Pediatric Eosinophilic Granuloma Associated With Delayed Epidural Hematoma Following on Seizure: A Case Report.

Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is even more unusual for this condition to be accompanied by an epidural hematoma (EDH). This case is unique in that it is the first to involve delayed EDH following a seizure. We describe a remarkable example of EG accompanied by an EDH and consider the rarity of this comorbidity. A 32-month-old boy developed a rapidly growing skull mass following a minor head injury. During surgical preparation for a biopsy, the patient experienced a single convulsion. Imaging following the seizure revealed an EDH in the vicinity of the mass. The mass was excised and confirmed to be an EG, but with positive margins. The patient underwent chemotherapy after systemic skeletal evaluation, in accordance with the LCH III protocol established by the Histiocytosis Society. EG is a rare neoplasm that typically presents as a painless growth on the skull that gradually enlarges over time. The correlation between EG and EDH is exceedingly uncommon, with only a few documented cases. This case study underscores the significance of considering EG in the differential diagnosis of an expanding cranium mass, even when associated with EDH. Prompt diagnosis and treatment can prevent serious complications and improve patient outcomes.

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration.

Irregularities in insulin signaling have significantly increased the risk of various cancers, yet the precise underlying mechanisms remain unclear. Within our study, we observed that inhibiting neddylation enhances cancer cell migration across different cancer types by activating both insulin receptor substrates 1 and 2 (IRS1 and IRS2), along with the PI3K/AKT signaling pathway. Notably, in the context of high-grade serous carcinoma (HGSC) patients, whether they had type 2 diabetes mellitus or not, IRS1 and IRS2 displayed a parallel relationship with each other while exhibiting an inverse relationship with NEDD8. We also identified C-CBL as an E3 ligase responsible for neddylating IRS1 and IRS2, with clinical evidence further confirming a reciprocal relationship between C-CBL and pAKT, thereby reinforcing the tumor suppressive role of C-CBL. Altogether, these findings suggest that neddylation genuinely participates in IRS1 and IRS2-dependent insulin signaling, effectively suppressing cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment option for cancer patients, particularly those presenting with insulin signaling dysregulations linked to conditions like obesity-related type 2 diabetes or hyperinsulinemia.

Pediatric Traumatic Brain Injury : The Epidemiology in Korea.

Traumatic brain injury (TBI) is one of the leading causes of death in the pediatric population in Korea. In addition, it can cause disability in children and adolescents, with physical and mental consequences. This causes a substantial burden on the health care system and occurs globally and not just in Korea. We searched and reviewed current data on the epidemiologic characteristics of pediatric TBI in Korea. Our review provides the recent epidemiological trend mainly focusing on incidence and mortality along with worldwide reported data. This review will be helpful to understand the global epidemiology of pediatric TBI and its differences between countries.

Benign meningioma manifesting with acute subdural hematoma and cerebral edema: a case report and review of the literature.

BACKGROUND: Spontaneous subdural hematoma rarely presents with a hypervascular or malignant tumor but even less frequently in a benign tumor like meningioma. We encountered a patient with acute subdural hematoma associated with benign meningioma. Here, we report this case along with a review of previous reports, especially focusing on their clinical features and possible bleeding mechanisms. CASE PRESENTATION: A 53-year-old Asian woman presented with severe headache and progressive neurologic deterioration due to cerebral edema. The patient was submitted to open surgery for evacuation of the subdural hematoma and concurrent tumor removal on the ipsilateral parietal convexity. A hypervascular, encapsulated mass was identified during surgery and completely removed including the adjacent dura mater (Simpson grade 0). The tumor was histologically confirmed as an angiomatous meningioma (World Health Organization grade I). Her clinical course was uneventful after surgery. CONCLUSIONS: Although meningiomas are commonly benign according to their histological traits, they can lead to spontaneous bleeding and cause neurologically unstable condition. Therefore, meningiomas need to be considered as a cause of spontaneous subdural hematoma if radiologically suspicious, which should be reflected by proper management for a positive outcome.

The Effect of Neddylation Blockade on Slug-Dependent Cancer Cell Migration Is Regulated by p53 Mutation Status.

