Langerhans cell histiocytosis of the sella in a pediatric patient: case report with review of the literature.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare condition arising from the monoclonal expansion of myeloid precursor cells, which results in granulomatous lesions that characteristically express CD1a/CD207. We report a case of LCH in a 3-year-old male involving the sphenoid bone with extension into the sellar/suprasellar region. CASE REPORT: A 3-year-old male presented with progressively worsening headaches and associated night sweats, neck stiffness, and fatigue over the previous 4 weeks. Magnetic resonance imaging (MRI) revealed a 2.4-cm lytic lesion within the basisphenoid, exerting mass effect upon the pituitary gland. A biopsy was performed to determine the etiology of the lesion. Postoperatively, the patient developed an intralesional hematoma with visual complications requiring emergent surgical resection via endoscopic endonasal approach. Final pathology confirmed LCH. The patient had improvement in his vision long term. CONCLUSIONS: LCH extending into the sella is a rare but important diagnosis to consider in pediatric patients presenting with lesions in this region. We presented a case of a pediatric patient presenting with LCH of the sphenoid bone extending into the sella, with subsequent apoplexy and vision loss. Review of the literature showed varying treatment options for these patients, including purely surgical and non-surgical treatments. Early intervention may be necessary to avoid potentially devastating neurologic sequelae.

Traumatic atlantoaxial rotatory fixation in adults: a systematic review of published cases.

Atlantoaxial rotatory fixation (AARF) in adults is a rare and clinically challenging condition characterized by a spectrum of etiological factors, predominantly attributed to traumatic and inflammatory pathologies within the craniovertebral region. Trauma is the most frequently identified cause within the adult population, with the first case report published in 1907. This study aims to conduct a systematic review that addresses the clinical presentations and management strategies relating to traumatic atlantoaxial rotatory fixation in adults. A comprehensive search of the PubMed database was executed, adhering to the PRISMA guidelines. The inclusion criteria encompassed case reports and series documenting AARF cases in individuals aged 18 and above, spanning database inception to July 2022. Studies not published in the English language were excluded. A total of 61 articles reporting cases of AARF in the adult population were included in the study. The mean age of affected individuals was 36.1 years (± 15.6), with a distribution of 46% females and 54% males. Predominant mechanisms of injury included motor vehicle accidents and falls, constituting 38% and 22% of cases, respectively. Among the classification systems employed, Fielding and Hawkins type I accounted for the majority at 63%, followed by type II at 10%, and type III at 4%. Conservative management was used for treatment in 65% of acute (65%) cases and 29% of chronic cases. Traumatic AARF is a rare phenomenon in the adult population, is more common in younger adults, and does not often present with neurologic deficits. Patients diagnosed acutely are more likely to be successfully treated with conservative management, while patients diagnosed chronically are less likely to be reduced with conservatively and often require surgical treatment. Surgery should be considered for patients with irreducible dislocations, ligamentous injuries, unstable associated fractures, and persistent pain resistant to conservative management.

Traumatic Brain Injury: A Comprehensive Review of Biomechanics and Molecular Pathophysiology.

Traumatic brain injury (TBI) is a critical public health concern with profound consequences for affected individuals. This comprehensive literature review delves into TBI intricacies, encompassing primary injury biomechanics and the molecular pathophysiology of the secondary injury cascade. Primary TBI involves a complex interplay of forces, including impact loading, blast overpressure, and impulsive loading, leading to diverse injury patterns. These forces can be categorized into inertial (e.g., rotational acceleration causing focal and diffuse injuries) and contact forces (primarily causing focal injuries like skull fractures). Understanding their interactions is crucial for effective injury management. The secondary injury cascade in TBI comprises multifaceted molecular and cellular responses, including altered ion concentrations, dysfunctional neurotransmitter networks, oxidative stress, and cellular energy disturbances. These disruptions impair synaptic function, neurotransmission, and neuroplasticity, resulting in cognitive and behavioral deficits. Moreover, neuroinflammatory responses play a pivotal role in exacerbating damage. As we endeavor to bridge the knowledge gap between biomechanics and molecular pathophysiology, further research is imperative to unravel the nuanced interplay between mechanical forces and their consequences at the molecular and cellular levels, ultimately guiding the development of targeted therapeutic strategies to mitigate the debilitating effects of TBI. In this study, we aim to provide a concise review of the bridge between biomechanical processes causing primary injury and the ensuing molecular pathophysiology of secondary injury, while detailing the subsequent clinical course for this patient population. This knowledge is crucial for advancing our understanding of TBI and developing effective interventions to improve outcomes for those affected.

Combined intracranial Acriflavine, temozolomide and radiation extends survival in a rat glioma model.

Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF) regulatory pathways, recent evidence has shown that Acriflavine (ACF) can effectively target glioma invasiveness and recurrence. However, local delivery of ACF and its combinatory effects with Temozolomide (TMZ) and radiation therapy (XRT) have not yet been optimized. In this study we test a novel polymeric matrix that can gradually release ACF at the tumor bed site in combination with systemic TMZ and XRT. In vitro cytotoxicity assays of ACF in combination with TMZ and XRT were performed on rodent and human cell lines with CCK-8 and flow cytometry. In vitro drug release was measured and intracranial safety was assessed in tumor-free animals. Finally, efficacy was assessed in an intracranial gliosarcoma model and combination therapy with TMZ and XRT evaluated. Combination therapy of ACF, TMZ, and XRT was able to reduce cell viability and induce apoptosis in glioma cells. In vitro and in vivo release of ACF was measured in benchtop and animal models. Efficacy was established in an in vivo gliosarcoma model in which intracranial ACF (p < 0.01) significantly improved median survival and the combination therapy of ACF, TMZ and XRT (p < 0.01) significantly improved median survival and led to long-term survival (LTS). We provide evidence that ACF, combined with TMZ and XRT, led to LTS in an intracranial model of rat gliosarcoma. These findings, in combination with the use of a novel polymeric matrix that allows more gradual drug delivery, constitute a first step in the translation of this novel strategy to human use.

Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model.

BACKGROUND: Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. METHODS: The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. RESULTS: Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. CONCLUSIONS: Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

OBJECTIVE: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma. METHODS: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. RESULTS: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004). CONCLUSIONS: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.

Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

Evaluating the Effects of Cerebrospinal Fluid Protein Content on the Performance of Differential Pressure Valves and Antisiphon Devices Using a Novel Benchtop Shunting Model.

BACKGROUND: Hydrocephalus is managed by surgically implanting flow-diversion technologies such as differential pressure valves and antisiphoning devices; however, such hardware is prone to failure. Extensive research has tested them in flow-controlled settings using saline or de-aerated water, yet little has been done to validate their performance in a setting recreating physiologically relevant parameters, including intracranial pressures, cerebrospinal fluid (CSF) protein content, and body position. OBJECTIVE: To more accurately chart the episodic drainage characteristics of flow-diversion technology. A gravity-driven benchtop model of flow was designed and tested continuously during weeks-long trials. METHODS: Using a hydrostatic pressure gradient as the sole driving force, interval flow rates of 6 valves were examined in parallel with various fluids. Daily trials in the upright and supine positions were run with fluid output collected from distal catheters placed at alternating heights for extended intervals. RESULTS: Significant variability in flow rates was observed, both within specific individual valves across different trials and among multiple valves of the same type. These intervalve and intravalve variabilities were greatest during supine trials and with increased protein. None of the valves showed evidence of overt obstruction during 30 d of exposure to CSF containing 5 g/L protein. CONCLUSION: Day-to-day variability of ball-in-cone differential pressure shunt valves may increase overdrainage risk. Narrow-lumen high-resistance flow control devices as tested here under similar conditions appear to achieve more consistent flow rates, suggesting their use may be advantageous, and did not demonstrate any blockage or trend of decreasing flow over the 3 wk of chronic use.

Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer.

Glioblastoma multiforme (GBM) has few clinically approved therapeutic regimens. One of these therapeutic options includes placing biodegradable wafers releasing BCNU (Gliadel®) into the tumor bed at the time of surgical removal of the tumor. Due to the significant benefit this polymer technology has had clinically, we have prepared wafers releasing Temozolomide (TMZ), an anticancer drug used systemically for treating GBM. TMZ delivered via polymer wafer could be used as a complementary treatment with or as an alternative to Gliadel®. TMZ is an alkylating agent which is water soluble. To remain comparable with the preclinical studies that led to Gliadel® the same size of wafers were formulated with TMZ. Wafers were loaded with 50% w/w TMZ in poly(lactic acid-glycolic acid) (PLGA) and showed reliable release of high dose TMZ for a period of 4 weeks. To achieve this 30-day release of the highly water soluble drug, we developed an encapsulation method, where the drug powder was first coated with the polymer to form core-shell particles in which the coating shell served as a rate controlling membrane for the drug particles. Wafers were also made with a co-loading of TMZ and BCNU. All wafers were tested in vivo by treating an intracranial 9 L gliosarcoma model in F344 rats. Rats that were either untreated or treated with blank wafer died within 11 days while the median survival for rats treated with systemic TMZ was 18 days. The group that received the BCNU alone wafer had a median survival of 15 days, the group that received the TMZ wafer alone had a median survival of 19 days, and the group treated with the BCNU-TMZ wafer had a median survival of 28 days with 25% of the animals living long term (p < .0038 vs. Control; p < .001 vs. Blank Polymer). These findings demonstrate the potential of this newly designed wafer for treating GBM. Moreover, this concept, can pave the way for other drug combinations that may improve the clinical application of numerous agents to treat solid tumors.

Sleep-disordered breathing and stroke: A relation to be considered.

Stroke is a leading cause of death and disability. Despite expensive and elaborative research in finding out mechanisms of interrelation between sleep-disordered breathing (SDB) and stroke, there is yet much attention to be given in stroke units worldwide to the prompt diagnosis and treatment of SDB in order to improve morbidity and mortality rates related with stroke. The preventive diagnosis and treatment of SDB reduce stroke rate and improves penumbra area in case of ischemic stroke. Stroke itself predispose to SDB, making the interrelationship more complicated. The review by Parra O and Arboix A reflects the results from carefully selected reviews reported in the literature so far. This review of the literature and presentation of the original study of the Authors based on their patients' data, enhances the conviction that there exists a direct relation between SDB and stroke. Diagnosis of SDB in new stroke cases should be sought and treated carefully whenever present.