Chun Lin Liu

Adjuvant Immunotherapy with Whole-Cell Lysate Dendritic Cells Vaccine for Glioblastoma Multiforme: A Phase II Clinical Trial

BACKGROUND This study sought to evaluate effectiveness of autologous dendritic cell vaccine (immunotherapy) for glioblastoma multiforme (GBM). METHODS Patients 14 to 70 years of age with newly diagnosed GBM and Karnofsky Performance Scale (KPS) score >70 who were receiving initial treatment were enrolled and were randomized into 2 groups during the 5-year study period. Eighteen patients underwent conventional treatment (surgery, radiotherapy, and chemotherapy) and received adjuvant autologous dendritic cell vaccine, and 16 patients (control group) underwent conventional treatment only. Administration of the vaccine was begun within 1 to 2 months postoperatively, with 10 inoculations given over 6 months. Outcome measures were overall survival (OS); progression-free survival (PFS); 1-, 2-, and 3-year survival rates, and quality of life (QoL). RESULTS Follow-up time ranged from 14 to 56 months (median, 33 months). The 1-, 2-, and 3-year survival rates were 88.9%, 44.4%, and 16.7% for the vaccine group, respectively, and 75.0%, 18.8%, and 0%, respectively, for the control group, (P = 0.299, 0.0035, 0.0014, respectively). The median OS for the vaccine group was 31.9 months and for the control group was 15.0 months (P < 0.002). The median progression-free survival (PFS) for the vaccine group was 8.5 months, and 8.0 months for the control group (P = 0.075). The surviving fraction was significantly higher in the vaccine group based on Kaplan-Meier analysis. CONCLUSIONS Adjuvant immunotherapy with whole-cell lysate dendritic cell vaccine may improve short-term survival. It seems to be safe, and its long-term effectiveness is worthy of further investigation.

Targeting cancer stem cells for treatment of glioblastoma multiforme

Cancer stem cells (CSCs) in glioblastoma multiforme (GBM) are radioresistant and chemoresistant, which eventually results in tumor recurrence. Targeting CSCs for treatment is the most crucial issue. There are five methods for targeting the CSCs of GBM. One is to develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitizer to enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing gene therapy may be helpful. New therapeutic agents for targeting a signal pathway, such as epidermal growth factor (EGF) and vascular epidermal growth factor (VEGF) or protein kinase inhibitors, have been used for GBM but for CSCs the effects still require further evaluation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase-2 (Cox-2) inhibitors have proven to be effective for increasing radiation sensitivity of CSCs in culture. Autologous dendritic cells (DCs) are one of the promising immunotherapeutic agents in clinical trials and may provide another innovative method for eradication of CSCs. Bone-morphogenetic protein 4 (BMP4) is an agent used to induce CSCs to differentiate into normal glial cells. Research on gene therapy by viral vector is also being carried out in clinical trials. Targeting CSCs by eliminating the GBM tumor may provide an innovative way to reduce tumor recurrence by providing a synergistic effect with conventional treatment. The combination of conventional surgery, chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising treatment for reducing GBM recurrence and improving the survival rate.

Endoscopic Surgery for Intraventricular Hemorrhage (IVH) Caused by Thalamic Hemorrhage: Comparisons of Endoscopic Surgery and External Ventricular Drainage (EVD) Surgery

BACKGROUND Intraventricular hemorrhage (IVH) caused by thalamic hemorrhage has high mortality and morbidity. The aim of this study was to investigate the efficacy and the results of endoscopic surgery for the evacuation of IVH caused by thalamic hemorrhage compared with that of external ventricular drainage (EVD) surgery. METHODS From January 2006 to December 2008, 48 patients with IVH caused by thalamic hemorrhage were enrolled and treated in our department. Patients with IVH caused by thalamic hemorrhage who also resulted in acute hydrocephalus were indicated for surgery; the patients who were included were randomly divided into an EVD group and an endoscopic surgery group. The clinical evaluation data included the Glasgow Coma Scale, length of intensive care unit (ICU) stay, age, intracerebral hemorrhage volume, and severity of IVH. Outcome was measured using the 30-day and 90-day mortality rate, ventriculoperitoneal (VP) shunt dependent rate, and Glasgow Outcome Scale after three months. RESULTS The clinical features of the 24 patients in each group showed no significant differences in age or Glasgow Coma Scale assessment on admission. There was also no significant difference in intracerebral hemorrhage volume or Graeb score between the endoscopic group and the EVD group. The length of ICU stay was 11 ± 5 days in the endoscopic surgery group and 18 ± 7 days in the EVD group. The endoscopic surgery group had a shorter ICU stay (P = 0.04) compared with the EVD group. The 30-day and 90-day mortality rates were 12.5% and 20.8% in the endoscopic surgery group and 12.5% and 16.6% in the EVD group, respectively. The mean Glasgow Outcome Scale score was 3.08 ± 1.38 in the endoscopic surgery group and 3.33 ± 1.40 in the EVD group. Outcome significantly correlated with initial consciousness level; the severity of IVH did not influence the outcome in all of the cases. There was no significant difference in mortality rate or outcome between the endoscopic group and the EVD group. The VP shunt rates were 47.62% in the endoscopic surgery group and 90.48% in the EVD group. Endoscopic surgery group had a significant lower VP shunt rate (P = 0.002; odds rate = 9.8) compared with the EVD group. CONCLUSIONS Endoscopic surgery was found to have significantly lower shunt-dependent hydrocephalus, and the ICU stay was shorter compared with EVD surgery. This can decrease the need for permanent VP shunts in patients with IVH caused by thalamic hemorrhage.

