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.

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.

Pineal region tumors--neurosurgical review.

The treatment for the pineal region tumors depends on tumor histology. Nowadays, germinomas can be cured by radiotherapy and chemotherapy without surgical resection but the other pineal region tumors should be primary treated by surgery. Two microsurgical approaches, the infratentorial supracerebellar and the occipital transtentorial, are accepted as the main standard accesses to the pineal region. For benign pineal tumors (pineocytoma, meningioma, mature teratomas, symptomatic pineal cysts, etc.) radical surgical resection can be curative. For malignant tumors radical surgical resection is not an objective. Serum and CSF markers contribute to the diagnosis of pineal parenchymal tumors. b-HCG is mainly positive in choriocarcinomas, embryonal carcinomas and mixed germ cell tumors and AFP is expressed by yolk sac tumors, embryonic carcinomas, immature teratomas and mixed germ cell tumors, b-HCG is usually low in germinomas which are often positive for PLAP on immunohistochemistry. Fifty-one pineal region tumors were surgically treated by senior author (NdT). Only 17 of them were the neoplasms originating from pineal body (pineal tumors). In conclusion it can be stressed that management of pineal tumors requires a multidisciplinary cooperation. With the exception of germinoma where only a biopsy is needed, the role of the surgeons still remains prominent as resection of pineal tumors requires high technical skill and experience as well as precise clinical judgment.

Cefuroxime prophylaxis is effective in noninstrumented spine surgery: a double-blind, placebo-controlled study.

STUDY DESIGN: Double-blind, placebo-controlled randomized clinical trial. OBJECTIVE: To assess the efficacy of 1 preoperative 1.5 g dose of cefuroxime in preventing surgical site infection after surgery for herniated disc. SUMMARY OF BACKGROUND DATA: Antibiotic prophylaxis was only tested in nonconclusive trials in this setting. METHODS: The study was conducted in 2 university hospitals in Switzerland. Patients were assessed for occurrence of surgical site infection (defined by the criteria of the Centers for Diseases Control and Prevention), other infections, or adverse events up to 6 months after surgery. Outcome measures were compared in a univariate, per-protocol analysis. RESULTS: Baseline characteristics were similar in patients allocated to cefuroxime (n = 613) or placebo (n = 624). Eight (1.3%) patients in the cefuroxime group and 18 patients (2.8%) in the placebo group developed a surgical site infection (P = 0.073). A diagnosis of spondylodiscitis or epidural abscess was made in 9 patients in the placebo group, but none in the cefuroxime group (P < 0.01), which corresponded to a number necessary to treat of 69 patients to prevent one of these infections. There were no significant adverse events attributed to either cefuroxime or placebo. CONCLUSION: A single, preoperative dose of cefuroxime significantly reduces the risk of organ-space infection, most notably spondylodiscitis, after surgery for herniated disc.

Frontobasal interhemispheric trans-lamina terminalis approach for suprasellar lesions.

The frontobasal interhemispheric approach for suprasellar tumors currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. This technique is a valid choice for the removal of suprasellar lesions with extension into the third ventricle without major sequelae related to the surgical approach. The method described here reflects the combination of the frontal interhemispheric and trans-lamina terminalis approaches.

Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.

PURPOSE: Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. PATIENTS AND METHODS: Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. RESULTS: An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response. CONCLUSION: This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.

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%.

Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells.

During the priming phase of an antitumor immune response, CD8(+) T cells undergo a program of differentiation driven by professional APCs in secondary lymphoid organs. This leads to clonal expansion and acquisition both of effector functions and a specific adhesion molecule pattern. Whether this program can be reshaped during the effector phase to adapt to the effector site microenvironment is unknown. We investigated this in murine brain tumor models using adoptive transfer of tumor-specific CD8(+) T cells, and in spontaneous immune responses of patients with malignant glioma. Our data show proliferation of Ag-experienced tumor-specific T cells within the brain parenchyma. Moreover, CD8(+) T cells further differentiated in the brain, exhibiting enhanced IFN-gamma and granzyme B expression and induction of alpha(E)(CD103)beta(7) integrin. This unexpected integrin expression identified a subpopulation of CD8(+) T cells conditioned by the brain microenvironment and also had functional consequences: alpha(E)(CD103)beta(7)-expressing CD8(+) T cells had enhanced retention in the brain. These findings were further investigated for CD8(+) T cells infiltrating human malignant glioma; CD8(+) T cells expressed alpha(E)(CD103)beta(7) integrin and granzyme B as in the murine models. Overall, our data indicate that the effector site plays an active role in shaping the effector phase of tumor immunity. The potential for local expansion and functional reprogramming should be considered when optimizing future immunotherapies for regional tumor control.

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.

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.

Intracranial aneurysm stenting: follow-up with MR angiography.

Intracranial stenting is increasingly being used to treat intracranial aneurysms and stenoses. We wanted to assess the utility of magnetic resonance angiography (MRA) in the follow-up of patients treated with various types of intracranial stents and to assess the utility of performing gadolinium-enhanced MRA. A total of 19 patients having undergone intracranial stenting for aneurysms were imaged by MRI at 1.5T. A total of 20 stents were placed in 19 patients. In addition to conventional T2- and diffusion-weighted MRI, 3D time-of-flight MRA was performed before and after contrast administration. In the case of metallic INX stents (N = 7), there was a signal drop at the level of the vessel. which did not allow to evaluating the parent vessel, whereas this was visible in Nitinol stents (N = 8). Additionally a stent with a wire had a small artifact (N = 3). Contrast administration also improved vessel lumen visualization. In the case of Nitinol stents, MRA can be used to reliably demonstrate the vessel lumen after intracranial stenting. The use of postcontrast 3D time-of-flight imaging helps improve the intraluminal definition.

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.

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.

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.

Frontobasal interhemispheric trans-lamina terminalis approach for suprasellar lesions.

The frontobasal interhemispheric approach for suprasellar tumors currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. This technique is a valid choice for the removal of suprasellar lesions with extension into the third ventricle without major sequelae related to the surgical approach. The method described here reflects the combination of the frontal interhemispheric and trans-lamina terminalis approaches.