Gene expression profile of glioblastoma peritumoral tissue: an ex vivo study.

The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of "apparently normal" cells presenting a gene profile compatible with a precancerous state or even "quiescent" cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.

Surgical pathway and management of pineal region tumours in children.

BACKGROUND: Pineal region tumours are rare. Surgery is associated with high morbidity, and consensus on ideal management pathways remains variable. METHOD: Patients with pineal region tumours were identified from the neuro-oncology database, and their data were retrospectively reviewed. Data collection included presentation, germ cell markers, tumour size and location, imaging, histology, treatment and control/relapse rates. RESULTS: Twenty-four patients were treated at Alder Hey Children's Hospital between 1998 and 2010. Median age at diagnosis was 12.7 years. Sixteen patients presented with hydrocephalus. Twelve were successfully treated with endoscopic third ventriculostomy (EVT), and four required shunt insertion during follow-up. Fifteen patients had endoscopic biopsies. Eleven biopsies were performed at the same time as third ventriculostomy, and four patients without significant hydrocephalus had endoscopic image-guided biopsies. Eight patients had stereotactic biopsies (either because of slit ventricles at diagnosis or because of a ventriculoperitoneal shunt already in place), and only one patient had an open biopsy. No morbidity or mortality was associated with the biopsies. Histology showed four pineal parenchymal tumours, nine gliomas and eleven germ cell tumours. Thirteen patients underwent surgical resection. Significant tumour debulking was achieved in all of these patients, with gross total resection in 70 % of cases. There was one intraventricular haemorrhage (full recovery) and one mild hemiparesis. There was no surgical mortality. CONCLUSION: The mainstay of hydrocephalus management is EVT which provides a safe and reliable route for biopsy. In our experience, craniotomy and tumour resection are effective and safe.

Postoperative infection may influence survival in patients with glioblastoma: simply a myth?

BACKGROUND: It is a prevalent myth that a postoperative infection may actually confer a survival advantage in patients with malignant glioma. This contention is based largely on anecdotal reports. Recently, a single-center study showed there was no survival advantage in those patients who had glioblastoma with postoperative infection. OBJECTIVE: To examine the impact of postoperative infections on outcome in patients with glioblastoma treated at our center. METHODS: This study included 197 patients with newly diagnosed primary glioblastoma treated from January 2001 to January 2008. Of the 197 patients, 10 (5.08%) had postoperative bacterial infection. The Kaplan-Meier method, log-rank test, and Breslow test were used in the univariate approach; Cox regression was used in the multivariable approach. RESULTS: The median survival was 16 months (95% confidence interval [CI], 14-18 mo). The infection group had a significant advantage in the median survival: 30 months (95% CI, 21-39) vs 15 months (95% CI, 13-17) for patients without postoperative infection. This advantage was also confirmed by Cox regression; in fact, patients not developing a postoperative infection showed an adjusted hazard ratio for death of 2.3 (95% CI, 1-5.3). CONCLUSION: The association between infection and prolonged survival is not definitive; we acknowledge the considerable difficulties in undertaking this type of study in a retrospective manner. Our results can instead stimulate further multicentric studies (to increase the number of patients) or experimental studies using genetically modified bacteria for treatment of glioblastoma.

Endoscopic third ventriculostomy for the treatment of osteopetrosis-related hydrocephalus: a case-based update.

BACKGROUND: Osteopetrosis is a heterogenous group of disorders characterised by a failure of normal bone maturation and abnormal bone sclerosis secondary to the failure of osteoclasts to resorb bone. The most serious consequences of this disorder affect the nervous system. Patients with infantile osteopetrosis (also called malignant osteopetrosis) can develop a gradual occlusion of, or narrowing of the skull foramina at the skull base, resulting in the compression of vital nerves and vessels. Hydrocephalus has been identified in these patients, particularly those with the autosomal recessive variety of osteopetrosis. Although the exact aetiology is uncertain, it is possible that venous outflow obstruction at the cranial foramina along with a reduced intracranial space for cerebrospinal fluid (CSF) to flow around the hemispheres could be contributing factors. There are few reports in the literature on the management of this unusual association, hydrocephalus secondary to osteopetrosis. The authors report one such case where this association has been successfully surgically treated with endoscopic third ventriculostomy as a form of CSF diversion. CASE REPORT: We successfully treated a 9-month-old girl with osteopetrosis and symptomatic hydrocephalus with an endoscopic third ventriculostomy (ETV). She later went on to have stem cell transplantation to treat the osteopetrosis. CONCLUSIONS: Most reports in the literature have identified ventriculoperitoneal (or other distal site) shunting as the treatment of choice for hydrocephalus in this setting. We would like to highlight that ETV is another effective and often very suitable method of CSF diversion in these patients.