The tumor suppressor protein p53 is frequently inactivated in human malignancies, in which it is associated with cancer aggressiveness and metastasis. Because p53 is heavily involved in epithelial-mesenchymal transition (EMT), a primary step in cell migration, p53 regulation is important for preventing cancer metastasis. p53 function can be modulated by diverse post-translational modifications including neddylation, a reversible process that conjugates NEDD8 to target proteins and inhibits the transcriptional activity of p53. However, the role of p53 in cancer migration by neddylation has not been fully elucidated. In this study, we reported that neddylation blockade induces cell migration depending on p53 status, specifically via the EMT-promoting transcription factor Slug. In cancer cell lines expressing wild type p53, neddylation blockade increased the transcriptional activity of p53 and expression of its downstream genes p21 and MDM2, eventually promoting proteasomal degradation of Slug. In the absence of p53, neddylation blockade increased cell migration by activating the PI3K/Akt/mTOR/Slug signaling axis. Because mutant p53 was transcriptionally inactivated but maintained the ability to bind to Slug, neddylation blockade did not affect the migration of cells expressing mutant p53. Our findings highlight how the p53 expression status influences neddylation-mediated cell migration in multiple cancer cell lines via Slug.

Neddylation blockade induces HIF-1α driven cancer cell migration via upregulation of ZEB1.

Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor 1α (HIF-1α) through the PI3K-Akt pathway, which eventually regulates the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) in various cancer cell lines. As induction of HIF-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the role of neddylation between HIF-1α and ZEB1.

Pituitary Blastoma in a 19-Year-Old Woman: A Case Report and Review of Literature.

BACKGROUND: Pituitary blastoma is a malignant neoplasm of the pituitary gland that was recognized by the World Health Organization in 2017. It is commonly diagnosed in children before 24 months of age. Here, we report the first case of a young adult patient who was diagnosed with pituitary blastoma with increased levels of growth hormone instead of adrenocorticotropic hormone and provide a review of the literature. CASE DESCRIPTION: A 19-year-old woman presented to our hospital with visual disturbance. She had a medical history of Wilms' tumor and multinodular goiter. The brain imaging showed a 3.2 × 2.5 × 1.8-cm solid sellar and suprasellar cystic mass that upwardly displaced the optic chiasm. She had an elevated level of growth hormone but a normal level of adrenocorticotropic hormone, cortisol, and prolactin. The mass was subtotally removed through the left pterional craniotomy. The pathologic examination suggested a pituitary blastoma. Thereafter, the patient was treated with chemotherapy and radiotherapy. At 4-year follow-up postsurgery, her overall well-being is good. CONCLUSIONS: Although in this case the patient was a young adult, pituitary blastoma should be taken into consideration when children have an enhanced sellar and suprasellar mass with peripherally located cysts.

Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.

Relationship between Circadian Variation in Ictus of Aneurysmal Subarachnoid Hemorrhage and Physical Activity.

OBJECTIVE: The circadian pattern of the onset time of aneurysmal subarachnoid hemorrhage (aSAH) has been reported by various authors. However, the effect of the degree of physical exertion on the circadian pattern has not been studied in detail. Therefore, we conducted this study to investigate the effect of physical exertion on the circadian pattern of aSAH. METHODS: Of the 335 patients presenting with aSAH from January 2012 to December 2017, 234 patients with identifiable onset time and metabolic equivalent (MET) values were enrolled. The onset time of aSAH was divided into 4-hour intervals. The patient's physical exertion was then assessed on a scale between 1 and 8 METs using generally accepted MET values, and categorized into two groups-light exertion (1 to 4 METs) and moderate to heavy exertion (5 to 8 METs)-to determine the effect of the degree of physical exertion on the onset time distribution of aSAH. Multivariate analysis was used to calculate the odds ratio (OR) between the two groups to determine the effect of the degree of physical exertion on each set of time periods. RESULTS: There was a definite bimodal onset pattern that peaked at 08:00-12:00 hours followed by 16:00-20:00 hours (p <0.001). MET values at all time intervals were found to be significantly higher than the night time (00:00-04:00 hours) values (p<0.031). The MET value distribution showed a unimodal pattern that slightly differed from the bimodal distribution of the onset time of aSAH. There were no significant differences in the ORs of each time interval according to the degree of the MET value. CONCLUSION: This study reaffirmed that aSAH occurs in a bimodal pattern, especially showing the highest prevalence in the morning. Although aSAH could be related to daily activity, there were no significant changes in diurnal variations affected by the degree of physical exertion.

