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.

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.

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.

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.

Wnt pathway inhibitors are strongly down-regulated in pituitary tumors.

The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P <0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Wnt pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at both mRNA and protein level, supportive of activation of the Wnt-beta-catenin pathway. Nuclear accumulation of beta-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Wnt pathways are important in pituitary tumorigenesis.

Variation of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in serial samples in glioblastoma.

Methylation of the promoter region of the O ( 6 ) -methylguanine-DNA methyltransferase (MGMT) gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma. Contrastingly, little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor. About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing. Of these, 20 were also analyzed using Methylation Specific PCR (MSP). The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing. In four patients, the MGMT promoter was unmethylated at primary surgery, but displayed some methylation (32, 44, 12, and 4%) on post-treatment sampling. Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients. In another patient, methylation increased from 40% on initial sampling to 68% on the second sample. The remaining two patients initially demonstrated some degree of methylation (72% and 12%); subsequent sampling showed no methylation of the MGMT promoter. To ensure variable methylation status was not due to intra-tumoral variability, three to four specimens were sampled from different regions of large glioblastomas (n = 7). Promoter sequencing revealed minimal variation in methylation in all but two sites examined. Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors. This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment, necessitating caution in clinical decision-making based on this analysis.

IQGAP1 and IGFBP2: valuable biomarkers for determining prognosis in glioma patients.

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.

The presence of necrosis and/or microvascular proliferation does not influence survival of patients with anaplastic oligodendroglial tumours: review of 98 patients.

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.