Acute deterioration of a Chiari I malformation: an uncommon neurosurgical emergency.

OBJECTIVES: Report and discuss acute neurological deterioration of Chiari I malformation (CMI), surgical treatment and timing, clinical outcome and literature review. CASE REPORT: We report a recent case of a 15-year-old girl admitted for an acute neurological deterioration caused by an undiagnosed hindbrain herniation that required an urgent foramen magnum decompression and external ventricular drainage insertion. Moreover, we report and discuss the literature. To the authors' knowledge, this is only the third paediatric patient identified in this setting to be treated for an acute neurological deterioration due to a previous asymptomatic hindbrain herniation. The patient made an uncomplicated recovery and was discharged home on the seventh postoperative day and has remained well at review. DISCUSSION: Acute deterioration of CMI in completely asymptomatic patients in absence of concomitant pathological findings is rarely reported in the literature, and exceptional in children. CONCLUSIONS: CMI is typically treated electively, but as this case illustrates, it can present with rapidly deteriorating neurological signs. Symptoms usually respond well to surgical intervention with rapid improvement.

The role of inflammation in the genesis of the cystic component of craniopharyngiomas.

BACKGROUND: Craniopharyngioma accounts for 5-10% of childhood tumors and, despite of the benign histological features, its clinical course can be malignant because of critical anatomical relationships with neural and vascular structures and the possible morbidity associated to resection. Only a few studies have addressed the molecular characterization of the cyst fluid so far and the mechanisms of action of intracystic agents are not clearly understood yet. METHODS: The acidic soluble proteins contained in the cystic fluid of six patients with cystic craniopharyngioma, three of them treated with intratumoral interferon-α, were analyzed. A high performance liquid chromatography electrospray ionization mass spectrometry analysis was performed. FINDINGS: The antimicrobial peptides α-defensins 1-3 relevant for innate immunity were detected in the cystic fluid before the intratumoral treatment. Amount of peptides significantly decreased in cystic fluid during pharmacological treatment. INTERPRETATION: Detection of α-defensins 1-3 excludes that cyst fluid formation can derive from disruption of blood-brain barrier and suggests the involvement of innate immune response in pathology of craniopharyngioma cyst formation. The reduction of α-defensins could derive both from direct antitumoral effect of interferon-α on squamous epithelial cells of craniopharyngioma cyst and from its immuno-modulatory effects on the recruitment of cells of innate immune systems. Interestingly, the clinical patient outcome well correlates with the gradual reduction of α-defensins 1-3 amount. Additional studies will be necessary to establish the role of these molecules in the pathogenesis of craniopharyngioma, and further investigations will be necessary to confirm the efficacy of the antitumoral activity of interferon-α.

Preoperative and postoperative neurological, neuropsychological and behavioral impairment in children with posterior cranial fossa astrocytomas and medulloblastomas: the role of the tumor and the impact of the surgical treatment.

INTRODUCTION: The aim of the present study was to prospectively investigate if a correlation might exist between preoperative and postoperative neurological conditions, neuroradiological/intraoperative findings and results of a complete neuropsychological evaluation in children with posterior fossa medulloblastomas and astrocytomas. MATERIALS AND METHODS: Of the 65 children admitted at the Pediatric Neurosurgery of the UCSC of Rome between January 2005 and October 2009, 41 were selected; the only two exclusion criteria were represented by age under 24 months and severe neurological conditions, seen that in both cases it would not have been a possible reliable evaluation. All children underwent a preoperative and immediate postoperative complete MR study. Hydrocephalus was graded on the Evans score; brainstem infiltration was defined on intraoperative findings. Neuropsychological assessment consisted of a battery of tests tailored on the patient's age, cognitive level, and level of cooperation. Post operative neuropsychological evaluation was performed at a mean time of 2.5 min (2 mos, max 4.5 mos) from the operation, before any eventually needed adjuvant treatment (i.e., chemotherapy, radiotherapy). RESULTS: Concerning neurological status, we found a statistically significant relation between the presence of oculomotor impairment and both verbal fluency deficits (p = 0.044) and imagery disorders (p = 0.03); also, the presence of ataxia/dysmetria was significantly correlated to attention dysfunction (p = 0.01) and, more tightly, to planning dysfunction (p = 0.006). For neuroradiological/intraoperative features, Intelligence Quotient (IQ) impairment was significantly correlated to the intraoperative evidence of tumor infiltration of the brainstem (p = 0.003), a severe hydrocephalus at diagnosis (p = 0.001) and the histological diagnosis of medulloblastoma (MB) (p = 0.002). For selective skills, a significant correlation was found between linguistic processing deficits and the evidence of dentate nuclei infiltration (blindly defined on MR); procedural memory defects and imagery disorders related to the severity of the hydrocephalus (p = 0.02), infiltration of the brain stem (p = 0.01) and a histological diagnosis of MB (p = 0.01). After surgery no patient showed a worsening of his/her cognitive profile; the relationships between clinical, intraoperative, and radiological findings were substantially confirmed. DISCUSSION: Our results support the hypothesis that when present, neuropsychological impairment is already present at diagnosis and that the most statistically significant factors, which might be related with cognitive deficits in the preoperative as well as in the postoperative period, are tumor infiltration of the brainstem, the severity of hydrocephalus, and a histological diagnosis of MB.