Matrix metalloproteinase-9 in the ventricular cerebrospinal fluid correlated with the prognosis of traumatic brain injury.

AIM Matrix metalloproteinase 9 (MMP-9) has been shown to be a potential biomarker for outcome prediction after neuron damage. This study investigated whether MMP-9 could be used for outcome prediction after traumatic brain injury (TBI). MATERIAL AND METHODS For the TBI group, cerebrospinal fluid (CSF) was collected at different days after surgery from 6 head injury patients who had received surgical intervention with external ventricular drainage insertion. CSF collected from non-TBI patients (N=85) diagnosed with isolated hydrocephalus by a ventricular puncture during a ventriculo-peritoneal shunt surgery was used as control. RESULTS The mean concentration of MMP-9 in the CSF of 85 non-TBI patients was determined to be 1.172 ± 0.859 ng/mL. We found that the CSF MMP-9 concentration from TBI patients was elevated immediately after head injury with a median of 1.926 ng/mL (range, 0.673 to 24.990). Despite an early increase in the concentration of MMP-9, levels decreased within 72 hrs and nearly reached the normal range. Nevertheless, the concentration of MMP-9 was negatively correlated with the Glasgow Coma Scale (γ = - 0.337, p = 0.013). CONCLUSION MMP-9 concentration in the CSF of TBI patients correlated with neurological outcome and may represent an early indicator for the prognosis of this condition.

A newly developed endoscopic sheath for the removal of large putaminal hematomas

This report describes the removal of large putaminal hematomas using an endoscopic surgical technique with a 3 mL syringe barrel as a conduit. The 3 mL syringe barrel (outer diameter, 8mm) was used as an endoscopic sheath and a 14 F Foley catheter was modified as an endoscopic stylet. With the patient in the supine position, we used an entry point on the temporal scalp, ipsilateral to the hematoma. From January 2005 to January 2006, 25 patients with large putaminal hematomas underwent endoscopic surgery. The inclusion criteria for endoscopic surgery were: (i) putaminal hemorrhage with hematoma volume>40 mL; and (ii) a Glasgow Coma Scale (GCS) score of 3 to 12 with a focal neurological deficit. The exclusion criteria were: (i) a hemorrhage due to tumor, trauma, aneurysm, or arteriovenous malformation; (ii) non-putaminal hemorrhages; and (iii) coagulopathy. No surgical complications occurred. The time from the onset of symptoms to surgery ranged from 1 hour to 5 hours (median, 2 hours). Preoperative hematoma volumes ranged from 40 mL to 180 mL (median, 78 mL); postoperative hematoma volumes ranged from 2 mL to 16 mL (median, 6 mL). Therefore, 90 to 97% (median, 93%) of the hematoma was evacuated. The preoperative GCS scores ranged from 3 to 12 (median, 8); the postoperative GCS scores ranged from 6 to 15 (median, 12). The mortality rate was 16%; one year postoperatively, the mean Glasgow Outcome Scale score was 2.7. Thus, endoscopic removal of large putaminal hematomas is safe, effective, and minimally invasive. The new endoscopic sheath is inexpensive, disposable, and easy to use.

Multifocal osteolytic lesions of the skull: a primary cavernous hemangioma mimicking a neoplastic invasive lesion

Intraosseous cavernous hemangioma is a rare cause of osteolytic lesions of the skull, and its multifocal type is even more infrequent. This tumor is difficult to accurately diagnose by imaging and can be confused with osteolytic Langerhan’s cell histiocytosis or other neoplasms. Here we present a case of multifocal intraosseous cavernous hemangioma of the skull treated with surgical intervention in our hospital five years ago. A review of related literatures and case reports is also provided to help clarify the diagnosis and devise treatment regimens. In light of the difficulties of early diagnosis, early en bloc surgical removal is recommended.

s-Methyl cysteine enhanced survival of nerve growth factor differentiated PC12 cells under hypoxic conditions

