Tumefactive multiple sclerosis versus high grade glioma: A diagnostic dilemma.

Background: Tumefactive demyelinating lesions (TDL) share similar clinical features and magnetic resonance imaging (MRI) characteristics with high grade glioma (HGG). This study develops an approach to navigating this diagnostic dilemma, with significant treatment implications as the management of both entities is drastically different. Methods: A retrospective analysis of 41 TDLs and 91 HGG with respect to demographics, presentation and classical MRI characteristics was performed. A diagnostic pathway was then developed to help diagnose TDLs based on whole neuraxis MRI and cerebrospinal fluid (CSF) examination. Results: The diagnosis of TDL is more likely than HGG in younger females who present with subacute or chronic symptoms. MRI characteristics favoring TDL over HGG include smaller size, open rim enhancement, little or no associated edema or mass effect and the presence of a T2 hypointense rim. MRI of the whole neuraxis for detection of other lesions typical of multiple sclerosis (MS), in combination with a lumbar puncture (LP) showing positive CSF-specific oligoclonal bands (OCB), was positive in 90% of the TDL cohort. Conclusion: The diagnostic pathway, proposed on the basis of specific clinicoradiological features, should be followed in patients with suspected TDL. If MRI demonstrates other lesions typical of MS and LP demonstrates positive CSF-specific OCBs, then patients should undergo a short course of IV steroids to look for clinical improvement. Patients, who continue to deteriorate, do not demonstrate other lesions on MRI or where the LP is negative for CSF-specific OCB, should be considered for biopsy if safe to do so. This pathway will give the patients the best chance at neurological preservation.

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region following radiotherapy.

BACKGROUND: The impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. METHODS AND MATERIALS: Patients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. RESULTS: Thirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume. CONCLUSION: IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

Redo craniotomy or bevacizumab for symptomatic steroid-refractory true or pseudoprogression following IMRT for glioblastoma.

BACKGROUND: There is minimal evidence to support decision making for symptomatic steroid-refractory pseudoprogression or true progression occurring after intensity-modulated radiation therapy (IMRT) for glioblastoma (GBM). This study audited the survival outcome of patients managed with redo craniotomy (RedoSx) or bevacizumab (BEV) for steroid-refractory mass effect after IMRT for GBM. METHODS: Patients with GBM managed between 2008 and 2019 with the EORTC-NCIC Protocol were entered into a prospective database. Patients with symptomatic steroid-refractory mass effect within 6 months of IMRT managed with either RedoSx or BEV were identified for analysis. For the primary endpoint of median overall survival (OS) postintervention, outcome was analyzed in regards to potential prognostic factors, and differences between groups were assessed by log-rank analyses. RESULTS: Of the 399 patients managed with the EORTC-NCIC Protocol, 78 required an intervention within 6 months of IMRT completion for either true or pseudoprogression (49 with RedoSx and 29 with BEV). Subsequently, 20 of the 43 patients managed with RedoSx when BEV was clinically available, required salvage with BEV within 6 months after RedoSx. Median OS postintervention was 8.7 months (95% CI: 7.84-11.61) for the total group; and 8.7 months (95% CI: 6.8-13.1) for RedoSx and 9.4 months (95% CI: 7.8-13.6) for BEV (P = .38). Subsequent use of BEV in RedoSx patients was not associated with improved survival compared with RedoSx alone (P = .10). Age, time from IMRT, and ECOG performance status were not associated with OS. In the RedoSx patients, immunohistochemical features such as Ki-67% reduction correlated with survival. The presence of pure necrosis and residual tumor cells only had improved survival compared with the presence of gross tumor (P < .001). CONCLUSIONS: At time of symptomatic steroid-refractory true or pseudoprogression following IMRT for GBM, BEV was equivalent to RedoSx in terms of OS. Pseudoprogression with residual cells at RedoSx was not associated with worse outcome compared to pure necrosis.

Focal radiation therapy for limited brain metastases is associated with high rates of local control and low subsequent whole brain radiation therapy.

