Master of Science

thesisMeningiomas are the most common primary brain tumors, accounting for 36.6% of all tumors with ∼20,000 cases annually in the U.S. Although 65-80% of cases are benign (World Health Organization [WHO] Grade I), recurrence over a long period can be seen, especially for subtotal resections and higher-grade tumors (II and III). Radiotherapy is a common primary or adjuvant therapy, but its mechanisms of action in the setting of distinct subtypes of meningioma remain unknown. Hypoxia-inducible factor 1 (HIF1) plays a key role in cellular response to oxygen tension, modulates multiple downstream genes, controls tissue vascularization, and may serve as a resistance-promoting mechanism in tumors. The aim of this study was to evaluate the clinical impact of the HIF1-signaling pathway in meningioma characterization as well as the impact of radiotherapy on meningiomas in the setting of HIF1 knockout. Clinical samples from patients with meningiomas, primary derived cell lines (GAR, JEN, SAM, MCT, BSH, IOMM-LEE), and HIF1 generated knockouts (GAR-1589) were utilized. Multiple immunohistochemical markers and a fractal-based microvascularity quantification showed that Grade I meningiomas ≥3 cm showed greater staining for MIB and von Willebrand Factor as well as an average 19-month shorter survival. In addition, a MIB index ≥3 showed high specificity (82.5%) but not sensitivity (36%) for predicting progression-free survival. Cell proliferation and apoptosis in response to radiation doses depended on cell density, HIF1A mutational status, and oxygen tension. Higher plated densities of cells showed resistance to radiation for various primary meningioma cell lines. GAR cells demonstrated greater response to high-dose radiation than GAR-1589 cells in 2D and 3D cultures, while neither cell line responded to fractionated radiotherapy. Hypoxic environments reduced the efficacy of radiation, in fact showing increased cell proliferation with low doses of radiation. GAR-1589 cell, however, showed greater increases in cell apoptosis during radiotherapy in normoxic environments than GAR cells. Multimodal imaging using tumor bioluminescence, positron emission tomography tracers, and MRI showed potential for evaluating various characteristics of primary brain tumors noninvasively using an orthotopic rodent model. These results offer some correlation clinically and experimentally regarding the importance of HIF1 and tumor resistance

Cancer Immunotherapy Comes of Age

Modern cancer immunotherapy is the reemergence of an old field striving to use the body’s immune system to target cancer. Though cancer subverts the innate and adaptive immune systems, various non-cellular and cellu-lar based therapies have been developed to overcome these mechanisms. The variety of these techniques and their potential in the treatment of cancer has been a truly exciting development in medicine

Challenges in Stem Cell Therapy: Bench-To-Bedside

The article is a review of stem cell research and some of the challenges before the technology can become realizable patient therapy. We tried to make it a general review for individuals from various backgrounds

Social Networking Tools in the Modern Era of Human Rights Protection

Human rights are fundamental liberties that should be guaranteed to all human beings. These include things such as access to education and health care, food security, freedom from persecution and access to shelter, safety and security. Human rights promotion and international development have become popular philanthropic efforts and new technology is helping younger generations participate more easily. Whether through activism, fundraising or volunteering, there are many ways to make a difference. Pro- moting the awareness of and access to human rights is a job everyone can and should be a part of

Return to Play after Cervical Spine Injuries: A Consensus of Opinion

Study Design: Survey. Objective: Sports-related spinal cord injury (SCI) represents a growing proportion of total SCIs but lacks evidence or guidelines to guide clinical decision-making on return to play (RTP). Our objective is to offer the treating physician a consensus analysis of expert opinion regarding RTP that can be incorporated with the unique factors of a case for clinical decision-making. Methods: Ten common clinical scenarios involving neurapraxia and stenosis, atlantoaxial injury, subaxial injury, and general cervical spine injury were presented to 25 spine surgeons from level 1 trauma centers for whom spine trauma is a significant component of their practice. We evaluated responses to questions about patient RTP, level of contact, imaging required for a clinical decision, and time to return for each scenario. The chi-square test was used for statistical analysis, with p \u3c 0.05 considered significant. Results: Evaluation of the surgeons’ responses to these cases showed significant consensus regarding return to high-contact sports in cases of cervical cord neurapraxia without symptoms or stenosis, surgically repaired herniated disks, and nonoperatively healed C1 ring or C2 hangman’s fractures. Greater variability was found in recommendations for patients showing persistent clinical symptomatology. Conclusion: This survey suggests a consensus among surgeons for allowing patients with relatively normal imaging and resolution of symptoms to return to high-contact activities; however, patients with cervical stenosis or clinical symptoms continue to be a challenge for management. This survey may serve as a basis for future clinical trials and consensus guidelines

