Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury.

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

Epithelial Membrane Protein-2 (EMP2) Antibody Blockade Reduces Corneal Neovascularization in an In Vivo Model.

Purpose: Pathologic corneal neovascularization is a major cause of blindness worldwide, and treatment options are currently limited. VEGF is one of the critical mediators of corneal neovascularization but current anti-VEGF therapies have produced limited results in the cornea. Thus, additional therapeutic agents are needed to enhance the antiangiogenic arsenal. Our group previously demonstrated epithelial membrane protein-2 (EMP2) involvement in pathologic angiogenesis in multiple cancer models including breast cancer and glioblastoma. In this paper, we investigate the efficacy of anti-EMP2 immunotherapy in the prevention of corneal neovascularization. Methods: An in vivo murine cornea alkali burn model was used to study pathologic neovascularization. A unilateral corneal burn was induced using NaOH, and subconjunctival injection of either anti-EMP2 antibody, control antibody, or sterile saline was performed after corneal burn. Neovascularization was clinically scored at 7 days postalkali burn, and eyes were enucleated for histologic analysis and immunostaining including VEGF, CD31, and CD34 expression. Results: Anti-EMP2 antibody, compared to control antibody or vehicle, significantly reduced neovascularization as measured by clinical score and central cornea thickness, as well as by histologic reduction of neovascularization, decreased CD34 staining, and decreased CD31 staining. Incubation of corneal limbal cells in vitro with anti-EMP2 blocking antibody significantly decreased EMP2 expression, VEGF expression and secretion, and cell migration. Conclusions: This work demonstrates the effectiveness of EMP2 as a novel target in pathologic corneal neovascularization in an animal model and supports additional investigation into EMP2 antibody blockade as a potential new therapeutic option.

Prognostic factors and survival in low grade gliomas of the spinal cord: A population-based analysis from 2006 to 2012.

PURPOSE: Primary spinal cord tumors are rare, and evidence-based management of these patients remains a source of controversy. This study used a large cohort of low-grade spinal cord astrocytomas to determine the effectiveness of prognostic factors and survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify patients with WHO grade I-II primary spinal cord astrocytomas from 1973 to 2012; however, patients before 2006 were excluded due to ambiguity diagnosis. Univariate and multivariate Cox proportional hazard models were created to compare survival across covariates and summarized using the Kaplan-Meier method. RESULTS: A total of 561 patients with low-grade glioma (astrocytoma) were identified. Among these, 15.5% of patients received a gross total resection (GTR), 26.1% subtotal resection (STR), and 46.2% unidentified extent of resection. 59.4% did not receive any radiation therapy at any point of the treatment course, while 40.6% underwent radiation therapy. In our cohort, only patients with GTR demonstrated statistically improved survival (HR: 0.22, P < 0.001). Patients with STR had nearly identical survival compared to patients with no surgery (HR: 0.98), and radiotherapy was associated with increased odds of mortality (HR: 1.47, P < 0.001). Multivariate analysis demonstrated a significant survival benefit among patients with younger age, GTR and absence of radiotherapy. Histologic grade did not statistically impact survival. CONCLUSION: Our study suggests that GTR results in improved survival among patients with low-grade gliomas within the spinal cord. Future, considerable data research efforts will aim to better define the role of radiotherapy and tumor grading in this patient population.

Simultaneous cerebrospinal fluid and hematologic metastases in a high-grade ependymoma.

BACKGROUND: Ependymomas are relatively uncommon tumors that constitute about 7% of all primary intracranial neoplasms. Among these, high-grade ependymomas are locally aggressive and recur most commonly at the primary site following resection. Ependymomas are also known to be the one glial neoplasm that tends to frequently metastasize inside and outside the central nervous system (CNS) that complicates workup and management. Metastasis due to surgical manipulation is common and neurosurgeons should be well-versed in the most effective methods to remove these tumors in order to avoid such metastases. CASE DESCRIPTION: Here, we report a case of a 28-year-old female who initially presented with a parenchymal World Health Organization (WHO) grade III anaplastic ependymoma of the occipital lobe without metastasis. After multiple resections, the patient showed no evidence of disease recurrence for 2 years. During follow-up, new metastasis to the frontal lobe as well as to the lung were discovered 2 years after the initial surgery, without recurrence at the tumor's primary site. CONCLUSIONS: While uncommon, this case demonstrates the possibility for ependymomas to metastasize via cerebrospinal fluid to other locations within the CNS and hematologically to extraneural locations without recurring locally.

Intraosseous mucoepidermoid carcinoma: Outcome review.