A nerve growth factor-differentiated PC12 cell line was used to investigate the protective effects of s-methyl cysteine (SMC) at 1, 2, 4, and 8 μM under oxygen-glucose deprivation (OGD) conditions. OGD decreased the cell viability. However, SMC pre-treatments at 2, 4 and 8 μM improved the cell viability, decreased cleaved caspase-3 and Bax expression, and reserved Bcl-2 expression. Furthermore, SMC maintained the mitochondrial membrane potential, lowered the intracellular Ca(2+) concentration and DNA fragmentation, and decreased the activity and expression of caspase-3 and caspase-8. OGD increased the reactive oxygen species (ROS) and 3-nitrotyrosine production, decreased glutathione peroxide (GPX) and glutathione reductase (GR) activities and the expression, enhanced nitric oxide synthase (NOS) activity and inducible NOS (iNOS) expression. SMC pre-treatments at 2, 4 and 8 μM lowered the ROS and 3-nitrotyrosine formation, maintained GPX and GR activities and expression, and decreased NOS activity and iNOS expression. OGD up-regulated hypoxia-inducible factor (HIF)-1α, nuclear transcription factor kappa (NF-κ) B p50, NF-κB p65 and p-p38 expression. SMC pre-treatments at 1-8 μM lowered HIF-1α expression and decreased p38 phosphorylation. SMC at 2, 4 and 8 μM suppressed the protein expression of NF-κB p50 and NF-κB p65. When YC-1 (HIF-1α inhibitor), pyrrolidine dithiocarbamate (NF-κB inhibitor) or SB203580 (p38MAPK inhibitor) were used to block the activation of HIF-1α, NF-κB and p38, SMC pre-treatments did not affect the protein expression of HIF-1α, NF-κB and p-p38. These results indicated that SMC was a potent neuro-protective agent.

Rhabdomyolysis accompanied by spontaneous spinal subdural and subarachnoid hematoma related to amphetamine abuse.

Study Design. Case report. Objective. To describe the rare case of a patient presenting with rhabdomyolysis accompanied by spontaneous spinal subdural hematoma (SDH) and subarachnoid hematoma (SAH), presumably caused by amphetamine abuse. Summary of Background Data. Spontaneous SDH accompanied by SAH is an extremely rare condition. To date, only one case describing spinal SAH related to amphetamine abuse has been reported. Methods. A 41-year-old man who had a history of amphetamine abuse presented with severe frank pain and lower limb numbness with incomplete paraplegia. Urinary incontinence was subsequently noted. Thoracic-spine magnetic resonance imaging revealed SDHs in the dorsal aspect of the middle thoracic level and along the anterior part of the thecal sac, as well as SAH in the T11–T12 level. Diffuse paraspinal hyperintensity was detected, indicating rhabdomyolysis (creatine phosphokinase levels were also abnormally elevated). Results. The patient responded well to decompression surgical treatment and has since then exhibited no neurologic deficits. Conclusion. We have described a novel case of spinal SDH with SAH. The possible underlying cause of amphetamine abuse is discussed.

Head-to-head comparisons of bisphosphonates and teriparatide in osteoporosis: a meta-analysis.

PURPOSE This meta-analysis aimed to compare the efficacy and safety of teriparatide vs. bisphosphonates in the management of osteoporosis. METHODS A total of 1,967 patients from eight randomized controlled trials were analyzed; outcomes included bone mineral density (BMD) of the femoral neck, total hip and lumbar spine, vertebral and nonvertebral fractures and any adverse event. A subgroup analysis of treatment effectiveness was performed according to the etiology of osteoporosis; i.e., glucocorticoid-induced osteoporosis (GIO) vs. post-menopausal osteoporosis (PO). RESULTS Teriparatide increased the BMD of the lumbar spine, femoral neck and total hip to a greater extent than bisphosphonates. Patients treated with teriparatide also had a lower risk of vertebral fractures compared with bisphosphonates; however, no difference in risk of nonvertebral fractures (or adverse events) was found. GIO subgroups showed larger increases in BMD of the lumbar spine, total hip and femoral neck in patients treated with teriparatide compared with bisphosphonates. The PO subgroup showed larger increases in BMD of the lumbar spine in patients treated with teriparatide compared with bisphosphonates. Patients in the GIO subgroup (but not the PO subgroup) were less likely to suffer a vertebral fracture on teriparatide as compared with bisphosphonates. In contrast, no significant difference in the percentage of nonvertebral fractures was noted between the two types of treatment for either subgroup. CONCLUSION Teriparatide significantly increased the BMD of lumbar spine, total hip and femoral neck, particularly in GIO-induced osteoporosis. Teriparatide did not lower the risk of nonvertebral fractures when compared with bisphosphonates.

Single-port endoscopic removal of intraventricular central neurocytoma

Central neurocytoma is a rare benign intraventricular tumor which occurs in young adults. Craniotomy with tumor removal is associated with relatively high rates of morbidity and mortality. To improve the efficiency of endoscopic surgery for removal of this tumor, we used a polypropylene tube combined with a working channel endoscope. From January 2006 to October 2008, three patients with intraventricular central neurocytoma with acute hydrocephalus were treated by endoscopic surgery in our hospital. The tumor was almost totally removed. At 6-month follow-up no recurrence was found. One patient required a permanent ventriculoperitoneal shunt due to hydrocephalus during follow-up. We report that a working channel endoscope combined with a polypropylene endoscopic sheath facilitates the removal of intraventricular central neurocytoma. Endoscopic neurosurgery is a safe method for removing a central neurocytoma with low risk of permanent neurological deficits.