Clinical Theranostics in Recurrent Gliomas: A Review.

Gliomas represent the most commonly occurring tumors in the central nervous system and account for approximately 80% of all malignant primary brain tumors. With a high malignancy and recurrence risk, the prognosis of high-grade gliomas is poor, with a mean survival time of 12-18 months. While contrast-enhanced MRI serves as the standard diagnostic imaging modality for gliomas, it faces limitations in the evaluation of recurrent gliomas, failing to distinguish between treatment-related changes and tumor progression, and offers no direct therapeutic options. Recent advances in imaging modalities have attempted to address some of these limitations, including positron emission tomography (PET), which has demonstrated success in delineating tumor margins and guiding the treatment of recurrent gliomas. Additionally, with the advent of theranostics in nuclear medicine, PET tracers, when combined with therapeutic agents, have also evolved beyond a purely diagnostic modality, serving both diagnostic and therapeutic roles. This review will discuss the growing involvement of theranostics in diagnosing and treating recurrent gliomas and address the associated impact on quality of life and functional recovery.

Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods.

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.

Spinal Intradural Arachnoid Cysts in Adults: An Institutional Experience and Literature Review.

BACKGROUND: Adult spinal intradural arachnoid cysts are rare pathologic entities with an unclear etiopathogenesis. These lesions can be dichotomized into primary (idiopathic) or secondary (related to inflammation, intradural surgery, or trauma) etiologies. Limited series have depicted optimal management strategies and clinical outcomes. OBJECTIVE: To illustrate our experience with spinal intradural arachnoid cysts and to present a literature review of surgically treated cysts to elucidate the clinical and anatomic differences between etiologies. METHODS: Institutional review revealed 29 patients. Various data were extracted from the medical record. Initial and follow-up symptomatologies of the surgical cohort were compared. The literature review included case series describing cysts managed surgically. RESULTS: From patients treated surgically at our institution (22), there was a significant reduction in thoracic back pain postoperatively ( P = .034). A literature review yielded 271 additional cases. Overall, primary and secondary lesions accounted for 254 and 39 cases, respectively. Cysts of secondary origin were more likely localized ventral to the spinal cord ( P = .013). The rate of symptomatic improvement after surgical intervention for primary cysts was more than double than that of secondary cysts ( P < .001). Compared with primary etiologies, the rates of radiographic progression ( P = .032) and repeat surgery ( P = .041) were each more than double for secondary cysts. CONCLUSION: Surgical intervention for spinal intradural arachnoid cysts improves thoracic back pain. The literature supports surgical intervention for symptomatic primary spinal intradural arachnoid cysts with improved clinical outcomes. Surgery should be cautiously considered for secondary cysts given worse outcomes.

Corrigendum: Methadone alters the peripheral inflammatory and central immune landscape following prenatal exposure in rats.

[This corrects the article DOI: 10.3389/adar.2022.10792.].

Prenatal and postnatal insults differentially contribute to executive function and cognition: Utilizing touchscreen technology for perinatal brain injury research.

The use of touchscreen technology to evaluate cognitive deficits in animal models has grown tremendously over the past 20 years. The touchscreen apparatus encompasses many advantages, namely a high level of standardization and translational capability. Improvements in technology in recent years have expanded the versatility of the touchscreen platform, as it is able to test distinct cognitive modalities including working memory, attention, discrimination, and association. Importantly, touchscreen technology has allowed researchers to explore deficits in multiple pillars of cognition in a wide variety of perinatal disorders with neurological sequelae across critical developmental windows. The touchscreen platform has been used to dissect deficits in antenatal CNS injury including fetal alcohol syndrome, prenatal opioid exposure, and chorioamnionitis, to peripartum insults such as term hypoxic-ischemic encephalopathy, to early postnatal insults including infantile traumatic brain injury. Most importantly, touchscreen technology offers the sensitivity necessary to detect subtle injury and treatment-induced changes in cognition and executive function beyond those offered by more rudimentary tests of rodent cognition. Understanding the pathophysiology of these disorders in rodents is paramount to addressing these deficits in human infants and dissecting the neural circuitry essential to perinatal brain injury pathophysiology and responsiveness to novel therapeutics. Touchscreen testing provides an effective, facile, sophisticated technique to accelerate the goal of improving cognitive and behavioral outcomes of children who suffer perinatal brain injury.

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury.

Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT), could improve this trajectory. Thus, we administered EPO + MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ∼25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ∼1 year, rats were randomized to receive either a regimen of EPO + MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO + MLT were restored compared to vehicle-treated rats (p < 0.05) and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

A Comparison of PET Tracers in Recurrent High-Grade Gliomas: A Systematic Review.