BACKGROUND: Assess clinical outcomes of focal radiotherapy (RT) in patients with limited brain metastasis (LBM) with whole brain RT (WBRT) avoidance. METHODS: Patients diagnosed with LBM were entered into a database between January 2010 and February 2017. Patients were recommended WBRT avoidance with focal therapy and three-monthly magnetic resonance imaging. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, initial-site failure (ISF), distant brain relapse (DBF), leptomeningeal disease and rate of WBRT. Analysis involved Kaplan-Meier survival estimate with log-rank tests and Cox-regression analysis. RESULTS: One hundred and sixty-six patients were managed with median follow-up of 13 months and median overall survival of 15 months (95% confidence interval (CI) 10.8-19.2). Eighty-three patients had central nervous system (CNS) relapse with median progression-free survival of 11 months (95% CI 6.7-15.3), of which most failures were DBF (83.1%) with 27 ISF (32.5%). Of the ISFs, 12 (43%) had surgery alone, six had chemotherapy alone and nine received RT. Surgery or chemotherapy alone compared with RT had a significantly higher incidence of ISF with a hazard ratio of 4.96 (P < 0.0001, 95% CI 2.10-11.83) and 6.54 (P = 0.001, 95% CI 2.26-18.87), respectively. WBRT was utilized in only 24 patients, with 83% patients free of WBRT at 12 months. On univariate analysis, number of metastases (P = 0.04), symptomatic extracranial disease (P = 0.04) and early CNS relapse within 6 months (P < 0.01) had worse survival. No grade 3-4 toxicity events were noted in 129 patients undergoing RT. CONCLUSION: Focal RT has a low rate of ISF with low toxicity in patients with LBMs. CNS progression was mainly DBF with low rates of salvage WBRT.

Role of 18F-fluoro-ethyl-tyrosine Positron Emission Tomography in Investigation and Management of Suspected Gliomas.

BACKGROUND: This study aims to investigate the utility of 18F-fluoro-ethyl-tyrosine (18F-FET) positron emission tomography in surgical decision making in suspected glioma. METHODS: A retrospective review of patients undergoing 18F-FET positron emission tomography was performed. Previously published thresholds for maximum tumor background ratios (TBRs) were used for quantitative analysis. Forty-seven patients were included in the study, of whom 15 had confirmed glioma and 7 had a confirmed alternative diagnosis. RESULTS: 18F-FET showed significantly higher uptake in high-grade glioma than in nonglioma. CONCLUSIONS: Lesions with TBRmax >2.5 should be considered suspicious for glioma and biopsy considered. Threshold TBRmax >3.0 is useful for differentiating high-grade glioma from low-grade glioma. This may be a particularly useful tool for directing management in eloquent areas, such as brainstem glioma.

FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes - A pilot study.

We aimed to determine the utility of FET PET in the management of indeterminate CNS lesions found on MRI. We performed a retrospective analysis of patients with FET PET at a single tertiary institution from 2011 to 2015. FET PET images were processed using usual methods and measurements taken including SUVmax, TBRmax, and analysis of dynamic series where available (Kipeak, Vdpeak, as well as tumor:background ratio for these variables). Correlation studies were performed using ANOVA between cohorts of high-grade histology, low-grade histology, and benign histology/stable on observation. Thirty-five patients were included, of whom 34 were suitable for analysis with median follow-up of 5 months. The positive predictive value of FET PET in this cohort was 83.3%. FET SUVmax differentiated between patients with high-grade (mean SUV 3.38, 95% CI 2.21-4.55), low-grade (1.88, 95% CI 1.33-2.43) and benign/observation (1.42, 95% CI 1.13-1.71) cohorts (p = 0.0003). Similarly, tumour to brain ratio was significant (p < 0.0001). Kipeak distinguished between high grade and observation cohorts (p = 0.036), as did KiTBR (p = 0.025). Vd peak was not significantly different in these two cohorts (p = 0.057) but Vd TBR was (p = 0.041). In conclusion, FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort.

Survival improvements with adjuvant therapy in patients with glioblastoma.

BACKGROUND: Evaluate survival of patients diagnosed with glioblastoma multiforme (GBM) managed with adjuvant intensity modulated radiation therapy and temozolomide since the introduction of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) protocol. METHODS: All patients with GBM managed between May 2007 and December 2014 with EORTC-NCIC protocol were entered into a prospective database. The primary endpoint was the median survival. Univariate predictors of survival were evaluated with respect to tumour resection, age and Eastern Cooperative Oncology Group (ECOG) performance status using log-rank comparisons. RESULTS: Two hundred and thirty-three patients were managed under the protocol and analysed for outcome. The median age was 57 years; the rate of gross total resection, subtotal resection and biopsy were 47.2%, 35.2% and 17.6%, respectively. At progression, 49 patients had re-resection, and in addition to second-line chemotherapy, 86 patients had Bevacizumab including 26 with re-irradiation. Median survival was 17.0 months (95% CI: 15.4-18.6). On univariate evaluation, extent of resection (P = 0.001), age, ECOG performance status and recursive partitioning analysis class III were shown to significantly improve survival (P < 0.0001). The median survival for gross total resection, age <50 years, ECOG 0-1 and recursive partitioning analysis class III were 21, 27, 20 and 47 months, respectively. CONCLUSION: This study confirms the significant improvement in median survival in GBM that has occurred in recent years since introduction of the EORTC-NCIC protocol. Further improvements have occurred presumably related to subspecialized care, improved resection rates, sophisticated radiotherapy targeting and early systemic salvage therapies. However, the burden of the disease within the community remains high and the median survival improvements over time have plateaued.