Histone demethylase PHF2 activates CREB and promotes memory consolidation.

Long-term memory formation is attributed to experience-dependent gene expression. Dynamic changes in histone methylation are essential for the epigenetic regulation of memory consolidation-related genes. Here, we demonstrate that the plant homeodomain finger protein 2 (PHF2) histone demethylase is upregulated in the mouse hippocampus during the experience phase and plays an essential role in memory formation. PHF2 promotes the expression of memory-related genes by epigenetically reinforcing the TrkB-CREB signaling pathway. In behavioral tests, memory formation is enhanced by transgenic overexpression of PHF2 in mice, but is impaired by silencing PHF2 in the hippocampus. Electrophysiological studies reveal that PHF2 elevates field excitatory postsynaptic potential (fEPSP) and NMDA receptor-mediated evoked excitatory postsynaptic current (EPSC) in CA1 pyramidal neurons, suggesting that PHF2 promotes long-term potentiation. This study provides insight into the epigenetic regulation of learning and memory formation, which advances our knowledge to improve memory in patients with degenerative brain diseases.

The Effect of Vitamin D Supplementation in Patients with Acute Traumatic Brain Injury.

OBJECTIVE: To investigate the acute and long-term effects of vitamin D supplementation on the recovery of patients with traumatic brain injury (TBI). METHODS: A retrospective study was conducted involving 345 patients with TBI who visited a single trauma center. Vitamin D serum levels were measured without supplementation at admission, 1 month, and 3 months post-TBI (control group) from August to December 2016. From January 2017, vitamin D supplementation was provided to patients with TBI with low vitamin D serum levels at admission (supplement group). The outcomes were investigated by assessing performance function (Extended Glasgow Outcome Scale) and cognitive function (Mini-Mental Status Examination, and Clinical Dementia Rating) at 1 week and 3 months post-TBI. RESULTS: The mean vitamin D serum level in patients with TBI at admission was 13.62 ± 9.01 ng/mL. The level significantly increased from 14.03 ± 8.68 ng/mL at admission to 37.42 ± 12.57 ng/mL at 3 months post TBI in the supplement group (P < 0.001). The cognitive outcomes (Mini-Mental Status Examination/Clinical Dementia Rating, P = 0.042/P = 0.044) and GOS-E score (total TBI, P = 0.003; mild-to-moderate TBI, P = 0.002) significantly improved from the first week to 3 months post TBI in the patients with vitamin D supplementation. CONCLUSIONS: Administration of vitamin D supplements in mild-to-moderate TBI patients with significant vitamin D deficiency during the acute phase of the injury may improve long-term performance and cognitive outcomes. Therefore, the treatment strategies should be individually planned for the patients with TBI based on their baseline vitamin D level.

A new definition for wide-necked cerebral aneurysms.

BACKGROUND: Endovascular management of wide-necked aneurysms often requires assisted-techniques with adjunctive devices. Wide-necked aneurysm can be defined with a dome-to-neck ratio or aspect ratio; however, clinical definitions of wide-necked aneurysms vary. This study aimed to determine the most useful definition of wide-necked aneurysm to predict the need for an adjunctive device. METHODS: Among 552 cases of aneurysms, 343 (62.1%) and 209 (37.9%) cases of unruptured and ruptured aneurysms, respectively, were treated in a single institution. For each aneurysm, the (1) dome-to-neck ratio, (2) aspect ratio, and (3) K-ratio (defined as [dome height+maximum dome width]/[2×maximum neck width]) were measured. We statistically analyzed patient data to determine which of the three ratios was most predictive of the need for adjunctive devices. RESULTS: Among 552 cases of aneurysms, 277 (50.2%) and 275 (49.8%) cases were treated with and without adjunctive techniques, respectively. The mean dome-to-neck ratio, aspect ratio, and K-ratio were 1.17±0.39, 1.58±0.61, and 1.37±0.47, respectively. The K-ratio was the strongest predictor of the use of adjunctive devices (P<0.001), and 1.3 was the most appropriate K-ratio cut-off value (sensitivity, 72.9%; specificity, 63.6%). CONCLUSIONS: K-ratio was the most useful predictor of the need for adjunctive devices in the treatment of endovascular aneurysms. These results suggest that the K-ratio may be used to define wide-necked aneurysms requiring complicated management via adjunctive devices.

