ARL2 overexpression inhibits glioma proliferation and tumorigenicity via down-regulating AXL.

BACKGROUND: Glioma is the most common primary brain tumor in adults with a poor prognosis. As a member of ARF subfamily GTPase, ARL2 plays a key role in regulating the dynamics of microtubules and mitochondrial functions. Recently, ARL2 has been identified as a prognostic and therapeutic target in a variety range of malignant tumors. However, the biological functional role of ARL2 in glioma still remains unknown. The aim of this study was to explore the expression and functional role of ARL2 in glioma. METHODS: In this study, we investigated the expression of ARL2 in glioma samples by using RT-PCR, immunohistochemistry and western blot. The correlation between ARL2 expression and the outcomes of glioma patients was evaluated with survival data from TCGA, CGGA and Rembrandt dataset. Lentiviral technique was used for ARL2 overexpression in U87 and U251 cells. CCK8 assay, colony formation assay, wound healing test, transwell invasion assay and in vivo subcutaneous xenograft model were performed to investigated the biological functions of ARL2. RESULTS: ARL2 expression was down-regulated in glioma, and was inversely associated with poor prognosis in glioma patients. Furthermore, exogenous ARL2 overexpression attenuated the growth and colony-formation abilities of glioma cells, as well as their migration and invasive capabilities. Moreover, elevated expression of ARL2 inhibited in vivo tumorigenicity of glioma cells. Mechanistically, ARL2 regulated AXL expression, which was known as an important functional regulator of proliferation and tumorigenicity in glioma cells. CONCLUSION: Our study suggests that ARL2 inhibits the proliferation, migration and tumorigenicity of glioma cells by regulating the expression of AXL and may conduct as a new prognostic and therapeutic target for glioma.

The efficacy and safety of various dose-dense regimens of temozolomide for recurrent high-grade glioma: a systematic review with meta-analysis.

The goal of this meta-analysis was to identify the temozolomide (TMZ) regimen with optimal efficacy and tolerance for treatment of recurrent high-grade glioma (HGG). The PubMed and EMBASE databases were searched from the earliest records to February 2015, which identified 33 studies with 1760 participants that met the inclusion criteria. The standard schedule and three most common dose-dense regimens of TMZ therapy for recurrent HGG were included in this meta-analysis. The schedule of 7 days on/7 days off for the treatment of grade IV gliomas was significantly superior to the standard regimen with respect to progression-free survival at 6 months (34.8 %; 95 % confidence interval (CI) 27.0-43.4 %) and 12 months (15.5 %; 95 % CI 10.7-21.8 %). For grade III gliomas, this regimen conveyed a significantly greater overall survival (OS) rate at 12 months (79.0 %; 95 % CI 56.2-91.7 %), as compared to the standard schedule. Also, the 21 days on/7 days off regimen had significantly longer OS rates at 6 months (73.6 %; 95 % CI 63.4-81.8 %) and 12 months (40.6 %; 95 % CI 32.6-48.6 %) than the standard regimen for grade IV gliomas. In addition, the standard schedule showed a significantly higher clinical benefit rate than the 7 days on/7 days off and 21 days on/7 days off regimens. However, the grade 3-4 toxicity rate of lymphopenia of the standard schedule was 76.5 % (95 % CI 45.5-92.7 %), which was the highest among the four regimens. Recurrent HGG patients receiving personalized treatment should be closely followed up, especially those with concurrent hematological diseases.

Does the existence of HCMV components predict poor prognosis in glioma?

Human cytomegalovirus (HCMV) has been associated with malignant gliomas. The objective of the present study was to further investigate the existence and prognostic value of HCMV components in gliomas. Using immunohistochemical staining, HCMV proteins IE1-72 and pp65 were examined in 67 glioma specimens of various histologic grades, in comparison to 6 -control brain tissue samples. The HCMV DNA was measured in both the tumor tissues and the peripheral blood of the patients, using nested PCR. Kaplan-Meier analysis and Cox proportional hazards models were used to analyzed the prognostic value of HCMV components in glioma tissues. IE1-72 was detected in 76.1% (51/67) of glioma tissues, and pp65 was detected in 65.7% (44/67) of glioma tissues. HCMV DNA was detected in 52.2% (35/67) of glioma tissues and 29.9% (20/67) of peripheral blood samples of glioma patients. These HCMV components were not detected in control brain tissue. However, the existence of HCMV components showed no significant correlation with the prognosis of glioma patients. Our results demonstrate that although HCMV proteins and nucleic acids are present in gliomas, they do not correlate with the prognosis. The role of HCMV in gliomas needs to be carefully interpreted.

