Cytoplasmic crystalline inclusions in a anaplastic oligoastrocytoma

A 41-year-old male presented with an ill-demarcated mass involving the left fronto-temporal lobe and the basal ganglia. Light microscopically the tumor was diagnosed as an anaplastic oligoastrocytoma. Electron microscopy revealed several cytoplasmic crystalline inclusions in tumor cells of oligodendroglial lineage. No crystalline inclusions were membrane bound. The morphologic features with unique ultrastructural findings are presented.     

High-dose thiotepa with autologous bone marrow rescue in recurrent malignant oligodendroglioma: A case report

High-dose thiotepa with autologous bone marrow rescue is a new and promising treatment modality in several kinds of solid tumors. We used this regimen in a pediatric patient who had the third recurrence of his malignant oligodendroglioma of brain that developed during 8 in 1 chemotherapy. We achieved complete response after a total dose of 1125 mg/m² of intravenous thiotepa. Good penetration into the CNS renders thiotepa potentially useful for chemosensitive brain tumors, and one course of high-dose thiotepa can be administered with acceptable toxicity by utilizing autologous bone marrow rescue.     

Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors.

BACKGROUND: Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150-200 mg/m(2)/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. PATIENTS AND METHODS: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting daily dose was 200 mg/m(2) in a group of at least six patients, with subsequent increments of 50 mg/m(2) in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonald's criteria were used to evaluate antitumor activity. RESULTS: Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 1-3). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m(2)/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m(2), respectively. Grade 3-4 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m(2)/day, respectively. Grade 3-4 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m(2)/day temozolomide, respectively. At a dose of 350 mg/m(2), sustained grade 2-3 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m(2)/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients. CONCLUSIONS: Temozolomide can be given safely using a dose-dense regimen of 300 mg/m(2)/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.     

Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study with Sainte-Anne malignancy grade, growth fraction and patient survival

Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies.     

Effectiveness of radiotherapy for elderly patients with anaplastic gliomas

Postoperative radiotherapy (RT) is utilized routinely in the management of anaplastic World Health Organization Grade III gliomas (AG), including anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO). However, the optimal role of RT in elderly AG patients remains controversial. We evaluated the effectiveness of RT in elderly AG patients using a national cancer registry. The USA Surveillance, Epidemiology, and End Results database (1990–2008) was used to query patients over 70 years of age with AA or AO. Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Among 390 elderly patients with AG, 333 (85%) had AA and 57 (15%) had AO. Approximately two-thirds of AA patients (64%) and AO patients (65%) received RT. Most AO patients (58%) and many AA patients (41%) underwent surgical resection; the remainder had biopsy. The median overall survival for all patients who underwent RT was 6 months (95% confidence interval [CI], 5–7 months) versus 2 months (95% CI 1–6) in patients who did not have RT. Patients who had gross total resection (GTR) plus RT had a median overall survival of 11 months (95% CI 7–14). Multivariate analysis for all patients showed that undergoing RT was significantly associated with improved survival (hazard ratio [HR] 0.52, p < .0001). AA tumor type (HR 1.37, p = .03) was associated with worse survival than AO tumor type; female sex (HR 0.59, p < .0001) and being married (HR 0.66, p = .002) significantly improved survival. Patients that underwent GTR had a significant reduction in the hazards of mortality compared to biopsy (HR 0.72, p = .04). Elderly AG patients undergoing RT had better overall survival compared to patients who did not receive RT. Treatment strategies involving maximal safe resection plus RT should be considered in the optimal management of AG in elderly patients.     

BRAF V600E mutant oligodendroglioma‐like tumors with chromosomal instability in adolescents and young adults

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with “molecular GBM.” Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of “pediatric‐type” gliomas.     

Regulation of phospholipase D activity in a human oligodendroglioma cell line (HOG)

Oligodendroglial cells express many specific proteins, such as myelin basic protein (MBP), which are physiologically phosphorylated by protein kinase C (PKC). Diacylglycerols are physiological activators of PKC and can be liberated from phospholipids by the direct receptor-mediated activation of phospholipase C (PL-C) or indirectly via the activation of phospholipase D (PL-D). In a well-characterized human oligodendroglioma (HOG) cell line, PL-C (measured by release of [³H]inositol phosphates) and PL-D (formation of [³H]myristoylated or palmitoylated phosphatidylethanol) were activated by both carbachol (blocked by pirenzepine, suggesting an M1 receptor) and histamine (H1 receptor) but not glutamate, bradykinin, or phenylephrine. PL-C stimulation by carbachol or histamine was completely inhibited by short-term treatment (<30 min) with phorbol ester (TPA), a PKC activator. In contrast, PL-D activation by either carbachol or histamine was stimulated in additive fashion by TPA, suggesting at least two distinct mechanisms for PL-D activation. Down regulation of PKC by prolonged (24 hr) treatment with TPA reversed the inhibitory effects of TPA on PL-C and the stimulatory effects on PL-D. However, the PKC inhibitors H-7 and galactosylsphingosine did not inhibit the TPA-mediated stimulation of PLD while the less-specific PKC inhibitor, staurosporine, was only partially inhibitory. Preexposure of cells to carbachol, greatly reduced both PL-C and PL-D activation by carbachol, suggesting homologous desensitization. Time-course studies indicated that PL-D activation (10 sec or less) was at least as fast as PL-C activation, and the affinity of carbachol and histamine for the receptor coupled to either phospholipase (EC₅₀ = 5–10 μM) was about the same. We conclude that in this oligodendroglioma, and by inference in oligodendroglial cells, the receptor-coupled PL-D pathway, is at least as important as the PL-C pathway as a source of DAG and that its relationship to PKC is complex. © 1993 Wiley-Liss, Inc.     

Statistical validation of brain tumor shape approximation via spherical harmonics for image-guided neurosurgery

RATIONALE AND OBJECTIVES: Surgical planning now routinely uses both two-dimensional (2D) and three-dimensional (3D) models that integrate data from multiple imaging modalities, each highlighting one or more aspects of morphology or function. We performed a preliminary evaluation of the use of spherical harmonics (SH) in approximating the 3D shape and estimating the volume of brain tumors of varying characteristics. MATERIALS AND METHODS: Magnetic resonance (MR) images from five patients with brain tumors were selected randomly from our MR-guided neurosurgical practice. Standardized mean square reconstruction errors (SMSRE) by tumor volume were measured. Validation metrics for comparing performances of the SH method against segmented contours (SC) were the dice similarity coefficient (DSC) and standardized Euclidean distance (SED) measure. RESULTS: Tumor volume range was 22,413-85,189 mm3, and range of number of vertices in triangulated models was 3674-6544. At SH approximations with degree of at least 30, SMSRE were within 1.66 x 10(-5) mm(-1). Summary measures yielded a DSC range of 0.89-0.99 (pooled median, 0.97 and significantly >0.7; P < .001) and an SED range of 0.0002-0.0028 (pooled median, 0.0005). CONCLUSION: 3D shapes of tumors may be approximated by using SH for neurosurgical applications.