Mesencephalic enlarged Virchow-Robin spaces in a 6-year-old boy: a case-based update.

BACKGROUND: Perivascular spaces or Virchow-Robin spaces are normal anatomical structures within the brain, typically less than 5 mm in diameter. Rarely, they can reach much larger sizes and adopt bizarre single or multi-cystic configurations, as was the case in the patient that we report on. When there is such markedly gross dilatation, the phenomenon is known as Giant or tumefactive perivascular space enlargement. CASE REPORT: We report a 6-year-old boy with a multi-cystic mesencephalic lesions presenting with obstructive hydrocephalus secondary to obstruction of the aqueduct of Sylvius due to tumefactive dilatation of Virchow-Robin spaces. The patient underwent an endoscopic fenestration and biopsy of the cystic portion abutting into the ventricular system. CONCLUSION: In this paper, we discuss the phenomenon of perivascular (Virchow-Robin) spaces and their treatment options and review the relevant literature. To our knowledge, this is the first pediatric case of tumefactive dilatation of the Virchow-Robin spaces causing obstructive hydrocephalus that were directly fenestrated using neuroendoscopy.

Molecular pathogenesis of craniopharyngioma: switching from a surgical approach to a biological one.

Craniopharyngioma has long been considered a benign tumor because of its pathological aspect. This primordial view of craniopharyngioma fit with the primitive treatment attempts based on blind resection of the tumor each time it recurred. The limits of this management strategy were proven early by the high morbidity related to the resection and recurrence risk despite radical lesion removal. Nowadays, craniopharyngioma must be considered a complex molecular disease, and a detailed explanation of the mechanisms underlying its aggressive biological and clinical behavior, despite some benign pathological features, would be the first step toward defining the best management of craniopharyngioma. Indeed, advances in the knowledge of the molecular mechanisms at the base of craniopharyngioma oncogenesis will lead to comprehension of the critical checkpoints involved in neoplastic transformation. The final research target will be the definition of new biological agents able to reverse the neoplastic process by acting on these critical checkpoints. This biological approach will lead to a refined therapy combining higher efficacy and safety with lower morbidity. In this paper the authors reveal state-of-the-art comprehension of the molecular biology of craniopharyngioma and the consequent therapeutic implications.

Craniopharyngiomas: intratumoral chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases.

OBJECT: The authors assessed the efficacy of intratumoral interferon-alpha (IFNalpha)-based chemotherapy in pediatric patients with cystic craniopharyngiomas. METHODS: In a prospective multicenter study of 60 pediatric patients, the authors assessed the efficacy of intratumoral INFalpha2A-based chemotherapy. The study was conducted between 2000 and 2009 at 3 locations: the Medical School of the Federal University of São Paulo, Catholic University of Rome, and the Neurosurgery Institute of Santiago, Chile. The assessment included clinical and radiological control examinations, side effects observed, and total dose used. RESULTS: Sixty cases of cystic craniopharyngioma were analyzed. The cohort consisted of 35 male and 25 female children (mean age 11 years). Clinical and radiological improvement was achieved in 76% of the cases. New endocrinological deficits were observed in 13% of the cases. In approximately 30% of the patients, the evolution included some light side effects, the most common being headache (33%) and eyelid edema (28%). The number of cycles varied from 1 to 9 (mean 5 cycles), and the total dose applied per cycle was 36,000,000 IU. CONCLUSIONS: This has been the largest documented series of intratumoral chemotherapy using INFalpha for the control of cystic craniopharyngiomas. The treatment has proved efficacious; there was no mortality, and morbidity rates were low.

