Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen.</p><p><b>METHODS</b>A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS).</p><p><b>RESULTS</b>The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively.</p><p><b>CONCLUSIONS</b>Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results.</p>

An intervention study of differential expressions of miRNA-21 in rats with traumatic brain injury / 中华神经医学杂志

Objective To evaluate the dynamic changes ofmiRNA-21 expression in injured brain tissues of rats with traumatic brain injury (TBI),and explore the effect of ectogenic miRNA-21 on neuronal apoptosis of the rats and their neurological functions.Methods Eighty-four rats were randomly divided into sham-operated group,TBI model group,blank-intervention group and miRNA-21-intervention group (n=21).Rats in the sham-operated group were only performed scalp incision and window bone removal without beating,and those in the other three groups were performed beating to induce TBI models; liposomes with/without miRNA-21 were injected into the latter two groups.Several time points after the brain injury/intervention:12,24,48 and 72 h,and 1 and 2 weeks,respectively,were chosen to measure the neurological functions using Modified Neurological Severity Scale (mNSS) and footfault test.Then,the animals were sacrificed to observe the miRNA-21 expression levels by using quantitative real-time-PCR and to examine the neuronal apoptosis in rat cerebral corticesby TUNEL.Results The miRNA-21 expression began to obviously increase in injured brain tissues at 2 h after TBI,peaked at 48 h after TBI in the cerebral cortices; the miRNA-21 expression level was still higher than that in the sham-operated group 7 d after TBI (P＜0.05); the miRNA-21 expression level was higher than that in the TBI model group and blank-intervention group at 24,48 and 72 h after TBI (P＜0.05).Began with 24 h of TBI,mNSS showed that the scores of miRNA-21-intervenion group were significantly lower than those in the TBI model group and blank-intervention (P＜0.05).TUNEL indicated that the count of apoptotic cells in the traumatic area of miRNA-21-intervenion group was significantly smaller than that in the TBI model group (P＜0.05) Conclusion MiRNA-21 may be involved in the process of recovery after traumatic brain injury to inhibit the apoptosis in the traumatic area.

Construction of an adenoviral vector containing mouse Hes1 gene and its expression in the hippocampus of adult mice / 中华神经医学杂志

Objective To construct an adenoviral vector containing mouse Hes1 gene, observe its expression in the hippocampus of adult mice and build a basis for further investigation of Hes1 gene in adult neurogenesis. Methods The restriction endonuclease was used to digest plasmid pEGFP-mHes1 and pDC316, and then, the products were recovered and connected by T4 DNA ligase and the shuttle plasmid pDC316-mHes1 was constructed which was identified by the method of PCR and EcoRI+HindⅢ digestion. After that, the shuttle plasmid pDC316-mHes1 was cotransfected into 293 cells with the adenovirus skeleton plasmid pBHGlox_E1,3Cre to obtain the produced replication defective recombinant adenovirus Ad5-mHes1. Then, the recombinant adenovirus could be further amplified and purified. The report recombinant adenoviruses were Ad5-EGFP containing enhanced green fluorescent protein (EGFP).Then, Ad5-mHes1 and Ad5-EGFP were stereotactic injected into the hippocampus of the adult C57BL/6 mice and their expressions in the hippocampus were detected. Western blotting was used to detect the Hes1 protein level 7 d after the injection. Fluorescent microscopy was used to observe the expression of EGFP in the hippocampus. Results The experimental results of identification by the methods of PCR and EcoRI+HindⅢ digestion were in accordance with the anticipated results, and the sequences were also the same with mHeslCDS sequences; Hes1 gene was expressed in the hippocampus of both the PBS injection group and the Ad5-mHes1 injection group 7 d after the injection, and the expression of Hes1/GAPDH in Ad5-mHes1 injection hippocampus (0.705 ±0.128) was statistically different as compared with that in PBS injection group (0.363±0.053, P＜0.05). Ad5-EGFP strongly expressed in the granular cell layer and subgranular zone (SGZ) of dentate gyrus. Conclusion The adenoviral vector of mouse Hes1 gene is successfully established and Hes1 gene is expressed in the hippocampus of C57BL/6 adult mice.

