mean visual analogue scale scores had decreased from 8.03±1.97-1.37±0.52 in the teriparatide group and from 7.91±1.95-4.23±1.21 in the antiresorptive group.For the treatment of new-onset adjacent VCF after PVPs, the therapeutic effects of teriparatide is better than that of the combined vertebroplasty and an antiresorptive agent in fracture prevention, BMD change, and sustained pain relief.

The accessory middle cerebral artery can provide collateral blood supply in moyamoya disease. We report a case of unilateral moyamoya disease which demonstrates the anatomy of the right accessory middle cerebral artery and a ruptured peripheral aneurysm on the artery. Our patient was a 56-year-old woman who initially suffered from headache and lethargy. Right caudate nucleus hemorrhage with intraventricular extension and spontaneous subarachnoid hemorrhage were found on brain computed tomography. A ruptured peripheral accessory middle cerebral artery aneurysm associated with unilateral moyamoya disease was diagnosed on cerebral angiography. Surgical intervention to excise the peripheral accessory middle cerebral artery aneurysm assisted by frameless navigation guidance to reduce the risk of damage to collateral vessels was done successfully. Histopathology of excised tissue showed this anomaly was a pseudoaneurysm. The management of an aneurysm in moyamoya disease should be modified based on its location and collateral vessels. Prevention of aneurysm bleeding and preservation of collateral vessels during craniotomy are the critical when managing hemorrhagic moyamoya disease. This case suggests that surgical intervention for ruptured intracranial aneurysms is safe with the use of frameless navigation guidance to minimize collateral vessel injuries.

Spinal metastatic tumor is a common problem and represents a challenging problem in oncology practice. Patients with osteolytic metastases often suffer from intractable local and/or radicular pain. Percutaneous vertebroplasty is a minimally invasive, radiologically guided procedure whereby bone cement is injected into structurally weakened vertebrae to provide immediate biomechanical stability. Vertebroplasty is also used to relieve pain by stabilizing metastatically compromised vertebrae that are at risk of pathological burst fracture. In this retrospective study, a total of 57 patients (78 vertebrae) with spinal metastatic tumor were treated with PMMA vertebroplasty. The mean value of the visual analogue scale (VAS) was 8.1 +/- 0.67 preoperatively, and significantly decreased to 3.8 +/- 1.9 (1-8, p < 0.015) one day after vertebroplasty. The mean VAS value 6 months after vertebroplsty was 2.8 +/- 2.0 (p < 0.001). Mean injected bone cement amount in our study is 5.16 +/- 1.6 mL. The complication rate is about 21.8%, bone cement extravasation without neurological deficit is the most common complication. No new or adjacent vertebral fracture has occurred in more than 2 years follow-up. Percutaneous vertebroplasty is a minimally invasive procedure that offers a remarkable advantage of effective and immediate pain relief with few complications.

Massive epistaxis following blunt craniofacial trauma should alert clinicians to possible traumatic internal carotid artery (ICA) aneurysm. This article describes a case of a 46-year-old female patient with traumatic ICA pseudoaneurysm presenting similar to a sphenoid sinus mass lesion. Massive bleeding occurred during the endoscopic procedure. Brain angiography revealed two lobulated ICA pseudoaneurysms over a cavernous segment. The patient successfully underwent endovascular stent assisted coil embolization. Timely diagnosis and treatment of the ICA psuedoaneurysm produced a favourable outcome.

Optimally, internal carotid artery (ICA) injury associated with craniofacial trauma should be treated soon after diagnosis. However, diagnosis is difficult and often delayed. The typical symptoms and signs for diagnosis of traumatic ICA injuries are sometimes easily neglected. Clinically, some patients were initially diagnosed by craniofacial fracture nearby the course of ICA. This investigation retrospectively reviews clinical experience in patients with traumatic ICA injury with a focus on the importance of craniofacial fracture nearby the course of ICA observed on brain or facial bone computed tomography. Eighteen patients with traumatic ICA injury were diagnosed at Chang Gung Memorial Hospital, Taiwan, from June 1998 to April 2004, including 10 patients with pseudoaneurysm formation, seven patients with occlusion, and one patient with laceration. Brain or facial bone computed tomography was reviewed retrospectively. The sample included 14 (78%) patients with skull base fractures involving the intracranial course of ICA and three (17%) patients with mandibular and cervical spine fractures near the course of extracranial ICA. Only one (5%) patient did not have evident fracture. Fractures involving the carotid canal were noted in three (17%) patients. Eight patients received interventional treatments. No further interventional treatments for traumatic ICA occlusion were performed as a result of good collateral flow from contralateral ICA or large infarction noted when diagnosed. Three patients with pseudoaneurysm received expectant management. One patient with arterial laceration with extravasation received no further management. Through meticulously evaluating routine brain and facial bone computed tomography, craniofacial fracture involving intracranial or extracranial course of ICA may be an adjuvant indicator of traumatic ICA injury for early diagnosis.

Background: Traumatic aneurysms of the anterior cerebral artery (ACA) were retrospectively reviewed in an effort to identify patients at high risk of ACA aneurysm. Methods: Blunt craniofacial trauma patients featuring vascular injuries over the region of the ACA were studied. Results: Six patients featuring eight ACA aneurysms were diagnosed between June 1992 and December 2005, inclusively. Seven aneurysms were located at nonbranched sites and one was located over the right ACA-anterior communicating artery junction. One patient died immediately of massive intracranial lobar hemorrhage (ICH). The other 5 patients experienced rebleeding during a period of from 1 to 29 days. Brain computed tomography revealed subarachnoid hemorrhage (SAH) in 1 of these 6 patients, ICH over the medial frontal area or cingulated gyrus in 4 patients, intraventricular hemorrhage (IVH) in 3 patients, and an interhemispheric subdural hematoma (SDH) in 2 patients. Conclusion: Delayed-onset deterioration of neurological deficit is the most common clinical presentation of traumatic ACA aneurysms. Midline hemorrhage such as medial frontal hemorrhage or cingulate gyrus hemorrhage, and the presence of an interhemispheric SDH associated with SAH and IVH subsequent to blunt craniofacial trauma should be further evaluated, as they pre-sent a high risk of traumatic ACA aneurysms to patients.

Background: Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg) in rats, but the mechanism is still unclear. Results: Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF) in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3) in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg) in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats. Conclusions: Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.