Neuro-Oncology and Radiogenomics: Time to Integrate?

Radiogenomics aims to predict genetic markers based on imaging features. The critical importance of molecular markers in the diagnosis and management of intracranial gliomas has led to a rapid growth in radiogenomics research, with progressively increasing complexity. Despite the advances in the techniques being examined, there has been little translation into the clinical domain. This has resulted in a growing disconnect between cutting-edge research and assimilation into clinical practice, though the fundamental goal is for these techniques to improve patient care. The goal of this review, therefore, is to discuss possible clinical scenarios in which the addition of radiogenomics may aid patient management. This includes facilitating patient counseling, determining optimal patient management when complete molecular characterization is not possible, reclassifying tumors, and overcoming some of the limitations of histologic assessment. The review also discusses considerations for selecting relevant radiogenomic features based on the clinical setting.

Use of tissue plasminogen activator in the treatment of shunt blockage secondary to intraventricular haemorrhage.

A 51-year-old woman with a history of idiopathic aqueduct stenosis, treated initially with insertion of a ventriculo peritoneal shunt, presented to our institution with shunt dysfunction. She had previously undergone multiple shunt revisions for shunt infection, shunt blockage and low-pressure symptoms, most recently with conversion to a ventriculo atrial (VA) shunt. Her VA shunt was again revised, with replacement of the ventricular catheter, however surgery was complicated by a large intraventricular haemorrhage (IVH) requiring placement of an external ventricular drain (EVD). Prior to eventual removal of her EVD it was determined that the VA shunt had blocked as a result of the IVH. Subsequently alteplase, a recombinant tissue plasminogen activator (tPA), was administered into the shunt reservoir, resulting in successful return of shunt function, therefore avoiding the need for further shunt revision. This is the first description of the use of tPA to unblock a shunt obstructed by blood.

MRI grading versus histology: predicting survival of World Health Organization grade II-IV astrocytomas.

BACKGROUND AND PURPOSE: Histologic grading of intracranial astrocytomas is affected by sampling error and substantial inter- and intraobserver variability. We proposed that incorporating MR imaging into grading will predict patient survival more accurately than histopathology alone. MATERIALS AND METHODS: Patients with a new diagnosis of World Health Organization grades II-IV astrocytoma or mixed oligoastrocytoma diagnosed between September 2007 and December 2010 were identified. Two hundred forty-five patients met the inclusion criteria. Preoperative MRIs were independently reviewed by 2 readers blinded to the histologic grade, and an MR imaging grade was given. The MR imaging and histopathologic grades were compared with patient survival. RESULTS: Patients with grade II or III astrocytomas on histology but evidence of necrosis on MR imaging (consistent with a grade IV tumor) had significantly worse survival than patients with the same histology but no evidence of necrosis on MR imaging (P = .002 for grade II histology and P = .029 for grade III). Their survival was not significantly different from that in patients with grade IV tumors on histology (P = .164 and P = .385, respectively); this outcome suggests that all or most are likely to have truly been grade IV tumors. MR imaging evidence of necrosis was less frequent in grade II and III oligoastrocytomas, preventing adequate subgroup analysis. CONCLUSIONS: MR imaging can improve grading of intracranial astrocytomas by identifying patients suspected of being undergraded by histology, with high interobserver agreement. This finding has the potential to optimize patient management, for example, by encouraging more aggressive treatment earlier in the patient's course.

Glutamate quantification in patients with supratentorial gliomas using chemical shift imaging.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r² = 0.95, p = 0.002, and r² = 0.97, p < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r² = 0.22, p = 0.04) and ratios of Glu to Cr (r² = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma.

Neurosurgical considerations in von Hippel-Lindau disease.

Von Hippel-Lindau disease is an inherited syndrome predisposing to a variety of benign and malignant neoplasms of the central nervous system and viscera that requires comprehensive screening and follow-up of individuals and their families. As such, it is important for the neurosurgeon to be aware of its clinical features and management issues. In this article we review the clinical aspects, management and surveillance of von Hippel-Lindau disease for neurosurgical practice.

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs.

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

Electrophoretic sequencing of heparin/heparan sulfate oligosaccharides using a highly sensitive fluorescent end label.

The sequencing of heparan sulfate oligosaccharides has recently become possible using integral Glycan Sequencing, which utilizes a combination of chemical and enzymatic degradation steps followed by polyacrylamide gel electrophoresis. This technique has previously employed the fluorescent label, anthranilic acid, and has been used to sequence low nmol amounts of purified saccharides. Here, we present an improved method, which uses the alternative label, 7-aminonapthalene-1,3-disulfonic acid, the reducing agent sodium triacetoxyborohydride and optimizes the nitrous acid step in heparin/heparan sulfate degradation. These improvements increase the sensitivity at least ten-fold taking the amount of starting material required into the pmol range. We show that this label is compatible with the integral glycan sequencing methodology and demonstrate its application to the sequencing of chemically modified heparin derivatives. Advances in sequencing techniques for heparan sulfate saccharides will permit detailed structure-function studies and will in the future underpin novel proteomics-based approaches aimed at studying their diverse functional roles as protein regulators.

Metastatic atypical meningioma: case report and review of the literature.

Extracranial metastasis of an intracranial meningioma is rare. We discuss the clinical, radiological and histopathological presentation of an elderly man with pulmonary metastases from a recurrent meningioma of atypical histology, and review the literature pertaining to this phenomenon.

Pineal region tumours in childhood. A 30-year experience.