Survival Outcomes of Elderly Patients With Glioblastoma Multiforme in Their 75th Year or Older Treated With Adjuvant Therapy.

PURPOSE: To assess the outcomes of the most elderly cohort of patients with a diagnosis of glioblastoma multiforme (GBM) after intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: The data of patients with GBM who had underwent IMRT from May 2007 to December 2015 were entered into a prospective database. Analysis was performed on the data from patients diagnosed during or after 75 years of age. The primary endpoint was the median survival. Univariate and multivariate analyses were performed with respect to survival for patients aged 74 to 80 versus >80 years, Eastern Cooperative Oncology Group performance status of 0 to 1 versus 2 to 3, extent of resection, a high radiation dose (60 Gy) versus any hypofractionated schedule, MGMT methylation status, planning target volume, and the use of temozolomide (TMZ) versus no TMZ. RESULTS: Of the 108 patients, 35 received best supportive care, 1 received TMZ alone, 40 received RT alone, and 32 received combined RT and TMZ. IMRT was delivered with a hypofractionated technique (40 Gy) in 58 patients or long-course RT (60 Gy) in 11 patients. The median age was 79 years, with 61.6% of patients aged 74 to 80 years and 38.4% aged >80 years. Of the 108 patients, 64 died during the follow-up period, with a median survival of 10 months (95% confidence interval 7.1-11.9), projected 12-month survival rate of 35.6%, and 24-month survival rate of 7.9%. On univariate analysis, the independent predictors of survival included younger age (P=.02), better performance status (P=.014), greater resection extent (P=.002), and TMZ use (P<.001). MGMT methylation status, RT dose, and planning target volume showed no significant differences between the groups. Only chemotherapy use remained statistically significant (P=.035) on multivariate analysis. CONCLUSION: The current data underrepresent elderly patients aged >75 years with GBM. Despite elderly patients having a worse prognosis, the results of the present study suggest the presence of survival benefits with IMRT for selected patients that can be further extended with addition of TMZ. Further study of this cohort and an understanding of the appropriate selection criteria are warranted.

Globus pallidus internus deep brain stimulation as rescue therapy for refractory dyskinesias following effective subthalamic nucleus stimulation.

BACKGROUND: Deep brain stimulation (DBS) at the subthalamic nucleus (STN) or globus pallidus internus (GPi) can effectively treat the motor symptoms of Parkinson's disease, but dual implantation is rare. We report the first cases of additional GPi stimulation as rescue therapy for disabling dyskinesias following successful STN stimulation. METHODS: Two patients, initially treated with bilateral STN DBS, underwent subsequent bilateral GPi DBS after the development of refractory dyskinesias within 1 and 6 years of STN surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgeries for STN and GPi DBS. RESULTS: GPi DBS effectively suppressed dyskinesias in these patients and improved their quality of life, as demonstrated by their videos and UPDRS scores. CONCLUSIONS: Additional bilateral GPi DBS may be considered in the rare instance of patients who develop refractory dyskinesias early or late after bilateral STN DBS.

Deep brain stimulation of the antero-medial globus pallidus interna for Tourette syndrome.

