Faculty Bibliography

Paraganglioma (PGL) of the filum terminale is a rare tumor of extra-adrenal paraganglia. The reported cases of filum terminale and cauda equina PGLs often present with low-back pain and sciatica. While sensory or motor deficits and paraplegia may occur, the incidence is relatively low. We present a case of a 51-year old male with hemorrhagic paraganglioma of the filum terminale. He presented with acute paraplegia and was treated via emergent laminectomy, evacuation of hematoma, and resection of tumor. The patient had a significant but incomplete neurological recovery. The clinical, radiologic, and histopathological characteristics of the condition are described

Background: CNS tumors are the second most common cancer in children and the leading cause of mortality due to disease. New therapies are desperately needed. Specific Aims: The primary aim of this phase I study was to determine the safety and feasibility of administering HLA-A2 restricted, tumor associated antigenic peptides with Montanide ISA-51 VG to children with refractory CNS tumors. Secondary aims were to evaluate immune response to the vaccine and tumor response. Methods: Each vaccine consisted of HLA-A2 restricted peptides targeting epitopes on the tumor associated antigens Her2, Trp2, EphA2 and gp100 mixed with Montanide ISA-51 VG as the immune adjuvant. The neoantigen KLH was given with the first vaccine as a control. Patients received the vaccines divided into 2 subcutaneous injections on weeks 1, 4 and 7. Immune responses induced by the vaccine were evaluated by tetramer and intracellular cytokine staining. Results: 15 patients, females=8, median age 12 years (range 7- 20 y) were treated between August 2009 and May 2012. Diagnoses included pilocytic astrocytoma=1, low grade glioneuronal tumor=1, pilocytic/pilomyxoid tumor=2, anaplastic astrocytoma= 3, DIPG=2, radiation-induced glioblastoma=1, and ependymoma=3. Two patients had unbiopsied presumed low grade astrocytomas. One patient with an ependymoma was removed after only 2 immunizations because of progressive disease. 14 pts received all 3 vaccines. Several patients had grade 1 local skin reactions at the injection sites. No patients had grade 2 or higher adverse reactions related to the vaccine. Analysis of immune response shows induction of T cell responses to the tumor associated antigens. Impressively, most patients evaluated so far had detectable T cell responses to gp100 and Her-2 post vaccination. Furthermore, both antibody and T cell responses to the control antigen KLH were detected in most patients. Five of 6 patients with low grade astrocytomas have had stable disease for a median of 24 months (range 6-36 mo). Three patients with anaplastic astrocytomas have stable disease for 16, 24, and 24 months. Conclusions: Vaccine therapy using tumor associated antigenic peptides with Montanide ISA-51 VG was well tolerated. Despite being heavily pre-treated, these children were able to mount both humoral and adaptive immune response. Stable disease was seen in children with refractory low grade and high grade gliomas

Glioblastomas (GBMs), the most common primary brain tumor in adults, are characterized by resistance to chemotherapy and radiotherapy. One of the defining characteristics of GBM is an abundant and aberrant vasculature. The processes of vascular co-option, angiogenesis, and vasculogenesis in gliomas have been extensively described. Recently, however, it has become clear that these three processes are not the only mechanisms by which neovascularization occurs in gliomas. Furthermore, it seems that these processes interact extensively, with potential overlap among them. At least five mechanisms by which gliomas achieve neovascularization have been described: vascular co-option, angiogenesis, vasculogenesis, vascular mimicry, and (the most recently described) glioblastoma-endothelial cell transdifferentiation. We review these mechanisms in glioma neovascularization, with a particular emphasis on the roles of hypoxia and glioma stem cells in each process. Although some of these processes are well established, others have been identified only recently and will need to be further investigated for complete validation. We also review strategies to target glioma neovascularization and the development of resistance to these therapeutic strategies. Finally, we describe how these complex processes interlink and overlap. A thorough understanding of the contributing molecular processes that control the five modalities reviewed here should help resolve the treatment resistance that characterizes GBMs.

The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.