Subependimoma

Subependymoma of the Cervicothoracic Spinal Cord

Yvan Maque-Acosta1 , Carol K Petito1 , Michael E Ivan2 , Charif Sidani3 and Macarena I de la Fuente4,5*

1 Departments of Pathology, University of Miami, Florida, USA
2 Department of Neurosurgery, University of Miami, Florida, USA
3 Department of Radiology, University of Miami, Florida, USA
4 Department of Neurology, University of Miami, Florida, USA
5 Sylvester Comprehensive Cancer Center, University of Miami, Florida, USA

Background

Subependymomas are rare, World Health Organization (WHO) grade I tumors [1,2]. They typically arise in the ventricles and represent less than 1% of intracranial tumors [3]. Spinal subependymomas are even less frequent, comprising approximately 2% of all symptomatic spinal cord tumors [4]. They are usually intramedullary and located in the cervical region, however thoracic and lumbar lesions have also been reported [2,5,6].

Radiologically, intracranial subependymomas present as well defined intraventricular lesions that are classically T2-weighted images (WI) hyper intense and T1WI hypo or isointense to white matter in MRI [5,7]. Heterogeneity on T2WI is often reported and is related to cystic changes, blood products or calcifications, particularly in larger lesions [5]. Calcifications and blood products can manifest as low signal intensity on T2WI gradient echo sequence. Subependymomas typically do not enhance or only mildly enhance. Avid enhancement has been reported particularly in lesions located in the fourth ventricle. The tumor size typically ranges from 1 to 2 cm, however lesions greater than 5 cm have also been reported [2,5]. Spinal subependymomas usually present as eccentric, well-defined lesions with mild to moderate enhancement. Lesions of the spine have significant associated edema [2,6].

Histologically, subependymomas are characterized by the presence of nuclear clustering and a densely fibrillar and paucicellular background [1]. Microcysts can be present, particularly in lesions located closer to the foramen of Monro. Subtle pseudorosettes can also be seen [1,8]. In tumors located far from the foramen of Monro, the nuclear clustering is more prominent. Occasionally, an ependymoma component can be identified, although this is more common in fourth ventricle tumors. By immunohistochemistry, subependymoma are diffusely positive for glial fibrillary acidic protein (GFAP) which demonstrate its glial origin and positive for epithelial membrane antigen (EMA) (showing a dot-like pattern) which is consistent with an ependymal origin. They usually have a low Ki-67 proliferative index, although it can be variable [1,8].

We describe a case of spinal subependymoma and discuss the clinical, radiographic and histological characteristics.

Citation: Maque-Acosta Y, Petito CK, Ivan ME, Sidani C, de la Fuente MI (2016) Subependymoma of the Cervicothoracic Spinal Cord. J Neurol Neurobiol 2(3): doi http://dx.doi.org/10.16966/2379-7150.123

Avaliable: https://www.sciforschenonline.org/journals/neurology/JNNB-2-123.php

Md. Yvan Maque-Acosta, Ex-Miembro GII

HPV y CD8

Enhanced Cytotoxic CD8 T Cell Priming Using Dendritic Cell-Expressing Human Papillomavirus-16 E6/E7-p16INK4 Fusion Protein with Sequenced Anti-Programmed Death-1.

Garcia-Bates TM1, Kim E2, Concha-Benavente F3, Trivedi S4, Mailliard RB5, Gambotto A2, Ferris RL6.

1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15232;

2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15232;

3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15232; and.

4. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232;

5. Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15232;

6. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15232; and Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 ferrisrl@upmc.edu.

Abstract

The incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma has increased in recent decades, though HPV prevention vaccines may reduce this rise in the future. HPV-related cancers express the viral oncoproteins E6 and E7. The latter inactivates the tumor suppressor protein retinoblastoma (Rb), which leads to the overexpression of p16(INK4) protein, providing unique Ags for therapeutic HPV-specific cancer vaccination. We developed potential adenoviral vaccines that express a fusion protein of HPV-16 E6 and E7 (Ad.E6E7) alone or fused with p16 (Ad.E6E7p16) and also encoding an anti-programmed death (PD)-1 Ab. Human monocyte-derived dendritic cells (DC) transduced with Ad.E6E7 or Ad.E6E7p16 with or without Ad.αPD1 were used to activate autologous CD8 CTL in vitro. CTL responses were tested against naturally HPV-infected head and neck squamous cell carcinoma cells using IFN-γ ELISPOT and [(51)Cr]release assay. Surprisingly, stimulation and antitumor activity of CTL were increased after incubation with Ad.E6E7p16-transduced DC (DC.E6E7p16) compared with Ad.E6E7 (DC.E6E7), a result that may be due to an effect of p16 on cyclin-dependent kinase 4 levels and IL-12 secretion by DC. Moreover, the beneficial effect was most prominent when anti-PD-1 was introduced during the second round of stimulation (after initial priming). These data suggest that careful sequencing of Ad.E6E7.p16 with Ad.αPD1 could improve antitumor immunity against HPV-related tumors and that p16 may enhance the immunogenicity of DC, through cyclin-dependent pathways, Th1 cytokine secretion, and by adding a nonviral Ag highly overexpressed in HPV-induced cancers.

J Immunol. 2016 Mar 15;196(6):2870-8. doi: 10.4049/jimmunol.1502027. Epub 2016 Feb 5.

http://www.jimmunol.org/content/196/6/2870.long

Md. PhD. Fernando Concha. Ex-miembro del GII

EGFR y Cancer de Cabeza y Cuello

Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer.

Concha-Benavente F1, Srivastava RM2, Trivedi S2, Lei Y3, Chandran U4, Seethala RR5, Freeman GJ6, Ferris RL7.

1. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

2. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. Department of Periodontics and Oral Medicine, School of Dentistry and Department of Otolaryngology-Head and Neck Surgery, School of Medicine. University of Michigan, Ann Arbor, Michigan.

4. Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.

5. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

6. Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.

7. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.

Abstract

Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.

Cancer Res. 2016 Mar 1;76(5):1031-43. doi: 10.1158/0008-5472.CAN-15-2001. Epub 2015 Dec 16.

http://cancerres.aacrjournals.org/content/76/5/1031.long

Md. PhD. Fernando Concha. Ex-miembro del GII