OBJECTIVE: Identify the effect of patient characteristics, disease traits, and treatment modality on patient outcomes in the rare disease process of intraosseous mucoepidermoid carcinoma. STUDY DESIGN: Retrospective review of institutional case records and literature. METHODS: This study includes one case report, a literature review of the MEDLINE database from 1950 through June 2017 using keywords "intraosseous" and "mucoepidermoid," and a query of the University of California, Los Angeles, Department of Pathology database for all documented cases of intraosseous mucoepidermoid carcinoma of the head and neck. RESULTS: Indicators of poorer prognosis were male gender (P = 0.0071) and higher histological grade (P = 0.0095). Lesion site, size, association with odontogenic cyst, and treatment type did not have a statistically significant correlation with patient outcomes. There also was no statistically significant correlation observed between treatment modality and recurrent or progressive disease when stratified by histological grade of the cancer. CONCLUSION: This study identified male gender and high histological tumor grade as poor prognostic indicators; however, it did not reveal a statistically significant relationship between treatment modality and patient outcomes. Data regarding patient outcomes following treatment was limited due to loss to follow-up, suggesting that further investigation is required. Based on this review, decisions regarding treatment should be clinically guided and individually tailored to the patient's baseline health, disease severity, and the patient's treatment goals. A multi-disciplinary conference, as was utilized in the presented case report, may be the best approach to treatment planning for these patients at this time. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1083-1092, 2018.

Surgical nuances of partial sacrectomy for chordoma.

BACKGROUND: Sacral chordomas are rare, slow growing, locally aggressive tumors. Unfortunately, aggressive surgical resection is often associated with increased neurological morbidity. METHODS: This technical note focuses on the utilization of partial sacrectomy for the resection of complex spinal chordomas. RESULTS: The case presented documents the potential range of postoperative morbidity seen in patients undergoing partial sacrectomy for chordomas. Despite iatrogenic morbidity and tumor recurrence, with the cooperation of medical and surgical spine specialists, majority of patients can achieve good long-term outcomes. CONCLUSIONS: Sacral chordomas are rare lesions and pose a therapeutic challenge for spinal surgeons and oncologists. En-bloc surgical resection (e.g., partial sacrectomy) is the treatment of choice for these lesions, and the cooperation between subspecialists can lead to good neurologic outcomes, particularly if gross total resection is achieved.

Surgical nuances of circumferential lumbar spondylectomy: A case report and short literature review.

BACKGROUND: Chordomas are uncommon malignant bone tumors that are often minimally symptomatic for several years. By the time they are diagnosed, these lesions are typically large, involve major neural, bony, and vascular structures, and are no longer readily resectable. This leads to a high recurrence rate. CASE DESCRIPTION: In this case report, we present a 67-year-old male with nonmechanical axial back pain, neurogenic claudication, and a large mass centered at the L3 level on magnetic resonance imaging consistent with a locally invasive chordoma. The patient underwent surgical resection that required a complete lumbar spondylectomy utilizing a three-stage approach, leading to incomplete tumor excision. The patient's residual postoperative symptoms included paresthesias/numbness in the right anterior thigh and a partial (4/5) right-sided foot drop. At the time of discharge, there were plans for future proton beam therapy. CONCLUSIONS: Because of their relative resistance to chemotherapeutic agents, the optimal surgical management of chordomas is gross total en-bloc excision. Unfortunately, this is rarely feasible.

Adult sacrococcygeal teratoma with coccygectomy: A case report with a review of the literature.

BACKGROUND: Saccrococcygeal teratomas (SCT) are derived from embryonic germ cell layers. They frequently present at the base of the coccyx within the pelvis. While these tumors are common in children, they are exceedingly rare in adults. In adults, a majority of these tumors are intrapelvic and associated with a low risk of malignant transformation. Therefore, this contributes to a good prognosis following resection of mostly benign lesions. CASE DESCRIPTION: An adult female with chronic pelvic pain presented with a sacral teratoma. She failed conservative treatment and underwent a coccygectomy with an en-bloc excision of the tumor. Microscopic histological analysis showed no evidence of immature or malignant elements, confirming the diagnosis of a mature, benign, cystic SCT. CONCLUSIONS: Mature SCTs in adults are rare malignant lesions. In this case, the patient was cured following primary surgical excision requiring en-bloc coccygectomy.

Immunophenotypic profiles for distinguishing orbital mucosa-associated lymphoid tissue lymphoma from benign lymphoproliferative tumors.