Glioma Stem Cells as Immunotherapeutic Targets: Advancements and Challenges

Glioblastoma is the most common and lethal primary brain malignancy. Despite major investments in research into glioblastoma biology and drug development, treatment remains limited and survival has not substantially improved beyond 1–2 years. Cancer stem cells (CSC) or glioma stem cells (GSC) refer to a population of tumor originating cells capable of self-renewal and differentiation. While controversial and challenging to study, evidence suggests that GCSs may result in glioblastoma tumor recurrence and resistance to treatment. Multiple treatment strategies have been suggested at targeting GCSs, including immunotherapy, posttranscriptional regulation, modulation of the tumor microenvironment, and epigenetic modulation. In this review, we discuss recent advances in glioblastoma treatment specifically focused on targeting of GCSs as well as their potential integration into current clinical pathways and trials

Perioperative outcomes of a hydrocortisone protocol after endonasal surgery for pituitary adenoma resection

Adrenal insufficiency after transsphenoidal resection of pituitary adenoma (PA) can be seen in 1-12% of cases. In PA, the use of postoperative cortisol measurement and supplementation remains controversial. It is unclear whether postoperative cortisol supplementation has a measurable effect on improving outcomes in patients with pituitary adenoma undergoing endoscopic transsphenoidal surgery (ETS). The objective of the study was to evaluate a postoperative steroid treatment protocol in patients with PA undergoing ETS

Addressing the Limitations of Neurosurgical Care via Telemedicine

Novel telemedicine software successfully automates cranial nerve assessment of patients from the comfort of their hom

A review of multiomics platforms in pituitary adenoma pathogenesis

Pituitary adenomas (PA), or pituitary neuroendocrine tumors (PitNETs), represent 15% of all central nervous system tumors. Classic description of PitNETs solely by hormonal classification has given way to key transcription factors that play a role in the pathology of PitNETs including steroidogenic factor-1 (SF-1), t-box pituitary transcription factor (TPIT), and pituitary transcription factor 1 (PIT-1). Germline mutations in various familial PitNETs are discussed including those in familial isolated pituitary adenoma (FIPA), multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), and Carney complex. Recent advances in next generation sequencing have improved insight into the pathogenesis of PitNETs. A review of key studies in evaluating the genomic analysis of PitNETs was performed. Chromosomal mutations, whole exome sequencing, microRNA genomics, methylomics and transcriptomics were analyzed. Moreover, the multiomic analysis of various genomic panels has helped to better understand PA classification

Targeted Therapy in the Management of Modern Craniopharyngiomas

Background: The proximity of craniopharyngiomas (CPs) to critical neurovascular structures can lead to a host of neurologic and endocrine complications that lead to difficulty with surgical management. In this review, we examine the molecular and genetic markers implicated in CP, their involvement in tumorigenic pathways, and their impact on CP prognosis and treatment. Methods: We undertook a focused review of relevant articles, clinical trials, and molecular summaries regarding CP. Results: Genetic and immunological markers show variable expression in different types of CP. BRAF is implicated in tumorigenesis in papillary CP (pCP), whereas CTNNB1 and EGFR are often overexpressed in adamantinomatous CP (aCP) and VEGF is overexpressed in aCP and recurrent CP. Targeted treatment modalities inhibiting these pathways can shrink or halt progression of CP. In addition, EGFR inhibitors may sensitize tumors to radiation therapy. These drugs show promise in medical management and neoadjuvant therapy for CP. Immunotherapy, including anti-interleukin-6 (IL-6) drugs and interferon treatment, are also effective in managing tumor growth. Ongoing clinical trials in CP are limited but are testing BRAF/MET inhibitors and IL-6 monoclonal antibodies. Conclusions: Genetic and immunological markers show variable expression in different subtypes of CP. Several current molecular treatments have shown some success in the management of this disease. Additional clinical trials and targeted therapies will be important to improve CP patient outcomes