BACKGROUND: We have previously reported the results of Deep Brain Stimulation (DBS) of the antero-medial globus pallidus interna (GPi) for severe Tourette Syndrome (TS) in 11 patients. We extend this case series to 17 patients and a longer follow-up to a maximum of 46 months. METHODS: 17 patients (14 male; mean age 29.1 years, range 17-51 years) with severe and medically intractable TS were implanted with Medtronic quadripolar electrodes bilaterally in the antero-medial GPi. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS). Secondary outcome measures included the Yale-Brown Obsessive Compulsive Scale, Hamilton Depression Rating Scale, Gilles de la Tourette Quality of Life Scale and Global Assessment of Functioning. Follow up was at one month, three months and finally at a mean 24.1 months (range 8-46 months) following surgery. RESULTS: Overall, there was a 48.3% reduction in motor tics and a 41.3% reduction in phonic tics at one month, and this improvement was maintained at final follow-up. 12 out of 17 (70.6%) patients had a>50% reduction in YGTSS score at final follow up. Only 8 patients required ongoing pharmacotherapy for tics post-surgery. Patients improved significantly on all secondary measures. Adverse consequences included lead breakage in 4 patients, infection (1), transient anxiety (2), dizziness (1), poor balance (1) and worsening of stuttering (1). CONCLUSIONS: This case series provides further support that antero-medial GPi DBS is an effective and well tolerated treatment for a subgroup of severe TS, with benefits sustained up to 4 years.

MGMT expression and pituitary tumours: relationship to tumour biology.

Over the past half decade, temozolomide, an oral akylating chemotherapeutic agent, has been shown to have significant activity in the management of aggressive pituitary tumours. The expression of 06-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is an important predictor of response to therapy. Low MGMT expression has been reported with a higher frequency amongst more aggressive pituitary tumours, suggesting MGMT may play a role in pituitary tumour progression. In this study, we performed a microarray analysis to determine whether there was a distinct gene expression profile between tumours with low MGMT and high MGMT expression. Overall, 1,403 differentially expressed genes were identified with raw p values less than 0.05. Gene set enrichment analysis (GSEA) revealed significant differences in the gene expression profile between high and low MGMT expressing pituitary tumours. High MGMT expressing pituitary tumours were found to have upregulation of components of the FGFR family and downstream signaling cascades such as PI3 K/Akt and MAPK pathways. Activation of genes involved in the DNA damage response and DNA repair pathways, as well as genes involved in transcription, were identified in pituitary tumours with low MGMT expression. These results form the basis of our proposed model to describe the role of MGMT in pituitary tumorigenesis.

A multicenter study of primary brain tumor incidence in Australia (2000-2008).

There are conflicting reports from Europe and North America regarding trends in the incidence of primary brain tumor, whereas the incidence of primary brain tumors in Australia is currently unknown. We aimed to determine the incidence in Australia with age-, sex-, and benign-versus-malignant histology-specific analyses. A multicenter study was performed in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), which has a combined population of >7 million with >97% rate of population retention for medical care. We retrospectively mined pathology databases servicing neurosurgical centers in NSW and ACT for histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008. Data were weighted for patient outflow and data completeness. Incidence rates were age standardized and trends analyzed using joinpoint analysis. A weighted total of 7651 primary brain tumors were analyzed. The overall US-standardized incidence of primary brain tumors was 11.3 cases 100 000 person-years (±0.13; 95% confidence interval, 9.8-12.3) during the study period with no significant linear increase. A significant increase in primary malignant brain tumors from 2000 to 2008 was observed; this appears to be largely due to an increase in malignant tumor incidence in the ≥65-year age group. This collection represents the most contemporary data on primary brain tumor incidence in Australia. Whether the observed increase in malignant primary brain tumors, particularly in persons aged ≥65 years, is due to improved detection, diagnosis, and care delivery or a true change in incidence remains undetermined. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence that can be independent of multiple interstate cancer registries.

miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion.

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 ß1 (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 impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years' experience at a single centre.

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.

Schwannomatosis, sporadic schwannomatosis, and familial schwannomatosis: a surgical series with long-term follow-up. Clinical article.

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.

Increasing incidence of glioblastoma multiforme and meningioma, and decreasing incidence of Schwannoma (2000-2008): Findings of a multicenter Australian study.

