Genome wide DNA methylation landscape reveals glioblastoma's influence on epigenetic changes in tumor infiltrating CD4+ T cells.

CD4+ helper T (Th) cells play a critical role in shaping anti-tumor immunity by virtue of their ability to differentiate into multiple lineages in response to environmental cues. Various CD4+ lineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of endogenous anti-tumor immune response. In this clinical corelative study, we found that Glioblastoma (GBM) induces multi- and mixed-lineage immune response in the tumor microenvironment. Whole-genome bisulfite sequencing of tumor infiltrating and blood CD4+ T-cell from GBM patients showed 13571 differentially methylated regions and a distinct methylation pattern of methylation of tumor infiltrating CD4+ T-cells with significant inter-patient variability. The methylation changes also resulted in transcriptomic changes with 341 differentially expressed genes in CD4+ tumor infiltrating T-cells compared to blood. Analysis of specific genes involved in CD4+ differentiation and function revealed differential methylation status of TBX21, GATA3, RORC, FOXP3, IL10 and IFNG in tumor CD4+ T-cells. Analysis of lineage specific genes revealed differential methylation and gene expression in tumor CD4+ T-cells. Interestingly, we observed dysregulation of several ligands of T cell function genes in GBM tissue corresponding to the T-cell receptors that were dysregulated in tumor infiltrating CD4+ T-cells. Our results suggest that GBM might induce epigenetic alterations in tumor infiltrating CD4+ T-cells there by influencing anti-tumor immune response by manipulating differentiation and function of tumor infiltrating CD4+ T-cells. Thus, further research is warranted to understand the role of tumor induced epigenetic modification of tumor infiltrating T-cells to develop effective anti-GBM immunotherapy.

Comparative Anatomy of the Mammalian Corneal Subbasal Nerve Plexus.

Purpose: The subbasal nerve plexus (SNP) is the densest and most recognizable component of the mammalian corneal innervation; however, the anatomical configuration of the SNP in most animal models remains incompletely described. The purpose of the current study is to describe in detail the SNP architecture in eight different mammals, including several popular animal models used in cornea research. Methods: Corneal nerves in mouse, rat, guinea pig, rabbit, dog, macaque, domestic pig, and cow eyes were stained immunohistochemically with antiserum directed against neurotubulin. SNP architecture was documented by digital photomicrography and large-scale reconstructions, that is, corneal nerve maps, using a drawing tube attached to a light microscope. Results: Subbasal nerve fibers (SNFs) in mice, rats, guinea pigs, dogs, and macaques radiated centrally from the corneoscleral limbus toward the corneal apex in a whorl-like or spiraling pattern. SNFs in rabbit and bovine corneas swept horizontally across the ocular surface in a temporal-to-nasal direction and converged on the inferonasal limbus without forming a spiral. SNFs in the pig cornea radiated centrifugally in all directions, like a starburst, from a focal point located equidistant between the corneal apex and the superior pole. Conclusions: The results of the present study have demonstrated for the first time substantial interspecies differences in the architectural organization of the mammalian SNP. The physiological significance of these different patterns and the mechanisms that regulate SNP pattern formation in the mammalian cornea remain incompletely understood and warrant additional investigation.

Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets.

Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.

The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology.

Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28- senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28- senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.

Primary Central Nervous System Germ Cell Tumors: A Review and Update.

Importance: Primary central nervous system (CNS) germ cell tumors (GCT) are a heterogeneous group of tumors that are still poorly understood. In North America, GCTs comprise approximately 1% of primary brain tumors in pediatric and young adult patients. GCTs can occur as pure or mixed subtypes; they are divided into germinomas, which are the most common subtype, and non-germinomatous germ cell tumors (NGGCTs), which consist of approximately one-third of GCTs and include teratomas, embryonal carcinomas, choriocarcinomas, and yolk sac tumors. Observations: While the etiology of primary CNS GCT is not entirely clear, the various subtypes are lineage-related and may involve progenitor germ cells that fail to migrate and become trapped in midline locations. Primary CNS GCT most commonly arises in the pineal region but also occur in other areas. Presenting symptoms can include headache, Parinaud syndrome, diabetes insipidus, precosious puberty, ataxia, or hemiparesis. Diagnosis of primary CNS GCTs can be difficult and is often delayed. Various imaging studies and tumor markers can assist in specific diagnosis. Treatment plans differ depending on the subtype of GCT and may vary among physicians and institutions. Germinomas have a favorable prognosis with a greater than 90% overall survival, while NGGCTs only have survival rates ranging from 40-70%. Conclusions and Relevance: Germinomas seem to be most effectively treated with chemotherapy and radiation, while NGGCT usually require surgical resection, chemotherapy, and radiation with the exception of mature teratomas frequently curable with surgery alone. Gamma knife radiosurgery is a promising treatment that may be an effective additional treatment option. Cytogenic and molecular analyses are attempting to further specify the different GCT subtypes and are helping to direct the development of distinct therapeutic targets to improve treatment and prognosis.