The use of a reconstituted collagen foil dura mater substitute in paediatric neurosurgical procedures--experience in 47 patients.

BACKGROUND: CSF leakage is a common complication of neurosurgical procedures, with defective dural suture thought to be the most frequent cause. We report our experience with a new collagen foil (TissuDura, Baxter Healthcare SA, Switzerland) utilized as dural substitute in paediatric neurosurgical procedures. METHODS: TissuDura was used in children consecutively operated on at the department of paediatric neurosurgery, Catholic University, Rome, from March 2004 to August 2007. Children underwent surgical procedures in supratentorial, infratentorial and spinal compartments. In supratentorial and spinal procedures, the dural graft was used according to the overlay technique. In the posterior fossa procedures, the underlay technique was used. RESULTS: Forty-seven patients received TissuDura during surgery. Thirty-one patients underwent surgery for the removal of posterior fossa tumours, nine for supratentorial tumours and seven for spinal dysraphisms. No CSF leakage was observed following the use of TissuDura in supratentorial procedures. Two post-operative CSF leaks occurred in patients who had undergone spinal surgery. No post-operative hydrocephalus was noted in these two surgery groups. Three cases of CSF leakage occurred in patients who had undergone posterior cranial fossa surgery. All 3 cases had an associated supratentorial ventricular dilation present prior to the removal of the tumour (one case) or occurring after the tumour excision (two cases). No clinically evident adverse reactions directly related to TissuDura were observed. CONCLUSIONS: The main advantages of TissuDura were its apparent ability to prevent CSF leakage when utilized in a specific subset of patients, and the absence of reactions or postoperative infections.

Aperius PercLID stand alone interspinous system for the treatment of degenerative lumbar stenosis: experience on 152 cases.

STUDY DESIGN: This study is a retrospective clinical investigation of a new interspinous device implanted via a totally percutaneous technique involving 152 consecutive patients. OBJECTIVE: Evaluation of the efficacy of the percutaneous Aperius stand alone implant in patients with degenerative lumbar stenosis and neurogenic intermittent claudication that did not respond to conservative treatment. SUMMARY OF BACKGROUND DATA: The use of interspinous implants grew markedly during the last years. Nowadays, many extension controller devices are positioned through minimally invasive procedures. METHODS: From January 2007 to February 2008, 152 consecutive patients with neurogenic intermittent claudication were treated with Aperius PercLID system. Under a local anesthesia, a 1.5 cm skin incision was performed. Trocars for interspinous space distraction were positioned using fluoroscopy guidance. A suitable size Aperius was positioned and released in the interspinous space with a totally percutaneous technique. In 145 patients 1 level was treated, whereas 6 patients received 2 level treatments, and 1 patient received 3 level treatments. The levels treated were L4-L5 in 125 patients (78.2%), L3-L4 level in 26 patients (16.3%), L2-L3 level in 5 patients (3.1%), L5-S1 level in 3 patients (1.8%), and L1-L2 level in 1 patient (0.6%). RESULTS: The surgical time ranged from 8 to 14 minutes for 1 single level. No adverse events were noted. In 1 case (0.6%), Aperius was not implanted because of hypertrophic facet joints that have hindered the correct insertion of the device; we observed only 2 cases of therapeutic failure (1.3%). There was a significant improvement in the Visual Analog Scale and Zurich Claudication Questionnaire scores for low-back and leg pain and for neurogenic claudication. CONCLUSIONS: These results indicate that Aperius PercLID system offers an easy, safe, and effective treatment for patients with lumbar degenerative stenosis. Thus, this device system treatment represents a valid alternative to the traditional surgical techniques.

New presenting symptoms of Chiari I malformation: report of two cases.

OBJECTIVE: Chiari Malformation type I nowadays represents one of the most debated and treated entities of neurosurgery. Several different symptoms of cerebellar, brainstem and spinal cord pathology have been described and attributed to this malformation. In this paper, we reported a very uncommon association of Chiari I malformation with isolated hemihypertrophy in one case and clawing hands in the second case. CASE REPORTS: We report the first case of a 14-year-old girl who presented with a 6-month history of left claw hand, with no evidence of radiculopathy and myopathy; MRI scan revealed a symmetrical herniation of cerebellar tonsils to the level of C1 (0.7 mm), downward displacement of the obex and holocord syrinx. We assisted to the complete resolution of the left clawing hand immediately after decompressive craniectomy, C1 laminectomy, opening of the dura and collagen matrix duraplasty. The second case is a 9-year-old boy who presented with hemihypertrophy affecting the left arm and chest wall, without involvement of the face. CONCLUSIONS: These case reports can suggest the association of hemihypertrophy and claw hand with Chiari I malformation and syringomyelia. Further studies are necessary to assess the real incidence of focal motor deficits and mesodermic disorders in Chiari I malformation in order to clarify their pathogenetical mechanisms.