Patients aged under 16 years presenting to the Royal Children's Hospital between 1967 and 1997 with pineal region tumours were retrospectively reviewed. Thirty-seven patients were identified, with 13 germinomas, 7 nongerminomatous germ cell tumours, 6 pineoblastomas, 2 pineocytomas, and 3 astrocytomas, while in 6 patients no histopathological diagnosis was obtained. The most common presentation was with symptoms of raised intracranial pressure due to hydrocephalus. Thirty-two of the 37 patients required a shunt. Thirteen had a biopsy as a separate procedure, 3 of which were stereotactic. Tumour excision was performed in 21 patients and was complete in 4 and subtotal in 17. There were 2 perioperative deaths and 6 patients who were neurologically worse after surgery. Twenty-six patients had radiotherapy and 16 chemotherapy, with significant complications of radiotherapy in half of the patients who received it. The 5-year survival of patients with benign tumours was 75%, 5-year survival with germinomas 62% and with other malignant tumours 14%. This series demonstrates significant improvements in management of pineal region tumours in the last 30 years and highlights some of the current controversies. A collaborative research approach is necessary to determine optimal management of the varied tumour types occurring in the pineal region in childhood.

Surgical management of dural arteriovenous malformations of the cranium.

Ten patients undergoing surgical treatment of dural arteriovenous malformations of the cranium between June 1992 and June 1995 are presented. Indications for surgery were prevention of intracranial haemorrhage in eight cases and palliation of neurological deficits in two cases. The aim of surgery was attempted complete cure when considered technically feasible. Six patients underwent aggressive surgical resection in an ablation attempt and four underwent leptomeningeal venous disconnection only. In those undergoing aggressive surgical resection, one patient died, one was rendered disabled and angiographic cure was achieved in four without mishap. In those undergoing leptomeningeal venous disconnection, there was no mortality or morbidity but angiographic cure was achieved in only one of four patients. As a result of our experience our policy has changed. When the indications for surgery are to palliate leptomeningeal venous hypertension or as prophylaxis against future haemorrhage, interruption of the involved leptomeningeal venous drainage in the subarachnoid space without attempted cure is now the sole aim of surgery. The surgical technique employed should be based on the pathophysiological disturbance requiring correction rather than the resectability of the lesion.

Intracranial haemorrhage associated with anomalous venous drainage.

Two patients presented following small posterior fossa intraparenchymal haemorrhages from which they fully recovered. In one case this was a repeat haemorrhage. Both patients had sustained this haemorrhage within the bed of anomalous venous drainage. Angiography suggested that in both cases the anastomosis of the anomalous draining vein with the dural sinus was stenosed. These cases support the concept that anomalous venous drainage can be associated with intraparenchymal haemorrhage unassociated with cavernous malformation, that a compromised venous drainage may be the cause for such haemorrhage and that surgical resection of 'venous angiomas' is inappropriate.

Transcutaneous carbon dioxide measurement after craniotomy in spontaneously breathing patients.

OBJECTIVE: The purpose of this study was to determine the incidence of postoperative hypercarbia in patients undergoing intracranial neurosurgery. Postoperative hypercarbia is a well-recognized cause of postoperative morbidity. METHODS: Sixty-four patients undergoing craniotomy were monitored in the first 36 postoperative hours using transcutaneous CO2 monitoring. We collected and analyzed demographic data, complete medical histories and examinations, and details of surgery, anesthesia, and postoperative progress. The accuracy of the transcutaneous CO2 monitoring was evaluated by comparison with arterial blood gas CO2. INSTRUMENTATION: The "TINA" TCM3 Transcutaneous CO2 Monitor (Radiometer, Copenhagen, Denmark) was used. RESULTS: Thirty-nine patients (61%) developed no hypercarbia. Nineteen patients (30%) developed mild to moderate hypercarbia (46-59 mm Hg) and six patients (9%) developed severe hypercarbia (60 mm Hg or greater). Statistically significant differences were observed between the severely hypercarbic group and the other two groups combined, as follows: a higher incidence of preoperative and postoperative seizures, a lower average postoperative Glasgow Coma Scale score, a higher incidence of reintubation and ventilation, and a higher degree of intraoperative brain disturbance. Analysis of transcutaneous CO2 measurements and time-matched arterial blood gas CO2 measurements revealed an acceptable accuracy of the transcutaneous method. CONCLUSION: this study demonstrates that, in routine neurosurgical practice, a subgroup of patients are at risk of developing postoperative hypercarbia, which may be more common than is generally recognized and will not usually be detected by routine postoperative monitoring. Transcutaneous CO2 monitoring is a useful technique that may impact management decisions.

Surgery for cerebral arteriovenous malformation: risks related to lenticulostriate arterial supply.

The aim of this study was to compare complications of surgery in arteriovenous malformations (AVMs) supplied by the middle cerebral artery (MCA) with and without a lenticulostriate arterial contribution. Ninety-two consecutive surgical resections of AVMs with an angiographically demonstrated MCA supply were performed between January 1989 and July 1996. Ten of these cases had a significant lenticulostriate arterial contribution. The cases were graded according to the Spetzler-Martin classification. There were no deaths and 4.3% of cases developed new major neurological deficit by the 3-month follow-up examination. All cases had angiographically confirmed obliteration of the AVM. There were no complications in 16 patients with Spetzler-Martin Grade I AVMs, one case of complications in 40 patients with Grade II AVMs, eight cases of complications in 26 patients with Grade III AVMs, and seven cases of complications in 10 patients with Grade IV and V AVMs. The supply of blood from lenticulostriate branches was associated with complications in eight of the 10 cases. The effect of the presence of a lenticulostriate arterial supply was most apparent in cases of Grade III AVMs: complications were experienced in three of 20 patients whose AVMs were not supplied by the arteries and in five of six patients whose AVMs were fed by the lenticulostriate arteries. This difference is significant (p < 0.0001). The conclusions drawn from this study are that for Grade III AVMs, the presence of a lenticulostriate arterial supply can be considered a factor predictive of an increased risk of surgical complications.