Erythromycin pretreatment induces tolerance against focal cerebral ischemia through up-regulation of nNOS but not down-regulation of HIF-1α in rats.

The purpose of this study was to determine whether the antibiotic erythromycin induces tolerance against focal cerebral ischemia, and the possible underlying mechanism including the involvement of neuronal nitric oxide synthase (nNOS) and hypoxia-inducible factor-1α (HIF-1α). In rat focal cerebral ischemia models, we found that erythromycin preconditioning could significantly decrease the cerebral infarct volume and brain edema. Meanwhile, the neurological deficits from day 4 through 7 after surgery were also remarkably decreased after erythromycin preconditioning. Moreover, erythromycin preconditioning induced significantly increased nNOS levels and decreased HIF-1α levels in both mRNA and protein expression. This study for the first time indicated that erythromycin preconditioning could induce focal brain ischemic tolerance and attenuate brain injury of subsequent transient focal cerebral ischemia. The potential mechanism may be due to up-regulation of nNOS, but the HIF-1α system was not involved.

The unilateral occipital transtentorial approach for pineal region meningiomas: a report of 15 cases.

In the current study, we reviewed and re-evaluated the experiences of microsurgical management for pineal region meningiomas via the unilateral occipital transtentorial approach (Poppen's approach). Clinical data were obtained on 15 meningiomas of the pineal region, which underwent microsurgery via unilateral Poppen's approach from March 2009 to June 2012. These patients were hospitalized in our department; their data were collected and analyzed retrospectively. The tumors were removed via the right Poppen's approach in 12 cases and left Poppen's approach in 3 cases, and intraoperative external ventricular drainage was performed for hydrocephalus in 3 cases. As a result, gross total resection was achieved in 11 cases, near total resection in 3 cases and subtotal resection in 1 case. All resected tumors were pathologically confirmed. The postoperative complications included two cases of homonymous hemianopia, and deteriorated Parinaud syndrome and diplopia in one case. Ten cases were followed up (range 1-4 years) and no death occurred. On the basis of the existing literature and our experiences, the unilateral Poppen's approach is appropriate for most meningiomas of the pineal region that are small or intermediate in size. However, gross total resection might be difficult via the unilateral Poppen's approach for large-sized meningiomas with much contralateral infratentorial extension due to limited exposure. For these cases, combined supra-infratentorial or bilateral Poppen's approaches are recommended. Preoperative or intraoperative external ventricular drainage can increase tumor exposure and improve microsurgical effects.

Microsurgical management of bronchogenic cysts in the thalamus: an illustrative case and literature review.

Intracranial bronchogenic cysts are extremely rare. This is the first reported case of a bronchogenic cyst arising from the thalamus. Complete microsurgical resection was undertaken. A literature review was conducted to explore the etiologies, diagnostic approaches, and therapeutic strategies for this type of rare disease.

Microsurgical management of giant malignant peripheral nerve sheath tumor of the scalp: two case reports and a literature review.

Malignant peripheral nerve sheath tumors of the scalp are rare lesions of the nervous system. Only 14 cases have been reported to date. The field of neurosurgery has struggled with diagnosing and treating these tumors. In this report, we present two cases of giant malignant peripheral nerve sheath tumors of the scalp and retrospectively analyze the clinical features, imaging findings, pathological features, and prognoses of these two patients. Each underwent microsurgery and radiotherapy. In addition, based on a literature review, we discuss the diagnostic and therapeutic strategies used to treat these unusual lesions.

Primary central nervous system diffuse large B-cell lymphoma in fourth ventricle: Case report and literature review.