Expressions of nucleostemin and Ki-67 in pituitary adenomas and their clinical significance / 中华神经医学杂志

Objective To study the expressions of nucleostemin gene mRNA and Ki-67antigen in pituitary adenomas and investigate the role of nucleostemin gene in the tumorigenesis and development of pituitary adenomas. Methods Seventy-one samples of pituitary adenomas were collected. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of nucleostemin gene mRNA in samples. Immunohistochemistry technique was applied to examine Ki-67 antigen expression in the paraffin sections of samples. At the same time,coherent clinical data were collected. Results Nucleostemin gene mRNA was detectable in all samples of pituitary adenomas. Between invasive and noninvasive pituitary adenomas, the difference of nucleostemin expression was extremely significant (P＜0.01), and Ki-67 labeling index (LI) was also significantly different (P＜0.05). The difference of Ki-67LI between recurrent and non-recurrent groups was significant (P＜0.05). There was a positive correlation between nucleostemin gene and Ki-67LIlevels (r=0.237, P＜0.05). Conclusions Nucleostemin gene plays an important roles in the invasion of human pituitary adenoma. Expression of nucleostemin gene is positively related to Ki-67 antigen expression, and both may be the valid clinical detection markers for assessing proliferation, invasion and recurrence of pituitary adenomas.

Expression of hepatocyte growth factor in the brain tissue of rats following traumatic brain injury / 中华神经医学杂志

Objective To study the temporal expression pattern of hepatocyte growth factor (HGF) in the brain tissue of rats after traumatic brain injury (TBI) and provide evidence for HGF-targeted interventions for TBI. Methods Ninety-six Wistar rats were randomly divided into 8 groups including a sham-operated group and 7 TBI groups (n=12) examined at 2, 6, 12, 24, 72, 168 and 336 h after to fluid percussion injury of the brain. Each group was randomized into two subgroups (n=6), one for examining HGF expression and neuropathological changes in the brain with immunohistochemistry and HE staining, and the other for detecting the expression of HGF mRNA using RT-PCR. Results HGF expression increased at both the protein and mRNA levels after TBI. The number of HGF-positive cells began to increase on the margin of the injured area 24 h after the injury till reaching the peak level at 168 h. At 336 h after the injury, the number of HGF-positive cells declined but still maintained a high level. The expression of HGF mRNA began to increase 72 h after injury and reached the peak level at 168 h. Conclusion As a neurotrophic factor and an angiogenic factor, HGF may contribute to neuronal protection and nerve tissue repair and regeneration after TBI.

Development of glioblastoma mutiforme in situ following the surgery on a patient with cerebral trauma: case report and literature review / 中华神经医学杂志

Objective To discuss the etiological relationship between brain trauma and glioma.Methods A case of post-traumatic glioblastoma was reported with regard to his clinical manifestations,imaging features and pathological characteristics, and the related literatures were present. Results This case is consistent with the criteria on the glioblastoma mutiforme following cerebral trauma in literatures.Conclusion The development of a brain tumour following a cortical injury is possible, although rare. The presupposition for the development of a glioma following brain trauma is a predisposing genetic alteration of brain cells.

Stereotactic combined amygdala and hippocampus lesions for treatment of medial temporal lobe epilepsy / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the techniques of stereotactic combined amygdalohippocampotomy for management of medial temporal lobe epilepsy (MTLE).</p><p><b>METHODS</b>The Leksell stereotactic frame was used for all cases, and which almost paralleled the long axis of hippocampus. Stereotactic amygdalohippocampotomy was performed in 23 patients with unilateral medial temporal lobe seizures by using magnetic resonance imaging (MRI) localization for target planning, depth electrode for the electroencephalogram (EEG) monitoring and radiofrequency techniques for lesion production. All procedures were completed under local anesthesia.</p><p><b>RESULTS</b>Pre-lesion spikes or polyspike-waves complex were recorded by a depth electrode in the amygdala and hippocampus region in all patients, and the epileptiform discharges disappeared after the amygdalohippocampotomy. The MRI appearance of the lesion areas after 1 - 2 weeks surgical operation showed that mutiple areas of coagulation necrosis corresponding to the lesion sites were surrounded by zones of edema. Twenty-three patients were followed-up to 8 - 32 months with seizure free 43.48% (10/23), and the general efficiency (seizure reduction >or= 50%) was 91.30% (21/23 cases).</p><p><b>CONCLUSIONS</b>Stereotactic combined lesions of unilateral amygdala and hippocampus for minimally invasive treatment of MTLE is safe and effective, and it is worth to spread in clinical application.</p>