Thyroid neoplasm after central nervous system irradiation for medulloblastoma in childhood: report of two cases.

OBJECTIVE: Surgical excision combined with radio-chemotherapy represents the gold standard of therapy of medulloblastoma. The effectiveness of such a combined treatment has encouraged the use of radiotherapy even in young paediatric patients, in spite of the many adverse effects reported in literature, and, in particular, the increased risk of a second radioinduced malignancy. Irradiation is the well-known risk factor for development of benign and malignant thyroid tumours. Children are more exposed to this risk because of their thyroid gland is more sensitive to carcinogenic effect of ionising radiation. CASE REPORT: Two children underwent radiotherapy for the treatment of a medulloblastoma when they were 3 and 4 years old, respectively. At the age of 20 and 23, both of them underwent the surgical excision of a papillary thyroid carcinoma, 20 and 17 years after the radiotherapeutic treatment, respectively. CONCLUSIONS: Radioinduced thyroid tumours are a well-recognised nosographic entities due to the particular sensitivity of this gland to ionising radiations. However, only a few papers on radioinduced thyroid neoplasms after CNS irradiation have been published in the literature. We report on two additional cases of thyroid neoplasms following childhood CNS irradiation for the treatment of a posterior fossa medulloblastoma.

Retrieval of ventricular catheter with the aid of endoscopy: technical note.

Multilocular hydrocephalus usually requires placement of multiple ventricular catheters for the treatment of secondary cysts and intraventricular septation. The formation of strong adhesions can embed the catheters so that they cannot be removed without a higher risk of intraventricular hemorrhage. Moreover, the devices could represent a nidus for infection and a risk for formation and enlargement of intraventricular secondary cysts. Neuroendoscopy allows the surgeon safely to reach the ventricular catheters that have been left or lost in the ventricular cavity, and to remove them via a minimally invasive approach. In this paper, the authors document another application of ventricular endoscopy in the management of this kind of hydrocephalus. The removal of an unnecessary and no longer useful prosthetic device that is a possible focus of infection justifies endoscopic treatment, which, in this experience, is not associated with morbidity.

Radiation-induced brain tumours after central nervous system irradiation in childhood: a review.

OBJECTS: Radiation-induced cerebral tumours constitute a significant risk for subjects undergoing radiotherapy for the management of cerebral neoplasms. Age-related cerebral vulnerability could be a specific factor in the genesis of these complications. METHODS: The pertinent literature of both paediatric and adult series has been reviewed. Three personal cases were added. RESULTS: One hundred forty-two paediatric second brain tumours were evaluated. Out of them, 69 were malignant gliomas, 33 meningiomas, 8 sarcomatous lesions and 13 low-grade astrocytomas. The average latency period for the appearance of the second tumour was 8 years. Among the second tumours occurring in adults, meningioma is the most common. In this subgroup, the latency period ranged between 16 and 30 years. CONCLUSION: Paediatric radiation-induced brain tumours differ from the adult counterpart for both the histological subtypes. These figures indicate a specific vulnerability of the infantile brain demonstrated by the most frequent occurrence of highly malignant lesions.

Thoracic lipomeningocele associated with diastematomyelia, tethered spinal cord, and hydrocephalus. Case report.

Accessory human tails are uncommon malformations consisting of meningeal and neural structures and possibly occult spinal dysraphism (pseudotails). The thoracic location of a lipomeningocele constituting a pseudotail is very rare. The authors report the case of a young boy harboring a thoracic dorsal appendage consisting of a lipomeningocele and a dermoid cyst that was complicated by the presence of diastematomyelia, tethered spinal cord, syringomyelia, and mild hydrocephalus. The preoperative moderate ventricular dilation was decompressed by the surgical repair of the spinal malformation and required a specific treatment. The authors discuss the rare association of these clinical entities and conclude that complete spine and brain neuroimaging studies are necessary for the correct surgical planning of this kind of malformation.