J.J. Olson

Lipomatous glioneurocytoma of the posterior fossa with divergent differentiation: case report.

OBJECTIVE AND IMPORTANCE We report a case of a posterior fossa neuroepithelial tumor with unusual clinical presentation, magnetic resonance imaging appearance, and morphological features. CLINICAL PRESENTATION This 66-year-old man presented with a history of gait ataxia, dizziness, and tinnitus and was found to have a large tumor in the posterior fossa and cerebellopontine angle. INTERVENTION Gross total excision of the tumor was accomplished. Histologically, the most unique features were macrovesicular accumulations of lipid, giving the tumor (at least focally) an appearance virtually identical to that of mature adipose tissue. Evidence of biphasic neuronal and glial differentiation was noted by immunohistochemistry and electron microscopy. CONCLUSION A literature review is presented. Diagnostically, this neoplasm seems to fit in a unique group of rarely described, lipomatous neuroectodermal tumors that show divergent neuronal and glial differentiation.OBJECTIVE AND IMPORTANCE: We report a case of a posterior fossa neuroepithelial tumor with unusual clinical presentation, magnetic resonance imaging appearance, and morphological features. CLINICAL PRESENTATION: This 66-year-old man presented with a history of gait ataxia, dizziness, and tinnitus and was found to have a large tumor in the posterior fossa and cerebellopontine angle. INTERVENTION: Gross total excision of the tumor was accomplished. Histologically, the most unique features were macrovesicular accumulations of lipid, giving the tumor (at least focally) an appearance virtually identical to that of mature adipose tissue. Evidence of biphasic neuronal and glial differentiation was noted by immunohistochemistry and electron microscopy. CONCLUSION: A literature review is presented. Diagnostically, this neoplasm seems to fit in a unique group of rarely described, lipomatous neuroectodermal tumors that show divergent neuronal and glial differentiation.

Comparing Preoperative With Postoperative Stereotactic Radiosurgery for Resectable Brain Metastases: A Multi-institutional Analysis.

BACKGROUND Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

Carboplatin-Loaded PLGA Microspheres for Intracerebral Implantation: In Vivo Characterization

Carboplatin is a potent anticancer agent that has shown efficacy in clinical trials against malignant glioma, one of the most deadly cancers in humans. However, a high systemic dose is required to achieve an effective concentration in the brain because of the presence of the blood-brain barrier (BBB). Such a high dose can cause many side effects. Local delivery of antitumor agents to the brain using injectable and biodegradable microspheres is a new strategy for the treatment of malignant glioma. This method is able to bypass the BBB and allows maximal local exposure and minimal systemic exposure to avoid the severe side effects of carboplatin. Delivering sustained-release microspheres directly to the tumor site could also control local tumor recurrence and improve survival. In the present studies, carboplatin-loaded microspheres were delivered intracerebrally in rats. No signs of systemic or neurologic toxicity associated with the microspheres implanted in the rat brain were observed. The in vivo release of carboplatin followed apparently zero-order release kinetics up to 30 days. The surface characteristics of the microspheres retrieved from the rat brains changed with the progress of polymer biodegradation. Implantation of the microspheres evoked a transient and localized inflammatory reaction that was well tolerated by the animals.

Direct Intracerebral Delivery of Carboplatin from PLGA Microspheres Against Experimental Malignant Glioma in Rats

There has been an increasing interest in intracerebral delivery of anticancer agents using biodegradable polymers for the treatment of malignant glioma. This approach circumvents the blood-brain barrier (BBB) to achieve a high local drug concentration in the brain tumor sites and minimize side effects associated with a high systemic dose. It could also control local tumor recurrence and improve survival. In order to deliver anticancer drugs intracerebrally from polymers to tumor sites with minimal surgery, injectable poly(d,l-lactic-coglycolic acid) (PLGA) microspheres impregnated with carboplatin have been prepared. In the current studies, the brain tissue reaction to blank or carboplatin-loaded PLGA microspheres was investigated in rats. The PLGA micro-spheres were well tolerated by all of the rats. The brain tissue reaction to the blank microspheres was accompanied by mild edema, and macrophage/astrocyte/microglia proliferation. The tissue reaction to the carboplatin microspheres was characterized as edema, necrosis, and a more pronounced phagocytic inflammatory reaction. The observed inflammatory reactions decreased remarkably after 1 month. Carboplatin microspheres were then implanted intracerebrally in the rat glioma models. Higher drug concentrations were achieved in the brain tumor than in normal tissues. The survival and weight loss of the rats receiving carboplatin microspheres were compared with those of the rats receiving systemic doses. The local treatment was more effective in controlling the weight loss of the tumor-bearing rats, and was as effective as the systemic treatment in prolonging survival.

