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Supplementary Table S1 from Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma

Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D2 (PGD2) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD2, to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD2 substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas. [Mol Cancer Ther 2008;7(10):3420–8]

Intraneural haemangiomas are rare tumours that can affect peripheral nerves. We describe a case of a 10-year-old female with an incidental finding of a common peroneal nerve lesion following knee injury. MRI demonstrated avid heterogeneous enhancement and peri-lesional oedema, and an open biopsy was performed revealing haemangioma on histopathological analysis. The patient was managed with observation and remains intact at 24-month follow-up.

Background Spinal intradural arachnoid cysts (SIAC) are cerebrospinal fluid (CSF) filled sacs formed by arachnoid membranes and may be either idiopathic or acquired. Idiopathic cysts represent a separate entity and their aetiology remains uncertain. By far the most difficult differential diagnosis is distinguishing between idiopathic anterior spinal cord herniation (IASCH) and dorsal thoracic intradural arachnoid cysts (TIAC), due to their similarity in radiological appearance. Cine-mode (SSFP) is emerging as a novel technique in the diagnosis and operative planning of SIAC. Method Retrospective analysis of patients with idiopathic TIACs that were surgically managed at Royal North Shore Hospital and North Shore Private Hospital between November 2000 and November 2015. Results Ten patients were included in this study. Age ranged from 20 to 77 years with a mean age of 60 years and a female preponderance. The most common clinical features were progressive gait ataxia and lower limb myelopathy. Radicular pain tends to improve following surgery, however gait ataxia may not. Discussion While there are circumstances in which the distinction between dorsal thoracic intradural arachnoid cysts and idiopathic anterior spinal cord herniation are radiologically obvious, in cases where the appearances are less clear, cine-mode SSFP MRI imaging can provide an invaluable tool to differentiate these pathologies and lead the clinician towards the correct diagnosis and management. The mainstay of surgical management for dorsal TIACs is laminectomy and cyst excision or fenestration. Surgery for gait ataxia should be aimed towards preventing deterioration, while maintaining the potential for symptomatic improvement, whereas surgery for radicular pain should be curative.

Diagnosis of an anaplastic astrocytoma (World Health Organization grade III) is associated with a highly variable prognosis. The identification of clinical markers that allow a more careful delineation of this prognostic spectrum is urgently needed. In this study, we analysed 48 patients with a histological diagnosis of anaplastic astrocytoma and found peritumoral post-gadolinium contrast enhancement to be a clear prognostic marker of poor prognosis. Multivariate analysis also confirmed surgery type, Karnofsky Performance Status score (

Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase ( IDH1 mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes.

Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D2 (PGD2) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD2, to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD2 substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas. [Mol Cancer Ther 2008;7(10):3420–8]

✓Benign peripheral nerve sheath tumors include the neurofibroma, schwannoma, and their plexiform variants. Operative management begins with an assessment of the relative risks associated with surgery compared with observation. The risks of observation include the risk of malignancy, the progression of symptoms, risk of delayed surgery, and ongoing patient suffering. The risks of surgery include anesthetic problems, wound complications, and neurological injury. New neurological deficits have been reported to occur in approximately 10 to 15% of surgically treated cases. In general, surgery is recommended for symptomatic or progressive lesions. Although the surgical approach will vary depending on the location, type, and extent of tumor, adherence to certain principles will facilitate success. Adequate visualization and successful removal will be achieved with detailed anatomical knowledge, an adequate extensile exposure to visualize the proximal and distal tumor extent, circumferential dissection of the tumor, microsurgical dissection under appropriate magnification, and meticulous hemostasis throughout the procedure.

Accurate prognosis for patients with anaplastic oligodendroglial gliomas is increasingly difficult to make. Characterisation of these tumours remains challenging, increasing proportions of oligodendroglial diagnoses in gliomas are reported, and no WHO 2000 grade IV exists for them, so that highly anaplastic tumours can only be grouped with glioblastoma (GBM) or with grade III oligodendroglioma, which have differing clinical behaviour. Longer survival times reported for patients with glioblastoma containing an oligodendroglial element (GBMO) suggest that a grade IV for oligodendroglial tumours might exist. In patients with anaplastic gliomas containing an oligodendroglial element, we explored whether microvascular proliferation (MVP) and necrosis were associated with shorter survival, sufficient to create a grade IV. Biopsies for 98 patients with anaplastic oligodendroglioma, anaplastic oligoastrocytoma or tumours with an oligodendroglial and GBM element, discharged 1998-2004, were identified from databases at three allied neurosurgery units. Pathology reports were reviewed for the presence of MVP and necrosis. Anaplastic oligoastrocytoma and GBMO were combined to measure the effect of an astrocytic element on survival. For anaplastic oligodendroglioma patients, median survival time was 24 months, while for anaplastic oligoastrocytoma or GBMO patients, it was 9 months. Age 60 or over (P=0.006) and astrocytic element (P=0.01) were the only independent predictors of survival. Patients 60 and over with an astrocytic element had 4.6 times the risk of death of patients under 60 with anaplastic oligodendroglioma.A grade IV cannot be created using necrosis or MVP since neither feature predicted survival after adjustment for age and an astrocytic element. However age and an astrocytic element were strong predictors of poorer survival in patients with anaplastic oligodendroglial tumours.

