ABSTRACT
Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury-induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry. Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptor-mediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms.
ABSTRACT
BACKGROUND: Epidermoid tumors (ETs) of the central nervous system (CNS) are rare tumors that typically occur in the 4th decade. They typically grow around vital neurovascular structures which makes surgical treatment difficult. The objective of this paper is to report on the effectiveness and safety in the management of epidermoid tumors with gamma knife surgery (GKS). MATERIALS AND METHODS: This is a retrospective study of the medical records of 8 patients treated with GKS for epidermoid tumors between July 2010 to June 2019. The median prescription dose was 11 Gy, ranging from 10 to 12 Gy, 5 patients received the total dose target to the 50% line and 3 to the 55% isodose line. The mean tumor volume was 12.4 cc ranging from 4.4 to 24.8cc. The median follow-up time was 33.7 months and ranged from 0.9 to 58.8 months. At follow-up, patients were evaluated for neurological signs and symptoms and radiographic evidence of progression of disease. Two patients were treated after failure of linac stereotactic radiosurgery. One patient underwent stereotactic radiosurgery prior to GKS, and the other had failed surgical resection prior to GKS. RESULTS: The median age was 33 years old. There were two males and six females. The most common presenting manifestation was headaches followed by vision and hearing problems. Symptoms were resolved in all cases, except for one who had partial control of trigeminal neuralgia. All patients were locally controlled by imaging and neurological examination at first follow-up. CONCLUSION: Gamma knife surgery is a safe and effective alternative treatment in patients with CNS epidermoid tumors and should be included in the initial recommendation.
ABSTRACT
Background Glomus jugulare tumors are rare slow-growing hypervascular tumors that arise from the paraganglia of the chemoreceptor system within the jugulare foramen of the temporal lobe. The historical standard treatment has been surgical resection, but because of their high vascularity and involvement with cranial nerves (CNs), Gamma Knife radiosurgery (GKRS) has been advocated as an alternative. The goal of this study is to update and report long-term results of GKRS to achieve local control and symptomatic improvement and to reduce morbidity and mortality when treating glomus jugulare tumors. Materials and Methods This study retrospectively collected and reviewed clinical and radiographic data of 32 patients with glomus jugulare tumors treated with GKRS at the Miami Neuroscience Center, South Miami, FL, from 1995 to 2019. For the 32 patients, the mean volume treated was 13.9 cc (0.23 to 40.0 cc), with an average of 8.6 isocenters. The median prescription dose was 12.84 Gy ± 2.07 Gy (range: 10-20 Gy). Follow-up data were available for 29 out of 32 patients, with a median clinical follow-up time of 37.3 months (range: 4.3-169.1 months). At follow-up, patients were evaluated for neurological signs and symptoms and radiographic evidence of progression of disease. Results The median age of the cohort treated with GKRS was 60 years (range: 14-83 years). There were three males and 27 females. Presenting symptomatology was available for 30 out of 32 patients. The most common presenting symptom was hearing loss (21/30) and the most common CN deficit was in CN VIII (19/30). Out of 29 of the patients followed up, 28 patients had improvement (20/29) or resolution (8/29) of symptoms. At the most recent evaluation or contact, patients were without symptomatic progression of CN deficits. Radiographic tumor control was achieved in 28 out of 29 patients. One patient had a recurrence seven years after GKRS, which was treated with surgery. There were no complications, radionecrosis, or mortality reported from GKRS. Conclusion These data confirm that GKRS is a reasonable upfront treatment option for glomus jugulare tumors. GKRS should be considered more frequently given its excellent long-term local control with low morbidity and risk of complications.