Brain tissue reaction following intracerebral injection of free or liposomally encapsulated BSH

AbstractBoron neutron capture therapy (BNCT) is a potentially valuable treatment of malignant brain gliomas. A primary requirement for successful BNCT is achieving high local concentration of boron drugs in tumors. Intratumoral injection of liposomes containing boron drug has potential to meet this requirement and could prove to be of significance for BNCT. The brain tissue reaction following the intracerebral injection of a boron drug, BSH, either in solution form or in liposomally encapsulated form, was studied in rats. On histological examination, no evidence of tissue reaction was found after injecting BSH solution, suggesting that high local concentration of BSH was well tolerated. Injection of liposomal BSH was characterized by phagocytic activity at the site of injection, which was regressing by 24 h. Neither group of animals exhibited any signs of abnormal behavior or neurologic deficit. Direct intracerebral injection of BSH liposomes as per-formed in this report could be regarded as tolerable.

Abstract 874: Genetic variation in the NOTCH stem cell signaling network in relation to risk of adult-onset glioma

The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that plays a fundamental role during cell-fate specification in the developing mammalian nervous system. Mounting evidence suggest that this signaling network plays a critical oncogenic role in the development and progression of glioma. Stem-like cells in brain tumors require Notch for their survival and growth. Moreover, Notch-1 and its ligands, Delta-like-1 and Jagged-1 are overexpressed in both glioma cell lines and primary human gliomas. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. Finally, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in experimental models of brain tumors. In the present study, we tested whether single nucleotide polymorphisms (SNPs) in the genes encoding Notch-1 (NOTCH1 at 9q34) and its ligands, Delta-like-1 (DLL1 at 6q27) and Jagged-1 (JAG1 at 20p12-p11) are associated with the risk of glioma onset in a clinic-based case-control study conducted at medical centers in the southeastern US. A total of 29 candidate and haplotype tagging SNPs (10 SNPs in NOTCH1; 2 in DLL1 and 17 in JAG1) were genotyped using the Illumina Goldengate assay in 563 newly diagnosed (eg. nonrecurrent) glioma cases (including 324 WHO grade IV glioblastomas (GBM); 145 WHO grade II or III astrocytomas and 94 oligoastrocytomas and oligodendrogliomas) and 629 healthy controls with no history of brain tumor. DNA was isolated from saliva samples. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs adjusting for age and gender. No consistent associations were observed for either examined variant in DLL1. An intronic SNP (rs3013300) in NOTCH1 located 9.2kb from the start codon was associated with an increased risk of astrocytomas (per variant “T” allele OR: 1.48; 95% CI: 1.12-1.96; p=0.006; MAF: 0.31), though not other glioma subtypes. Another intronic SNP in NOTCH1 (rs11574903) in weak linkage with the rs3013300 variant (r 2 : 0.10) was significantly associated with risk of oligodendrogliomas (per variant ‘T” allele OR: 1.68; 95% CI: 1.18-2.40; p=0.004; MAF: 0.22). This SNP is located 62bp downstream of a nonsynonymous SNP (rs115563691; V1671I) in NOTCH1. A SNP in the 3’UTR of the NOTCH1 ligand, JAG1 (rs8708), located in a putative micro-RNA binding site, was significantly associated with the risk of GBM (per variant “A” allele OR: 1.30; 95% CI: 1.06-1.59; p=0.010; MAF: 0.45). To our knowledge, this is the first study implicating genetic variants in the Notch stem cell signaling network with cancer risk. Further research is needed to confirm these findings and to elucidate putative causal variants in this pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 874. doi:10.1158/1538-7445.AM2011-874