Surgical management of thoracic idiopathic spinal cord herniation. Technical case report and review.

Idiopathic spinal cord herniation (ISCH) is a rare spinal disease, in which chronic cerebrospinal fluid pulsations push the arachnoid and adjacent thoracic spinal cord region through an antero-lateral dural defect of congenital, post-traumatic, or inflammatory/erosive origin. Symptomatic patients commonly present around the 5th decade of life with slowly progressive myelopathy. Diagnosis relies on high-resolution magnetic resonance imaging. Stable mild cases may be observed, whereas in progressive symptomatic situations, surgical spinal cord reposition and dural defect repair with a dural patch is the preferred treatment. We present a case of ISCH at T5/6 and a review the literature.

Marker-independent identification of glioma-initiating cells.

Tumor-initiating cells with stem cell properties are believed to sustain the growth of gliomas, but proposed markers such as CD133 cannot be used to identify these cells with sufficient specificity. We report an alternative isolation method purely based on phenotypic qualities of glioma-initiating cells (GICs), avoiding the use of molecular markers. We exploited intrinsic autofluorescence properties and a distinctive morphology to isolate a subpopulation of cells (FL1(+)) from human glioma or glioma cultures. FL1(+) cells are capable of self-renewal in vitro, tumorigenesis in vivo and preferentially express stem cell genes. The FL1(+) phenotype did not correlate with the expression of proposed GIC markers. Our data propose an alternative approach to investigate tumor-initiating potential in gliomas and to advance the development of new therapies and diagnostics.

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.

Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome.

For patients with brain tumors identification of diagnostic and prognostic markers in easy accessible biological material, such as plasma or cerebrospinal fluid (CSF), would greatly facilitate patient management. MIC-1/GDF15 (growth differentiation factor 15) is a secreted protein of the TGF-beta superfamily and emerged as a candidate marker exhibiting increasing mRNA expression during malignant progression of glioma. Determination of MIC-1/GDF15 protein levels by ELISA in the CSF of a cohort of 94 patients with intracranial tumors including gliomas, meningioma and metastasis revealed significantly increased concentrations in glioblastoma patients (median, 229 pg/ml) when compared with control cohort of patients treated for non-neoplastic diseases (median below limit of detection of 156 pg/ml, p < 0.0001, Mann-Whitney test). However, plasma MIC-1/GDF15 levels were not elevated in the matching plasma samples from these patients. Most interestingly, patients with glioblastoma and increased CSF MIC-1/GDF15 had a shorter survival (p = 0.007, log-rank test). In conclusion, MIC-1/GDF15 protein measured in the CSF may have diagnostic and prognostic value in patients with intracranial tumors.

MGMT gene silencing and benefit from temozolomide in glioblastoma.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

Orthostatic mesodiencephalic dysfunction after decompressive craniectomy.

An extreme syndrome of the trephined after decompressive craniectomy is reported here. The most extensive clinical syndrome observed was established over 4 weeks and consisted of bradypsychia, dysartria, and limb rigidity with equine varus feet predominating on the right. The syndrome was aggravated when the patient was sitting with the sequential appearance over minutes of a typical parkinsonian levodopa-resistant tremor starting on the right side, extending to all four limbs, followed by diplopia resulting from a left abducens nerve palsy followed by a left-sided mydriasis. All signs recovered within 1-2 h after horizontalisation. It was correlated with an orthostatic progressive sinking of the skin flap, MRI and CT scan mesodiencephalic distortion without evidence of parenchymal lesion. Brain stem auditory evoked potential wave III latency increases were observed on the right side on verticalisation of the patient. EEG exploration excluded any epileptic activity. Symptoms were fully recovered within 2 days after cranioplasty was performed. The cranioplasty had to be removed twice due to infection. Bradypsychia, speech fluency, limb rigidity and tremor reappeared within a week after removal of the prosthesis. While waiting for sterilisation of the operative site, the symptoms were successfully prevented by a custom-made transparent suction-cup helmet before completion of cranioplasty.

Monovoxel 1H magnetic resonance spectroscopy in the progression of gliomas.