OBJECTIVE To help clarify the optimal surgical strategy for idiopathic, symptomatic ulnar nerve compression at the elbow in terms of overall outcome and morbidity by using objective criteria. METHODS Forty-four surgical candidates were recruited prospectively and were randomized into the neurolysis (n = 23) or transposition (n = 21) arm of the study. Preoperative and postoperative outcomes were assessed symptomatically and by performance on McGowen and Louisiana State University Medical Center grading systems at 1 month, 6 months, and 1 year. RESULTS Both procedures were equally effective in producing objective neurological improvement (61% in the neurolysis group, 67% in the transposition group). Wound complications, however, were more significant in the transposition group. Three of 21 in the transposition group compared with 0 of 23 in the neurolysis group experienced a deep wound infection. CONCLUSION Idiopathic symptomatic ulnar nerve compression at the elbow is adequately treated by both neurolysis in situ and submuscular transposition. Submuscular transposition was associated with a higher incidence of complications. The authors therefore suggest the simpler procedure of neurolysis in situ as the treatment of choice. Submuscular transposition remains appropriate in certain circumstances.

Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg to a maximum tolerated dose of 500 mg/d. Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300 mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival. Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.

The zygomaticotemporal approach with medial petrosectomy offers an alternative exposure for intradural lesions anterior to the brain stem. It improves access for tumours of the clivus and facilitates proximal control in low lying and giant basilar artery aneurysms. Twenty-three patients were operated on using this approach (12 aneurysms of the posterior circulation and 11 tumours). The permanent complications experienced with this exposure were ipsilateral hearing loss (two cases) and facial nerve palsy (one case). The experience in this series shows it is a useful alternative in accessing this difficult area.

The surgical technique for exposure of the brachial plexus via a posterior subscapular approach is reviewed, with its relevant anatomy. The author has used this approach for four brachial plexus procedures. The indications for this approach will be discussed, and a case history presented to illustrate the benefits of this procedure in recurrent thoracic outlet syndrome.

Object The aim of this study was to provide disease-specific information about schwannomatosis in its different forms and to present 2 particular cases of malignant schwannomas in the context of familial schwannomatosis (FS). Methods The authors analyzed patients with pathologically defined schwannomas and identified those with varied forms of schwannomatosis. Each case was retrospectively analyzed for patient sex and age, number of operations and tumors excised, symptoms, location and size of tumors, extent of resection, nerve function pre- and postoperatively, complications, other nonsurgically treated tumors, malignancy, results of brain MR imaging, and follow-up data. Results One hundred fifty-eight patients underwent the excision of 216 schwannomas. One hundred forty-two patients presented with solitary schwannomas, 2 had neurofibromatosis Type 2 (NF2), and 14 presented with schwannomatosis. The average follow-up was 52 months. Six individuals had sporadic schwannomatosis, whereas 8 had the familial form of the disease. These 14 patients had an average age of 28.3 years at the time of disease onset (median 27.5 years) and 35.4 years at the time of the first operation (median 37 years) Thirteen of the 14 patients with schwannomatosis experienced pain as the first symptom. Eight (57%) of the 14 patients presented with at least 1 tumor in the spinal canal or attached to the spinal nerve roots. Malignant schwannomas developed in 2 patients from the same family during the follow-up. Conclusions Patients suffering from schwannomatosis tend to be younger than those presenting with solitary schwannomas. Therefore, individuals presenting at a young age with multiple schwannomas but not meeting the criteria for NF2 should prompt the physician to suspect schwannomatosis. Patients with schwannomatosis who report pain should be exhaustively examined. The spine is affected in the majority of patients, and MR imaging of the spine should be part of the routine evaluation. Rapid enlargement of schwannomas in the context of FS should raise suspicion of malignant transformation.

Glioblastoma (GBM) represents a formidable clinical challenge for both patients and treating physicians. Due to better local treatments and prolonged patient survival, remote recurrences are increasingly observed, underpinning the importance of targeting tumour migration and attachment. Aberrant expression of microRNA (miRNA) is commonly associated with cancer and loss of miR-124a has previously been implicated to function as a tumour suppressor. The assessment of miR-124a in clinical specimens has been limited and a potential role in migration and invasion has been unexplored until now. We measured the expression levels of mature miR-124a in a retrospective series of 119 cases of histologically confirmed GBM and found its expression was markedly lower in over 80% of the GBM clinical specimens compared to normal brain tissue. The level of reduction in the clinical cohort varied significantly and patients with lower than the average miR-124a expression levels displayed shorter survival times. Endogenous miR-124a expression and the protein expression of three of its targets; IQ motif containing GTPase activating protein 1 (IQGAP1), laminin γ1 (LAMC1) and integrin β1 (ITGB1) were significantly reciprocally associated in the majority of the clinical cases. We confirmed this association in our in vitro model. Functionally, the ectopic expression of mature miR-124a in a GBM cell line resulted in significant inhibition of migration and invasion, demonstrating a role for miR-124a in promoting tumour invasiveness. Our results suggest that miR-124a may play a role in GBM migration, and that targeted delivery of miR-124a may be a novel inhibitor of GBM invasion.