Minimally-invasive surgical treatment of cervical radiculomyelopathy / 中华外科杂志

<p><b>OBJECTIVE</b>To discuss the effect of the posterior minimally-invasive surgical treatment of root type cervical spondylotic myelopathy.</p><p><b>METHODS</b>A posterior minimally-invasive operation was given to 32 nerve root type cervical spondylotic myelopathy patients, and the clinical result was followed.</p><p><b>RESULTS</b>An operation of enlargement of intervertebral foramen and disc excision was given for 14 young patients whose ligamentum flavum incrassated a little and the disc was soft. An operation of enlargement of intervertebral foramen only was given for 18 old patients whose ligamentum flavum incrassated much with ossification, and the disc was tenacious. All the patients' sign of nerve root was improved after operation. Twenty-eight patients were followed up 3 to 16 months, and there were no obstacle of neck movement and recurrence of clinical sign.</p><p><b>CONCLUSION</b>This method for the posterior minimally-invasive neurosurgical operations of cervical spondylotic myelopathy is safe, simple and effective. By this operation, we can removal most of the herniative cervical disk and decompression for the nerve root and get good stable of spondylopathy.</p>

The protective effect of p53 antisense oligonucleotide against neuron apoptosis secondary to traumatic brain injury / 中华外科杂志

<p><b>OBJECTIVE</b>To observe the phenomenon of delayed neuron death secondary to traumatic brain injury, and the protective effect of p53 antisense oligonucleotide against neuron apoptosis secondary to traumatic brain injury.</p><p><b>METHODS</b>This study was based on the rat diffuse brain trauma model established by a simple weight-drop device. The behavior scales of neural function of rats and TUNEL that examined the injury extent of DNA in the cortex were used as a general assessment of brain injury. Electron microscope was used to observe the histological and cellular morphology. mRNA and protein expression of p53 were detected by in situ hybridization and immunohistochemistry. In this model, the therapeutic effect of p53 antisense drug were observed.</p><p><b>RESULTS</b>Following trauma, the behavior scores of rats decreased rapidly and remarkably. Apoptotic neurons appeared in the traumatized cortex as early as 2 hours after impact, and peaked at 24 hours. As early as 2 hours after impact, p53 mRNA and p53 protein in the cortex were expressed increasingly.</p><p><b>CONCLUSION</b>Neural apoptosis plays an important role in delayed neuron death and is responsible for neural dysfunction following traumatic brain injury. So the inhibition of neural apoptisis would turn into a new therapic measure against delayed neuron death following traumatic brain injury.</p>

Human neuronal apoptosis secondary to traumatic brain injury and the regulative role of apoptosis-related genes / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To observe human neuronal apoptosis secondary to traumatic brain injury, and to elucidate its regulative mechanism and the change of expression of apoptosis-related genes.</p><p><b>METHODS</b>Specimens of brain were collected from cases of traumatic brain injury in humans. The histological and cellular morphology was examined by light and electron microscopy. The extent of DNA injury to cortical neurons was detected by using TUNEL. By in situ hybridisation and immunohistochemistry the mRNA changes and protein expression of Bcl-2, Bax, p53, and caspase 3 p20 subunit were observed.</p><p><b>RESULTS</b>Apoptotic neurons appeared following traumatic brain injury, peaked at 24 hours and lasted for 7 days. In normal brain tissue activated caspase 3 was rare, but a short time after trauma it became activated. The activity peaked at 20-28 hours and remained higher than normal for 5-7 days. There was no expression of Bcl-2 mRNA and Bcl-2 protein in normal brain tissue but 8 hours after injury their expression became evident and then increased, peaked at 2-3 days and remained higher than normal for 5-7 days. The primary expression of Bax-mRNA and Bax protein was high in normal brain tissue. At 20-28 hours they increased and remained high for 2-3 days; on the 7th days they returned to a normal level. In normal brain tissue, p53mRNA and P53 were minimally expressed. Increased expression was detected at the 8th hour, and decreased at 20-28 hours but still remained higher than normal on the 5th day.</p><p><b>CONCLUSIONS</b>Following traumatic injury to the human brain, apoptotic neurons appear around the focus of trauma. The mRNA and protein expression of Bcl-2, Bax and p53 and the activity of caspase 3 enzyme are increased.</p>