Humans with high-grade gliomas have a poor prognosis, with a mean survival time of just 12-18 months for patients who undergo standard-of-care tumor resection and adjuvant therapy. Currently, surgery and chemoradiotherapy serve as standard treatments for this condition, yet these can be complicated by the tumor location, growth rate and recurrence. Currently, gadolinium-based, contrast-enhanced magnetic resonance imaging (CE-MRI) serves as the predominant imaging modality for recurrent high-grade gliomas, but it faces several drawbacks, including its inability to distinguish tumor recurrence from treatment-related changes and its failure to reveal the entirety of tumor burden (de novo or recurrent) due to limitations inherent to gadolinium contrast. As such, alternative imaging modalities that can address these limitations, including positron emission tomography (PET), are worth pursuing. To this end, the identification of PET-based markers for use in imaging of recurrent high-grade gliomas is paramount. This review will highlight several PET radiotracers that have been implemented in clinical practice and provide a comparison between them to assess the efficacy of these tracers.

Methadone alters the peripheral inflammatory and central immune landscape following prenatal exposure in rats.

Opioid use during pregnancy continues to rise at alarming rates with a parallel trend in the number of infants and children exposed to opioid medications each year. Prenatal opioid exposure (POE) occurs at a critical timepoint in neurodevelopment disrupting intricate pathways essential for neural-immune maturation with the potential for devastating long-term consequences. Understanding the mechanisms underlying injury associated with POE is essential to address long-term outcomes and identify diagnostic and therapeutic biomarkers in this vulnerable patient population. Using an established preclinical model of POE, we investigated changes in cerebral and peripheral inflammation and peripheral blood mononuclear cell (PBMC) activity. We hypothesized that neuroinflammation, as defined by changes in specific cerebral immune cell populations, would exist in adult rats following POE concomitant with sustained peripheral immune hyperreactivity (SPIHR). Our data demonstrated alterations in cerebral immune cells at postnatal day 60 (P60) typified by increased regulatory T cells (p < 0.01) and neutrophils (p < 0.05) in rats with POE compared to controls. Evaluation of serum revealed increased levels of IL-6 (p < 0.05) and CXCL1 (p < 0.05) at P21 in rats with POE compared to controls with no significant difference in cytokine or chemokine levels between the two groups at P60. Additionally, PBMCs isolated from rats with POE at P21 demonstrated baseline hypersecretion of IL-6 (p < 0.01) and SPIHR with increased levels of TNF-α (p < 0.05) and CXCL1 (p < 0.05) following stimulation with LPS. At P60, however, there was no significant difference found in cytokine or chemokine levels secreted by PBMCs isolated from rats with POE at baseline or with LPS stimulation when compared to controls. Taken together, these data demonstrate cerebral inflammation months after prenatal opioid exposure and long after the resolution of systemic inflammation and SPIHR seen at toddler age equivalent. Chronic alterations in the cerebral immune cell populations secondary to prenatal opioid exposure may underly long-term consequences of developmental brain injury including deficits in cognition and attention. These findings may be invaluable to further investigations of precise biomarkers of injury and targeted therapeutics for this vulnerable population.

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity.

BACKGROUND: Monitoring and treating metastatic progression remains a formidable task due, in part, to an inability to monitor specific differential molecular adaptations that allow the cancer to thrive within different tissue types. Hence, to develop optimal treatment strategies for metastatic disease, an important consideration is the divergence of the metastatic cancer growing in visceral organs from the primary tumor. We had previously reported the establishment of isogenic human metastatic breast cancer cell lines that are representative of the common metastatic sites observed in breast cancer patients. METHODS: Here we have used proteomic, RNAseq, and metabolomic analyses of these isogenic cell lines to systematically identify differences and commonalities in pathway networks and examine the effect on the sensitivity to breast cancer therapeutic agents. RESULTS: Proteomic analyses indicated that dissemination of cells from the primary tumor sites to visceral organs resulted in cell lines that adapted to growth at each new site by, in part, acquiring protein pathways characteristic of the organ of growth. RNAseq and metabolomics analyses further confirmed the divergences, which resulted in differential efficacies to commonly used FDA approved chemotherapeutic drugs. This model system has provided data that indicates that organ-specific growth of malignant lesions is a selective adaptation and growth process. CONCLUSIONS: The insights provided by these analyses indicate that the rationale of targeted treatment of metastatic disease may benefit from a consideration that the biology of metastases has diverged from the primary tumor biology and using primary tumor traits as the basis for treatment may not be ideal to design treatment strategies.