The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p=0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma.

Combined intratemporal and cerebellopontine angle meningiomas are rejatively rare. There are unsolved problems with the stability of the skull and spine and the lower cranial nerves and there is a marked tendency for the tumor to involve the spinal cord. This article reports on five cases of combined intratemporal and cerebellopontine angle meningiomas.

Cerebral metastases from gastrointestinal primaries constitute about 3-5% of surgically resected brain secondaries. There has been a paucity of regional and worldwide data concerning the survival and clinical course of patients undergoing neurosurgical treatment of cerebral metastases from colorectal origin. The clinical course and survival of 32 patients undergoing neurosurgical intervention for colorectal carcinoma metastases between 1999 and 2007 was examined. The 21 male and 11 female patients examined had a median age of 61.8 years at diagnosis of colorectal cancer; median interval between colorectal cancer diagnosis and cerebral metastatic disease was 27.6 months; and 88% of patients underwent microsurgical resection. Median survival from neurosurgical intervention was 7.5 months. Perioperative mortality was 3%. Age, gender and infratentorial location of lesions had no significant impact on survival. Patients undergoing whole brain radiotherapy (WBRT) had a significantly longer survival than those not undertaking this treatment (median survival 10.6 vs. 5.2 months, p = 0.018). A randomised, controlled trial of the utility of WBRT following surgical resection in this tumour subtype seems appropriate.

Clinical treatment decisions and the survival outcomes of patients with gliomas are directly impacted by accurate tumor classification. New and more reliable prognostic markers are needed to better identify the variable duration of survival among histologically defined glioma grades. Microarray expression analysis and immunohistochemistry were used to identify biomarkers associated with gliomas with more aggressive biologic behaviors. The protein expression of IQGAP1 and IGFBP2, when used in conjunction with the World Health Organization grading system, readily identified and defined a subgroup of patients with grade III gliomas whose prognosis was poor. In addition, in patients with glioblastoma multiforme, in whom IQGAP1 and IGFBP2 were absent, long-term survival of more than 3 years was observed. The use of these markers confirmed a nonuniform distribution of survival in those with World Health Organization grade III and IV tumors. Thus, IQGAP1 and IGFBP2 immunostaining supplements current histologic grading by offering additional prognostic and predictive information.

Acceptance is increasing for pharmacological prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism (PE) for most types of surgery, but its use remains controversial in neurosurgical patients because of the threat of catastrophic hemorrhage. Consequently, mechanical measures such as sequential calf compression and graduated compression stockings are currently the preferred prophylaxis for neurosurgical patients. However, some patients remain at high risk despite these measures and may require prophylaxis with low molecular weight heparins or unfractionated heparin. In neurosurgical patients, known risk factors for DVT or PE include advanced age, malignancy, limb weakness, prolonged surgery, and cranial as opposed to spinal surgery. Using comprehensive neurosurgery databases, the authors identify more specific neurosurgical diagnoses and procedures as risk factors for DVT and PE, and show increases in the frequency of DVT and PE for the wider neurosurgery population and for glioma patients over time. DVT prophylaxis is compared in public and private hospital settings. This chapter contributes to the changing picture of DVT and PE in neurosurgical patients over the last two decades.

Four cases of occipital bone pneumatization and subsequent complications are described, which include a pathological fracture of C1 and the occipital bone, spontaneous subcutaneous emphysema and pneumatocele formation. Reviews of the published literature and possible aetiological factors have been discussed.

Objective Primary lymphomas of peripheral nerves are extremely rare, with the bulk of the literature being case reports. The nerve most commonly affected is the sciatic nerve, with 9 cases reported. To date, there are no reports in the English literature of isolated involvement of the radial nerve by a primary lymphoma. Clinical presentation A 69-year-old woman with a history of osteoporosis, irritable bowel disease, asthma, and Graves' disease presented with a 6-month history of paresthesia in her left superficial sensory radial nerve territory, weakness of thumb extension, and localized pain and swelling in the cubital fossa. Examination showed a painful tender mass in the line of the radial nerve in the cubital fossa, grade 4/5 supination, grade 4-/5 extensor carpi radialis longus and extensor carpi ulnaris, and grade 3/5 finger and thumb extension, all consistent with a radial nerve lesion at the level of the cubital fossa. Ultrasonography and computed tomography confirmed an intraneural tumor. Surgery revealed radial intraneural tumor just after the branch to the extensor carpi radialis longus. It was clearly an infiltrating lesion with no plane between tumor and nerve fascicles. Frozen section confirmed malignancy, and an incomplete excision was performed. Histopathology revealed diffuse large B-cell lymphoma. Surgery was followed with negative staging and a chemotherapy program. Conclusion Primary B-cell lymphoma of the peripheral nerve is exceedingly rare and to date has not been reported as an isolated occurrence in the radial nerve. We present a patient who is alive and disease free 65 months after incomplete excision and limited chemotherapy.