Post-factum autopsy to confirm cardiac structures visible on computed tomography images of Korean mummies: the radiological basis of paleo-cardiology.

Accurate interpretation of radiological data is important for reliable paleopathological study of mummies. This is especially true for the mummified heart, an anatomically complicated organ that is distorted and displaced due to long-term dehydration and the action of gravity. In the present study, we compared post-factum autopsy results for mummified hearts of differing preservation statuses with corresponding radiological (computed tomography [CT]-image) findings in order to obtain information necessary for accurate radiological diagnosis. We found that the valvular apparatus (especially the aortic valve and chordae tendinae) was easily distinguishable on the CT images of mummies in which more cardiac structures were preserved. We also identified several situations that are known to incur misdiagnosis of cardiac CT images: the presence of pseudo-cavities in the cardiac wall, confusion of the valvular apparatus with cardiac-wall debris, and invisibility of cardiac structures on CT images due to collapse or adhesion. While acknowledging the merits of top-priority CT scanning in non-invasive research, post-factum autopsy also has value as a complementary and confirmatory analysis for enhanced accuracy of diagnoses in paleo-radiological studies.

Does Neurosurgical Clipping or Endovascular Coiling Lead to More Cases of Delayed Hydrocephalus in Patients with Subarachnoid Hemorrhage?

OBJECTIVE: We investigated whether clipping or endovascular treatment (EVT) can reduce the incidence of delayed hydrocephalus. We also investigated whether additional procedures, namely lumbar drainage and extra-ventricular drainage (EVD), decrease the incidence of delayed hydrocephalus in patients with subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: One-hundred and fifty-two patients who had undergone an operation for SAH were enrolled in this study. Clinical data, radiological data, and procedural data were investigated. Procedural data included the operating technique (clipping vs. EVT) and the use of additional procedures (no procedure, lumbar drainage, or EVD). Delayed hydrocephalus was defined as a condition in which the Evan's index was 0.3 or higher, as assessed using brain computed tomography more than 2 weeks after surgery, requiring shunt placement due to neurological deterioration. RESULTS: Of the 152 patients, 45 (29.6%) underwent surgical clipping and 107 (70.4%) underwent EVT. Twenty-five (16.4%) patients developed delayed hydrocephalus. Age (p = 0.019), procedure duration (p = 0.004), and acute hydrocephalus (p = 0.030) were significantly correlated with the incidence of delayed hydrocephalus. However, the operation technique (p = 0.593) and use of an additional procedure (p = 0.378) were not significantly correlated with delayed hydrocephalus incidence. CONCLUSION: No significant difference in the incidence of delayed hydrocephalus was associated with operation technique or use of an additional procedure in patients with SAH. However, delayed hydrocephalus was significantly correlated with old age, long procedural duration, and acute hydrocephalus. Therefore, we recommend that additional procedures should be discontinued as soon as possible.

The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src.

Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src. After neddylation, c-Src is poly-ubiquitinated and degraded through the proteasome, which inhibits the PI3K-AKT pathway responsible for cell migration. In human lung cancer tissues, the downregulation of C-CBL was associated with c-Src/AKT, cancer metastasis, and poor survival in patients. Therefore, C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src. This study provides new insight about the role of neddylation in cancer metastasis. It also implies that the metastasis risk should be carefully evaluated before the clinical application of neddylation inhibitors as anticancer regimens.

Pediatric Glioma at the Optic Pathway and Thalamus.

Gliomas are the most common pediatric tumors of the central nervous system. In this review, we discuss the clinical features, treatment paradigms, and evolving concepts related to two types of pediatric gliomas affecting two main locations: the optic pathway and thalamus. In particular, we discuss recently revised pathologic classification, which adopting molecular parameter. We believe that our review contribute to the readers' better understanding of pediatric glioma because pediatric glioma differs in many ways from adult glioma according to the newest advances in molecular characterization of this tumor. A better understanding of current and evolving issues in pediatric glioma is needed to ensure effective management decision.

Clopidogrel Response Variability in Unruptured Intracranial Aneurysm Patients Treated with Stent-Assisted Endovascular Coil Embolization : Is Follow-Up Clopidogrel Response Test Necessary?