Survival and complications of stereotactic radiosurgery: A systematic review of stereotactic radiosurgery for newly diagnosed and recurrent high-grade gliomas.

BACKGROUND: Utilization of stereotactic radiosurgery (SRS) for treatment of high-grade gliomas (HGGs) has been slowly increasing with variable reported success rates. OBJECTIVE: Systematic review of the available data to evaluate the efficacy of SRS as a treatment for HGG with regards to median overall survival (OS) and progression-free survival (PFS), in addition to ascertaining the rate of radiation necrosis and other SRS-related major neurological complications. METHODS: Literature searches were performed for publications from 1992 to 2016. The pooled estimates of median PFS and median OS were calculated as a weighted estimate of population medians. Meta-analyses of published rates of radiation necrosis and other major neurological complications were also performed. RESULTS: Twenty-nine studies reported the use of SRS for recurrent HGG, and 16 studies reported the use of SRS for newly diagnosed HGG. For recurrent HGG, the pooled estimates of median PFS and median OS were 5.42 months (3-16 months) and 20.19 months (9-65 months), respectively; the pooled radiation necrosis rate was 5.9% (0-44%); and the pooled estimates of major neurological complications rate was 3.3% (0-23%). For newly diagnosed HGG, the pooled estimates of median PFS and median OS were 7.89 months (5.5-11 months) and 16.87 months (9.5-33 months) respectively; the pooled radiation necrosis rate was 6.5% (0-33%); and the pooled estimates of other major neurological complications rate was 1.5% (0-25%). CONCLUSION: Our results suggest that SRS holds promise as a relatively safe treatment option for HGG. In terms of efficacy at this time, there are inadequate data to support routine utilization of SRS as the standard of care for newly diagnosed or recurrent HGG. Further studies should be pursued to define more clearly the therapeutic role of SRS.

Cervical cancer metastasis to the brain: A case report and review of literature.

BACKGROUND: Intracranial metastasis from cervical cancer is a rare occurrence. METHODS: In this study we describe a case of cervical cancer metastasis to the brain and perform an extensive review of literature from 1956 to 2016, to characterize clearly the clinical presentation, treatment options, molecular markers, targeted therapies, and survival of patients with this condition. RESULTS: An elderly woman with history of cervical cancer in remission, presented 2 years later with a right temporo-parietal tumor, which was treated with surgery and subsequent stereotactic radiosurgery (SRS) to the resection cavity. She then returned 5 months later with a second solitary right lesion; she again underwent surgery and SRS to the resection cavity with no signs of recurrence 6 months later. According to the reviewed literature, the most common clinical presentation included females with median age of 48 years; presenting symptoms such as headache, weakness/hemiplegia/hemiparesis, seizure, and altered mental status (AMS)/confusion; multiple lesions mostly supratentorially located; poorly differentiated squamous cell carcinoma; and additional recurrences at other sites. The best approach to treatment is a multimodal plan, consisting of SRS or whole brain radiation therapy (WBRT) for solitary brain metastases followed by chemotherapy for systemic disease, surgery and WBRT for solitary brain lesions without systemic disease, and SRS or WBRT followed by chemotherapy for palliative care. The overall prognosis is poor with a mean and median survival time from diagnosis of brain metastasis of 7 and 4.6 months, respectively. CONCLUSION: Future efforts through large prospective randomized trials are warranted to better describe the clinical presentation and identify more effective treatment plans.

Atraumatic multifocal intracerebral hemorrhage.

This article describes a patient with atraumatic multifocal intracerebral, subarachnoid, and bilateral frontal convexity acute subdural hematomas. The patient is a 46-year-old Caucasian man who presented with a spontaneous severe progressive headache. Following a description of the case, this article reviews the reported incidence, proposed etiology, and current management strategies for multifocal spontaneous intracerebral hemorrhage.