RATIONALE: Primary central nervous system lymphoma (PCNSL) is rare, especially lymphoma arising in the fourth ventricle. Only a few cases have been reported. We report a case of fourth ventricular lymphoma and review the relevant literature. Characterizing these cases can provide a basis for optimizing the diagnosis and management of fourth ventricle lymphoma. PATIENT CONCERNS: A 48-year-old male with blurred vision, dizziness, staggering persisting for 2 months was admitted. DIAGNOSIS: Preoperative magnetic resonance imaging revealed a space occupying lesion of the fourth ventricle. The patient presented with symptoms of hydrocephalus before surgery, such as memory loss and slurred speech. Pathological analysis following complete resection confirmed the lesion as PCNSL. INTERVENTION: The patient underwent a midline posterior fossa craniotomy. OUTCOMES: The patient symptoms were relieved after surgery. Postoperative chemotherapy was administered with our regular follow-up. Follow-up 9 months after operation indicated a good prognosis. LESSONS: According to the literature, biopsy surgery and subsequent chemotherapy are generally considered as the best treatment options for PCNSL. We believe that for the special location of the fourth ventricle, lymphomas in this site are suitable for the combination of complete resection and subsequent chemotherapy. This approach facilitates tumor resection and reduces possibility of obstructive hydrocephalus.

Metastasis of pulmonary adenocarcinoma to right occipital parafalcine meningioma: A case report and literature review.

RATIONALE: Tumor-to-tumor metastasis is a rare clinical phenomenon. Although meningioma is the most common intracranial recipient of cancer metastasis, only a few cases have been reported. We present a case of metastasis of lung adenocarcinoma into intracranial meningioma and review the published literature. PATIENT CONCERNS: A 70-year-old woman was admitted to our hospital for a 1-month history of headache and pain in her lower extremities. DIAGNOSIS: Brain and lumbar vertebral magnetic resonance imaging showed an intracranial space-occupying lesion in the right occipital region and spinal canal stenosis. Pulmonary computed tomography showed an irregular mass in the right upper lobe of the lung. The postoperative histological examination demonstrated adenocarcinoma metastasis to meningioma. INTERVENTION: The patient underwent right occipital craniotomy for tumor removal and lumbar spinal canal decompression. OUTCOMES: There were no initial abnormal conditions after the operation. However, the patient died suddenly 7 days after surgery. LESSONS: Tumor-to-meningioma metastasis is a rare but important phenomenon. According to previous reports, it is associated with rapid onset of symptoms and a poor prognosis. Histological examination is of great importance in diagnosis. The history and process of malignant carcinoma should be closely monitored.

Primary Central Nervous System Angiosarcoma.

BACKGROUND: Primary angiosarcoma of the brain is an extremely rare malignant tumor that that arises from vascular endothelial cells of the brain or meninges. The presentation, characteristics, and prognosis of this disease are not well understood. Here we report such a case. CASE DESCRIPTION: A 68-year-old Chinese man presented with confusion and progressive impairment of right limb movement. Magnetic resonance imaging (MRI) revealed a hemorrhagic lesion in the left frontal lobe. Exploratory surgery revealed a hematoma-like lesion and extensive superficial hemosiderin deposition. The postoperative pathological diagnosis was angiosarcoma. The tumor recurred at 1 month after the operation, with extensive tumor regrowth in the left hemisphere. The patient died after 4 weeks. CONCLUSIONS: Although accurate preoperative diagnosis of angiosarcoma of the brain is difficult, radiologists and neurosurgeons need to be aware of this rare entity. The prognosis of intracranial angiosarcoma is heterogenous. Intraoperatively, the presence of extensive superficial hemosiderosis may aid in its diagnosis.

ISG20 promotes local tumor immunity and contributes to poor survival in human glioma.

Recent evidence has confirmed that a mutation of the isocitrate dehydrogenase (IDH) gene occurs early in gliomagenesis and contributes to suppressed immunity. The present study aimed to determine the candidate genes associated with IDH mutation status that could serve as biomarkers of immune suppression for improved prognosis prediction. Clinical information and RNA-seq gene expression data were collected for 932 glioma samples from the CGGA and TCGA databases, and differentially expressed genes in both lower-grade glioma (LGG) and glioblastoma (GBM) samples were identified according to IDH mutation status. Only one gene, interferon-stimulated exonuclease gene 20 (ISG20), with reduced expression in IDH mutant tumors, demonstrated significant prognostic value. ISG20 expression level significantly increased with increasing tumor grade, and its high expression was associated with a poor clinical outcome. Moreover, increased ISG20 expression was associated with increased infiltration of monocyte-derived macrophages and neutrophils, and suppressed adaptive immune response. ISG20 expression was also positively correlated with PD-1, PD-L1, and CTLA4 expression, along with the levels of several chemokines. We conclude that ISG20 is a useful biomarker to identify IDH-mediated immune processes in glioma and may serve as a potential therapeutic target.