BACKGROUND: The incidence of primary brain tumors by subtype is currently unknown in Australia. We report an analysis of incidence by tumor subtype in a retrospective multicenter study in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), with a combined population of >7 million with >97% retention rate for medical care. METHODS: Data from histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008 were weighted for patient outflow and data completeness, and age standardized and analyzed using joinpoint analysis. RESULTS: A significant increasing incidence in glioblastoma multiforme (GBM) was observed in the study period (annual percentage change [APC], 2.5; 95% confidence interval [CI], 0.4-4.6, n = 2275), particularly after 2006. In GBM patients in the ≥65-year group, a significantly increasing incidence for men and women combined (APC, 3.0; 95% CI, 0.5-5.6) and men only (APC, 2.9; 95% CI, 0.1-5.8) was seen. Rising trends in incidence were also seen for meningioma in the total male population (APC, 5.3; 95% CI, 2.6-8.1, n = 515) and males aged 20-64 years (APC, 6.3; 95% CI, 3.8-8.8). Significantly decreasing incidence trends were observed for Schwannoma for the total study population (APC, -3.5; 95% CI, -7.2 to -0.2, n = 492), significant in women (APC, -5.3; 95% CI, -9.9 to -0.5) but not men. CONCLUSION: This collection is the most contemporary data on primary brain tumor incidence in Australia. Our registries may observe an increase in malignant tumors in the next few years that they are not detecting now due to late ascertainment. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence by subtype, including the introduction of nonmalignant data collection.

Post-contrast enhancement as a clinical indicator of prognosis in patients with anaplastic astrocytoma.

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 (<70) and increasing age as independent adverse predictors of survival. The survival differences observed in the enhancing and non-enhancing lesions in patients diagnosed with anaplastic astrocytoma supports the existence of a broad anaplastic spectrum of disease, with enhancement being a clinical marker of tumour progression along this spectrum.

Nuclear accumulation of e-cadherin correlates with loss of cytoplasmic membrane staining and invasion in pituitary adenomas.

CONTEXT: Loss of the cell adhesion protein E-cadherin is associated with invasion and metastasis in a number of malignancies. Recent studies have highlighted that loss of E-cadherin cell membrane expression may be accompanied by its detection in the nucleus, suggesting cellular redistribution during neoplasia. Pituitary tumors, although typically benign, may be locally invasive, and loss of membranous E-cadherin has been reported as a marker of invasion in prolactinomas. OBJECTIVE: Our objective was to study E-cadherin expression in pituitary adenomas, specifically whether nuclear redistribution occurs in this setting. METHODS: Immunohistochemistry, RT-PCR, and direct sequencing were performed. RESULTS: Strong cytoplasmic membrane staining was present in all eight normal samples but completely absent in 21 of 44 adenomas (48%) with weak staining in an additional 11 adenomas using an antibody against the extracellular domain of E-cadherin. To identify nuclear translocation of the protein, immunohistochemistry was performed using an antibody against the cytoplasmic domain. Nuclear staining was present in 38 of 44 adenomas (86%) and absent in normal tissue. Nuclear E-cadherin inversely correlated with loss of E-cadherin cytoplasmic membrane staining and was associated with tumor invasion (P = 0.009). To investigate the mechanism of nuclear redistribution of E-cadherin, we performed RT-PCR of mRNA and sequenced tumor DNA. E-cadherin mRNA expression was reduced in only one of 30 samples (3%). No mutations were detected. CONCLUSIONS: E-cadherin was frequently lost at the cytoplasmic membrane but detected in the nucleus, suggesting that cleavage of the extracellular domain and nuclear translocation of E-cadherin is a common event that may determine local invasion in pituitary adenomas.

Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours.

CONTEXT: Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide. OBJECTIVE: To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours. PATIENTS: We report two patients with aggressive pituitary tumours treated with temozolomide, one who responded to temozolomide and the other who did not. MGMT expression was assessed in a further 88 archived pituitary tumour samples. DESIGN: MGMT expression was assessed by immunohistochemistry. MGMT promoter methylation was studied by methylation-specific polymerase chain reaction (MSP), sequencing of MGMT was performed and loss of heterozygosity (LOH) analysis undertaken. RESULTS: Low MGMT expression and MGMT promoter methylation were found in the pituitary tumour of the patient who responded to temozolomide. Conversely, high MGMT expression was seen in the patient demonstrating a poor response to temozolomide. Eleven out of 88 archived tumour samples (13%) had low MGMT expression. Prolactinomas were more likely to have low MGMT expression compared with other pituitary tumour subtypes (P < 0.001). There was no significant difference in MGMT expression between invasive and noninvasive tumours, or between recurrent and nonrecurrent tumours. A significant inverse correlation was found between MGMT expression and promoter methylation (P = 0.012). CONCLUSION: MGMT expression as assessed by immunohistochemistry may predict response to temozolomide therapy in patients with aggressive pituitary tumours. MGMT promoter methylation is likely to explain low MGMT expression in some, but not all, pituitary tumours.

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 D(2) (PGD(2)) 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, PGD(2), to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD(2) 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.