AIM: Can monovoxel magnetic resonance spectroscopy (MRS) reliably follow tumour progression in low-grade glioma? MATERIALS AND METHODS: 21 patients with low-grade glioma underwent at least 3 MRS. RESULTS: For progression from a grade II to grade III tumour, a sensitivity of 57.1% and specificity of 60% were observed, with a positive predictive value (PPV) of 48.8% and a negative predictive value (NPV) of 54.5%. For progression under treatment, we obtained a sensitivity of 57.1% by N-acetylaspartate (NAA)/choline (Cho) and myoinositol/creatine (Cr) and a specificity of 100% by Cho/Cr and lipids, with a PPV of 80% and a NPV of 63.6%. CONCLUSION: We found that NAA/Cho is the best marker of tumour progression before therapy, with a sensitivity of 53.9%. For the therapeutic response, sensitivity was only 28.2%.

Surgery for large vestibular schwannomas: how patients and surgeons perceive quality of life.

OBJECT: The aim of this study was to assess the consequences of total removal of a large vestibular schwannoma on the patient's symptoms and quality of life (QOL). METHODS: A questionnaire regarding preoperative and postoperative symptoms with measures of both daily and global QOL and a modified 36-Item Short Form Health Survey (SF-36) QOL instrument were sent to 103 patients who had undergone surgery via a retrosigmoid approach for total removal of a Grade III or IV vestibular schwannoma. In addition, 48 patients underwent follow-up clinical examinations to assess their conditions. Seventy-two of the 103 patients completed and returned the questionnaire. Forty-six (64%) of the schwannomas were Grade IV and 26 (36%) were Grade III. The patients' pre- and postoperative symptoms were similar to those reported in other studies. The patients' perceptions of facial movement were likely to be worse than the clinicians' estimation based on the House-Brackmann classification. All scores in the QOL categories were significantly reduced when compared with normative data. Patients with large vestibular schwannomas had lower scores in all SF-36 categories except pain compared with data from other studies. Psychological problems were the preponderant symptoms, and their presence was the most powerful predictive variable for global and daily QOL. CONCLUSIONS: Surgery for a large vestibular schwannoma has a significant impact on the patient's QOL. To improve QOL postoperatively, the patient should be prepared and well informed of the consequences of such a surgery on QOL. Clinicians must be aware that early involvement of a clinical psychologist may be very helpful.

Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes.

The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a). can be associated with specific biological functions; and (b). effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase 1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.

INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma.

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.

Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1.

Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis. In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the Tet-On system for p53 in the LN-Z308 glioblastoma cell line. The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling. Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines. MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway. Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected. In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Apoplexy in pituitary macroadenoma: eight patients presenting in 12 months.

Pituitary apoplexy is an ill-defined clinical entity. Some authors include hypoxic pituitary infarction, even in the absence of tumor after hemorrhagic delivery, whereas others apply this term strictly to hemorrhage within a pituitary adenoma. We conducted the present study to establish the prevalence, clinical characteristics, and outcome of pituitary apoplexy, defined as an endocrine crisis characterized by acute intense headache, with or without altered consciousness, rapid development of visual or motor ocular disorders, and pituitary failure, associated with a large pituitary adenoma. We describe 8 consecutive patients (1 woman and 7 men, aged 29-66 yr) presenting over 12 months with pituitary apoplexy. We reviewed patient charts for symptoms, imaging characteristics, hormonal data, management, pathologic findings, and outcome. We examined our pituitary tumors database for cases of macroadenoma without apoplexy occurring during the same period. In 5 patients, potential precipitating factors were present. In 6 patients (3 nonsecreting tumors, 1 free-alpha-subunit-secreting tumor, 1 growth hormone and prolactin-secreting tumor with acromegaly, and 1 prolactinoma), no pituitary disease was suspected before the acute event, representing 19% of newly diagnosed pituitary macroadenomas during the same period of time, a higher proportion than expected from our previously published series. The 2 other patients had known pituitary macroadenomas, a nonsecreting tumor and a prolactinoma on dopamine agonist therapy. Pituitary insufficiency at diagnosis included adrenal failure in 4 patients. Transsphenoidal tumor removal was performed 3-9 days after the onset of symptoms (mean, 5.3 d) in 7 of the 8 patients. Pathologic analysis disclosed tumor hemorrhage in 4 cases, ischemic necrosis in 2, and ischemia after intrasellar hemorrhage in 1. Preoperative magnetic resonance imaging was more sensitive than computed tomography for identifying hemorrhage. The newly diagnosed prolactinoma was treated with dopamine agonist. Complete neuro-ophthalmic recovery was observed in all cases, but only 2 patients displayed normal pituitary function on follow-up. The other 6 patients required long-term hormone replacement therapy. These data show that early surgical decompression prevents persistent neuro-ophthalmic deficit, but does not prevent persistent pituitary insufficiency. Moreover, published data indicate that the efficacy of surgery for the relief of neuro-ophthalmic symptoms decreases with increasing syndrome duration. Our data confirm that apoplexy occurs most often as the inaugural manifestation of pituitary macroadenoma, and suggest a recent increase of cases of apoplexy in our area.

Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.

PURPOSE: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression). CONCLUSIONS: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1.

The anti-tumor properties of cannabinoids have recently been evidenced, mainly with delta9-tetrahydrocannabinol (THC). However, the clinical application of this drug is limited by possible undesirable side effects due to a broad expression of cannabinoid receptors (CB1 and CB2). An attractive field of research therefore is to identify molecules with more selective tumor targeting. This is particularly important for malignant gliomas, considering their poor prognosis and their location in the brain. Here we investigated whether the most potent endogenous cannabinoid, arachidonylethanolamide (AEA), could be a candidate. We observed that AEA induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1). In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma against AEA-induced apoptosis. These data show that the selective targeting of VR1 by AEA or more stable analogues is an attractive research area for the treatment of glioma.

Cervical sympathetic block to reverse delayed ischemic neurological deficits after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The purpose of the present study was to evaluate the feasibility and safety of a locoregional cervical sympathetic block to improve cerebral perfusion in patients suffering from cerebral vasospasm after aneurysmal subarachnoid hemorrhage. METHODS: Nine consecutive patients with symptoms of delayed ischemic deficits, induced by angiographically confirmed cerebral vasospasm, were treated with the injection of locoregional anesthesia to block the ascending cervical sympathetic chain at the level of the superior cervical ganglion. Neurological status was recorded before and after the procedure, and cerebral angiography was performed before and after the procedure. RESULTS: No complications occurred in this short series. The procedure appeared to be simple and safe. Horner's signs appeared within 12+/-0.1 minutes and lasted for an average of 6.3+/-4 hours. In all patients, improved cerebral perfusion was detected at the confirmatory angiography but without change in vessel caliber. One patient died of the complications of the initial hemorrhage, and 2 died of the consequences of the severe vasospasm despite maximal medical treatment. In all the other cases, the neurological status promptly returned to normal within 48 hours after the locoregional treatment. CONCLUSIONS: Patients with mild to moderate symptoms seem to benefit greatly from transient ipsilateral cervical sympathetic block. This simple technique may be helpful when used as an adjunct to the standard therapy to improve cerebral perfusion.

Transient crossed aphasia evidenced by functional brain imagery.

Crossed aphasia refers to language deficits induced by unilateral right hemisphere injuries in right-handed people who had no previous history of brain damage. One of the intriguing questions concerning crossed aphasia is the atypical language representation in the brain. In this respect, fMRI is a valuable tool for understanding the neural basis of crossed aphasia. Here, we used neuropsychological and fMRI language tasks in a right-handed subject who presented a crossed aphasia due to a right frontal meningioma. fMRI maps from two language tasks showed bilateral patterns of activation. In the light of previous studies reporting much frequent bilateral than exclusive right hemisphere representations, we hypothesise that some crossed aphasia cases could occur in subjects with bilateral language representation.

Far-lateral lumbar disc herniation: the microsurgical transmuscular approach.

Intra- and extraforaminal disc herniations can be treated via a lateral approach. The far-lateral approach is a muscle-splitting approach that allows surgeons to reach the disc herniation without any facet bone removal. The target of the surgical exposure is the isthmus. Good knowledge of the anatomic features of the intervertebral foramen and intertransverse space is mandatory. The transmuscular approach is discussed. We provide illustrations and a video to emphasize some operative aspects.