Bilateral and symmetric C1-C2 dumbbell ganglioneuromas associated with neurofibromatosis type 1: A case report.

BACKGROUND: Ganglioneuroma (GN) is a rare and benign tumor that originates from autonomic nervous system ganglion cells. The most frequently involved sites are the posterior mediastinum, the abdominal cavity, and the retroperitoneal space. It rarely occurs in the cervical area, compressing the spinal cord. Neurofibromatosis type 1 (NF-1) is an autosomal dominant inheritance disorder, whose prevalence rate approximates one per 3000. CASE SUMMARY: We report an extremely rare case of bilateral and symmetric dumbbell GNs of the cervical spine with NF-1. A 27-year-old man with NF-1 presented with a one-year history of gradually progressive right upper extremity weakness and numbness in both hands. Magnetic resonance imaging showed bilateral and symmetric dumbbell lesions at the C1-C2 levels compressing the spinal cord. We performed total resection of bilateral tumors, and the postoperative histopathological diagnosis of the resected mass was GN. After operation, the preoperative symptoms were gradually relieved without complications. To our knowledge, this is the sixth report of cervical bilateral dumbbell GNs. CONCLUSION: In some cases, cervical bilateral dumbbell GNs could be associated with NF-1. The exact diagnosis cannot be obtained before operation, and pathological outcome is the current gold standard. Surgical resection is the most effective option, and disease outcome is generally good after treatment.

Microsurgical management of pediatric ependymomas of the fourth ventricle via the trans-cerebellomedullary fissure approach: A review of 26 cases.

In the present study, the microsurgical management of 26 ependymomas of the fourth ventricle in children via the trans-cerebellomedullary fissure (CMF) approach was reviewed and evaluated. Clinical data were obtained from 26 ependymomas of the fourth ventricle treated with microsurgery using the trans-CMF approach from March 2006 to September 2010 at the Department of Neurosurgery of The First Affiliated Hospital of China Medical University (Shenyang, China). These data were collected and analyzed. Suboccipital median posterior fossa craniotomy and trans-CMF approach were performed in all cases for the microsurgical removal of the tumors. An additional incision was performed in the inferior medullary velum of 5 patients, in order to obtain adequate exposure of the tumors. As a result, all tumors were well exposed during surgery. Gross total resection (GTR) was achieved in 22 cases, near total resection (NTR) in 3 cases and subtotal resection (STR) in 1 case. All excised tumors were pathologically confirmed. No mortality occurred intraoperatively, and no patient presented with mutism or any other surgery-related complications. One patient suffered from postoperative hydrocephalus and received ventriculoperitoneal shunting, which relieved the symptoms. Over the 3.0-7.5-year follow-up period (mean, 4.8 years), tumor relapse occurred in 1 case with GTR, 2 cases with NTR and 1 case with STR. In total, 3 patients succumbed to tumor relapse and 4 were lost to follow-up. According to the literature and the clinical experience of the present authors, the trans-CMF approach provides safe and sufficient access to the fourth ventricle without the requirement of an incision in the inferior vermis. This approach prevents damage to the normal cerebellum and improves the surgical outcome. Tumor removal, restoration of cerebrospinal fluid circulation and preservation of brainstem function are factors that should be taken into consideration during surgery. For patients with residual tumors, adjuvant radiotherapy and/or chemotherapy may be beneficial.

Multiple primary Ewing's sarcomas in cerebral cranium of a child: a case report and review of the literature.

Ewing's sarcoma is the second most common pediatric bone tumor. Primary Ewing's sarcoma occurring in the cerebral cranium is exceptionally rare, with only one reported case of multiple tumor lesions in adolescence to date. We report a case of a 5-year-old male patient with multiple primary Ewing's sarcomas associated with the cranial bones, the first pediatric case report to date. We also review 71 cases Ewing's sarcoma involving intracranial extension. The purpose of this article is to provide data concerning the clinical and therapeutic course of multiple primary Ewing's sarcomas in associated with cerebral cranium.

Diagnosis and treatment of primary central nervous system lymphoma: A report of nine cases and literature review.

Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant tumor type of the nervous system and is associated with poor prognosis. To investigate the efficacy of current treatment strategies for PCNSL, the present study retrospectively analyzed the clinical and pathological features, imaging results, clinical management, and prognoses of nine patients with PCNSL. Postoperative pathological examination confirmed a diagnosis of lymphoma in all the patients and the adopted treatment regimens were as follows: Stereotactic biopsy in combination with methylprednisolone (MP) and methotrexate (MTX) and/or radiotherapy; craniotomy in combination with dexamethasone or MP and/or radiotherapy; and neuroendoscopic surgery in combination with MP and MTX. The follow-up period was 5-27 months with an average duration of 10.1 months. After the initial three months of follow-up, the clinical symptoms of all the patients were significantly improved, with the tumor disappearing in seven patients and evidently reducing in size in two patients. However, six patients exhibited tumor recurrence, three of whom eventually succumbed to the disease during the follow-up period. Currently, comprehensive treatment strategies based on a combination of stereotactic biopsy, chemotherapy and radiotherapy are recommended for the treatment of PCNSL. However, the effectiveness of these treatments remains unsatisfactory. Thus, future studies are required to investigate methods for improving the efficacy of PCNSL treatment strategies.

Ependymoblastoma with cystic change in a child.

Ependymoblastoma is a rare and devastating primitive neuroectodermal tumor with ependymal differentiation. This tumor occurs very early in life and shows rapid growth and a diffuse infiltration through the leptomeningeal space. This neoplasm is characterized by uniform neuroepithelial cells, multilayered ependymal rosettes, perivascular pseudorosettes, and numerous mitotic figures. In this article, the authors report on a 4-year-old girl who was diagnosed as having an ependymoblastoma with cystic change. After a series of laboratory and imaging examinations, the left frontal solid-cystic lesion was surgically excised. Histological examinations confirmed the diagnosis of ependymoblastoma. The patient's intracranial hypertension symptoms were alleviated, and postoperative chemotherapy was performed. At the 6-month follow-up visit, MRI demonstrated evidence of relapse, and the girl died of tumor recurrence 14 months after surgery. Databases (PubMed, MEDLINE, Embase, and Web of Science) were searched for relevant articles published from 1970 to 2012; 71 eligible cases of ependymoblastoma were obtained, and 42 provided complete clinical details. Prognosis of children with ependymoblastoma is poor, and data on clinical behavior and optimal treatment strategies are lacking, but sustained remissions have been achieved after multimodal treatment according to existing literature. In this report, the clinical and histopathological features and therapeutic options of this tumor are discussed in the light of the published data. Further studies, especially those examining multimodality therapy, are needed to improve survival of children with this rare malignant CNS tumor.

Microneurosurgery in combination with endovascular embolisation in the treatment of solid haemangioblastoma in the dorsal medulla oblongata.

OBJECTIVE: To investigate the treatment of solid haemangioblastomas in the dorsal medulla oblongata using microneurosurgery in combination with endovascular embolisation. METHODS: Clinical data from 11 patients with solid haemangioblastomas in the dorsal medulla oblongata who were treated with endovascular embolisation followed by microneurosurgery were analysed retrospectively. Clinical results were evaluated using the modified Rankin scale. The patients were preoperatively evaluated by neuroimaging methods such as magnetic resonance imaging (MRI), contrast MRI and digital subtraction angiography (DSA). General anaesthesia was induced, the patients were tracheally intubated, and the abnormal vessels were embolised. Surgery to resect the haemangioblastoma was conducted after the blood-clotting index returned to normal levels (generally one month after the interventional treatment). RESULTS: Embolisation was accomplished in all 11 patients. DSA analysis revealed that most of the tumour vessels and tumour stains disappeared without any complications. The haemangioblastomas were completely resected. None of the patients received blood transfusion or died during surgery. The neurological deficit was reduced or eliminated in 10 patients, but 1 patient died after experiencing an acute myocardial infarction on the tenth postoperative day. No recurrence occurred during follow-up in patients who underwent total tumour resection. Postoperative grades using the modified Rankin scale were improved in all 10 patients. However, several complications occurred, including communicating hydrocephalus, incision infection, pneumonia and cerebrospinal fluid leakage from the incision. Notably, normal perfusion pressure breakthrough (NPPB) did not develop during or after endovascular embolisation or surgery. CONCLUSION: Preoperative endovascular embolisation is a safe and effective adjunct treatment. Employing this treatment, solid haemangioblastomas in the dorsal medulla oblongata can be safely and completely resected.