PURPOSE: To evaluate novel immunophenotypic profiles of patients with orbital lymphoproliferative tumors. METHODS: From 2006 to 2014, surgical biopsies from consecutive patients with newly diagnosed orbital mucosa-associated lymphoid tissue (MALT) lymphoma and IgG4-related ophthalmic disease (IgG4-ROD) were collected from Tokyo Medical University Hospital. A total of 44 tumors from 44 patients were analyzed, including 21 with orbital MALT lymphoma (11 men and 10 women, mean age 67.8 ± 13.4 years) and 23 with definitive IgG4-ROD (9 men and 14 women, mean age 60.5 ± 15.1 years). Patients with secondary orbital MALT lymphoma and MALT lymphoma with IgG4-ROD were excluded. All patients were immunocompetent Asian adults. Samples were analyzed by immunohistochemistry and flow cytometric analysis. Flow cytometry was performed with the following antibodies: CD3, CD4, CD5, CD8, CD10, CD19, CD20, CD23, CD25, CD30, CD34, and CD56 lambda and kappa chains. RESULTS: Expression of CD25 and CD19 was higher in patients with orbital MALT lymphoma compared to patients with IgG4-ROD (p < 0.001). In contrast, expression of CD3, CD4, and CD23 was higher in patients with orbital IgG4-ROD compared to those with MALT lymphoma (all p < 0.01). The presence of CD23 and CD25 in the specimens was confirmed by immunohistochemistry. CONCLUSION: The present study elucidated the novel immunophenotypic features of orbital MALT and benign lymphoproliferative disorders such as IgG4-ROD. Among them, CD23 and CD25 have shown a disease-specific expression pattern.

Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa.

Infectious agents have been identified as a major cause of specific types of human cancers worldwide. Several microorganisms have been identified as potential aggravators of ocular adnexal neoplasms; however, given the rarity of these neoplasms, large epidemiological studies are difficult to coordinate. This study aimed to conduct an exhaustive search for pathogenic DNA in lymphoproliferative disorders (LPD) of the ocular adnexa in a total of 70 patients who were diagnosed with LPD of the ocular adnexa between 2008 and 2013. Specimens were screened for bacterial, viral, fungal, and parasitic DNA by multiplex polymerase chain reaction (PCR) and quantitative real-time PCR. Among cases of conjunctival mucosa-associated lymphoid tissue lymphoma, human herpes virus (HHV)-6, HHV-7, chlamydia, Epstein-Barr virus (EBV) and bacterial 16S ribosomal DNA were detected. In cases of IgG4-related ocular disease, similar pathogens were detected but in a larger number of patients. Our PCR assays detected DNAs of various infectious agents in tumor specimens, especially HHV6, HHV7, and EBV, with different positive rates in various types of LPD. Chronic inflammatory stimulation or activation of oncogenes from these infectious agents might be involved in the pathogenesis of LPD of the ocular adnexa.

PGC-1α Induces Human RPE Oxidative Metabolism and Antioxidant Capacity.

PURPOSE: Oxidative stress and metabolic dysregulation of the RPE have been implicated in AMD; however, the molecular regulation of RPE metabolism remains unclear. The transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) is a powerful mediator of mitochondrial function. This study examines the ability of PGC-1α to regulate RPE metabolic program and oxidative stress response. METHODS: Primary human fetal RPE (hfRPE) and ARPE-19 were matured in vitro using standard culture conditions. Mitochondrial mass of RPE was measured using MitoTracker staining and citrate synthase activity. Expression of PGC-1 isoforms, RPE-specific genes, oxidative metabolism proteins, and antioxidant enzymes was analyzed by quantitative PCR and Western blot. Mitochondrial respiration and fatty-acid oxidation were monitored using the Seahorse extracellular flux analyzer. Expression of PGC-1α was increased using adenoviral delivery. ARPE-19 were exposed to hydrogen peroxide to induce oxidative stress. Reactive oxygen species were measured by CM-H2DCFDA fluorescence. Cell death was analyzed by LDH release. RESULTS: Maturation of ARPE-19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1α gene expression. Overexpression of PGC-1α increased expression of OXPHOS and fatty-acid ß-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation. PGC-1α gain of function also strongly induced numerous antioxidant genes and, importantly, protected RPE from oxidant-mediated cell death without altering RPE functions. CONCLUSIONS: This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1α as a potent driver of RPE mitochondrial function and antioxidant capacity.

The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy.

Proliferative retinopathic diseases often progress in 2 phases: initial regression of retinal vasculature (phase 1) followed by subsequent neovascularization (NV) (phase 2). The immune system has been shown to aid in vascular pruning in such retinopathies; however, little is known about the role of the alternative complement pathway in the initial vascular regression phase. Using a mouse model of oxygen-induced retinopathy (OIR), we observed that alternative complement pathway-deficient mice (Fb(-/-)) exhibited a mild decrease in vascular loss at postnatal day (P)8 compared with age- and strain-matched controls (P = 0.035). Laser capture microdissection was used to isolate the retinal blood vessels. Expression of the complement inhibitors Cd55 and Cd59 was significantly decreased in blood vessels isolated from hyperoxic retinas compared with those from normoxic control mice. Vegf expression was measured at P8 and found to be significantly lower in OIR mice than in normoxic control mice (P = 0.0048). Further examination of specific Vegf isoform expression revealed a significant decrease in Vegf120 (P = 0.00032) and Vegf188 (P = 0.0092). In conjunction with the major modulating effects of Vegf during early retinal vascular development, our data suggest a modest involvement of the alternative complement pathway in targeting vessels for regression in the initial vaso-obliteration stage of OIR.