Changes of interleukin-1 beta, tumor necrosis factor alpha and interleukin-6 in brain and plasma after brain injury in rats / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To study the changes of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) levels in brain and plasma after brain injury and to assess the relationship between the cytokine levels and injury severity in rats.</p><p><b>METHODS</b>A total of 51 male Wistar rats, weighing 280-340 g, were anesthetized with chloral hydrate (400 mg/kg body weight) through intraperitoneal injection and fixed on a stereotaxic instrument. Severe brain injury was created in 16 rats (severe injury group) and moderate brain injury in 18 rats (moderate injury group) by a fluid percussion model, and cytokine levels of IL-1beta, TNFalpha and IL-6 were measured with biological assay. And sham operation was made on the other 17 rats (control group).</p><p><b>RESULTS</b>In the control group, the levels of IL-1beta, TNFalpha and IL-6 were hardly detected in the cortex of the rats, but in the ipsilateral cortex of the rats in both injury groups, they increased obviously at 8 hours after injury. The increasing degree of these cytokines had no significant difference between the two injury groups. The levels of IL-6 in the plasma of all the rats increased slightly, whereas the levels of IL-1beta and TNFalpha were undetectable.</p><p><b>CONCLUSIONS</b>The increase of IL-1beta, TNFalpha and IL-6 levels is closely related to brain injury. The increased cytokine levels in the central nervous system are not parallel to those in the peripheral blood. It suggests that inflammatory cytokines play important roles in the secondary neural damage after brain injury.</p>

The effects of GM1 and bFGF synergistically inducing adult rat bone marrow stromal cells to form neural progenitor cells and their differentiation / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the effects of GM1 on inducing adult rat bone marrow stromal cells (MSCs) to form neural progenitor cells and their differentiation.</p><p><b>METHODS</b>Purified MSCs were induced by different components of basic fibroblast growth factor (bFGF) alone, GM1 alone or combination of bFGF with GM1. After 3 days' incubation, fibronectin and collagen I were detected with immunocytochemistry, and nestin was detected with immunofluorescence. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and galactose cerebroside (GalC) were detected with immunocytochemistry after 7 days' incubation.</p><p><b>RESULTS</b>After induction with bFGF alone or combination of bFGF and GM1, some MSCs exhibited the phenotypes of neural progenitor cells, and then neurons and astrocytes. In these two groups, the positive cells for fibronectin and collagen I decreased markedly after 3 days' induction. At the same time, the positive cells for nestin increased markedly. After 7 days' induction, NSE and GFAP-positive cells increased significantly. Furthermore, the addition of bFGF and GM1 caused the maximal variation. However, addition of GM1 alone had no inductive effects.</p><p><b>CONCLUSIONS</b>Combination of bFGF with GM1 may synergistically promote the transformation of MSCs and differentiation into neurons and astrocyte-like cells. The results suggest a promising route for the application of MSCs.</p>

Complications induced by decompressive craniectomies after traumatic brain injury / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To find out the optimal approach to decompress externally the severe injured brain and to avoid possible complications caused by external decompression.</p><p><b>METHODS</b>68 patients who underwent external decompression after traumatic brain injury were admitted into Tianjin Medical University General Hospital for cranioplasty from 1995 to 2001. Complications were retrospectively investigated and analyzed in all patients. The findings were compared between the patients who accepted the decompressive craniectomy in our hospital and in local hospitals. chi(2)-test was employed for statistical analysis and complication evaluation.</p><p><b>RESULTS</b>Large craniectomy definitely caused some side effects to patients. Among various complications, several of them showed significantly high incidence (P<0.05) in patients who underwent the decompressive operation in local hospitals such as shunt-dependent hydrocephalous, subdural fluid collection, and CSF leakage from scalp incision. The rest of the complications had no remarkable difference (P<0.05) between the two groups including dilation or/and migration of lateral ventricle underlying the cranial defect, skin flap concavity, encephalomalacia of the decompressive area, seizure and infection.</p><p><b>CONCLUSIONS</b>To reduce the incidence of iatrogenic side effects, surgical craniectomy should be performed according to the strict indication and standard and any abuse should be avoided.</p>

Therapeutic effect of nimodipine on experimental brain injury / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To study the therapeutic effect of nimodipine on experimental brain injury.</p><p><b>METHODS</b>Experimental and control rabbits were subjected to a closed head injury. In one group nimodipine was given intravenously and the effect evaluated by electron microscopy, brain water content, calcium levels, transcranial Doppler, and intracranial pressure monitoring.</p><p><b>RESULTS</b>In rabbits treated with nimodipine the level of neuronal cytosolic free calcium was markedly decreased. There were less cellular damage and less spasm of the middle cerebral artery seen on electron microscopy. No difference regarding intracranial pressure changes between the two groups was noted.</p><p><b>CONCLUSIONS</b>Nimodipine has a protective action on brain injury by blocking a series of pathological reactions induced by neuronal calcium overload, and by reducing the spasm of brain vessels and improving cerebral blood flow.</p>