OBJECTIVE: The purpose of this study was to analyze the variability of clopidogrel responses according to duration of a clopidogrel drug regimen after stent-assisted coil embolization (SAC), and to determine the correlation between the variability of clopidogrel responses and thromboembolic or hemorrhagic complications. METHODS: A total of 47 patients who underwent SAC procedures to treat unruptured intracranial aneurysms were enrolled in the study. Preoperatively, patients received more than seven days of aspirin (100 mg) and clopidogrel (75 mg), daily. P2Y12 reaction unit (PRU) was checked with the VerifyNow test one day before the procedure (pre-PRU) and one month after the procedure (post-PRU). PRU variability was calculated as the difference between the initial response and the follow-up response. Patients were sorted into two groups based on their response to treatment : responsive and hypo-responsive. RESULTS: PRU variability was significantly greater in the hypo-responsive group when compared to the responsive group (p=0.019). Pre-PRU and serum platelets counts were significantly correlated with PRU variation (p=0.005 and p=0.004, respectively). Although thromboembolic complication had no significant correlated factors, hemorrhagic complication was correlated with pre-PRU (p=0.033). CONCLUSION: In conclusion, variability of clopidogrel responses during clopidogrel medication was correlated to serum platelet counts and the initial clopidogrel response. Thromboembolic and hemorrhagic complications did not show correlation with the variability of clopidogrel response, or the clopidogrel response after one month of medication; however, hemorrhagic complication was associated with initial clopidogrel response. Therefore, it is recommended to test patients for an initial clopidogrel response only, as further tests would be insignificant.

Quantitative analysis in peritumoral volumes of brain metastases treated with stereotactic radiotherapy.

PURPOSE: The purpose of this study was to verify changes in diffusion tensor imaging (DTI) factors in patients with brain metastases treated with stereotactic radiotherapy (SRT). We also investigated the impact of SRT on peritumoral volumes though the use of DTI. METHODS: A total of 28 patients with brain metastases who had undergone SRT between March 2014 and December 2015 were enrolled. Magnetic resonance imaging with DTI factors, such as fractional anisotropy (FA) and apparent diffusion tensor (ADC) value, was performed 1 day before the procedure and 3 months after the procedure. DTI data from tumor lesions, edema volumes, and the volumes that received 12Gy were measured. RESULTS: Tumor volume (P=0.001) and ADC values in the volumes that received 12Gy (P=0.018) and the edema volumes (P=0.003) significantly decreased after the procedure. Decreases in tumor volume were only correlated with decreases in edema volumes (P<0.001). Decreases in edema volumes were correlated with increases in FA values and decreases in ADC values of the volumes that received 12Gy [P=0.019 (FA)/0.002 (ADC)] and the edema volumes [P=0.011 (FA)/0.002 (ADC)]. CONCLUSIONS: It was possible to quantify changes in peritumoral volumes in patients with brain metastases after SRT by using DTI. ADC values of peritumoral volumes decreased significantly after SRT. Therefore, it was confirmed through DTI that performing SRT on tumor lesions has a positive effect on the structure and function of peritumoral volumes.

Correlation between Head Trauma and Outcome of Chronic Subdural Hematoma.

OBJECTIVE: Our study examined the prognostic factors involved in the outcome of patients with chronic subdural hematoma (CSDH) who had undergone burr hole drainage procedures, and investigated the association between outcome and traumatic head injury. In addition, we explored factors related to recurrence. METHODS: This study enrolled 238 patients with CSDH who had undergone burr hole drainage. Patients with history of head injury were categorized into the head trauma group and were compared with the no head trauma group. Outcome was considered good when modified Rankin Scale scores improved from admission to discharge and the final follow-up. RESULTS: Among 238 patients, 127 (53.4%) were included in the head trauma group. One hundred thirty-three (55.9%) patients demonstrated good outcome at discharge, and 171 (71.8%) patients demonstrated good outcome at the final follow-up. None of the factors examined was significantly correlated with good outcome at discharge. However, only history of head injury (p=0.033, odds ratio 0.511, 95% confidence interval 0.277-0.946) was significantly correlated with poor outcome at long-term follow-up. Recurrence occurred in 20 (8.4%) cases in the total cohort and 11 (55%) patients in the head trauma group. CONCLUSION: History of head trauma is correlated with poor outcome at long-term follow-up in CSDH patients having undergone burr hole drainage. Therefore, CSDH patients with history of head injury are susceptible to poor outcome, warranting more careful evaluation and treatment after burr hole drainage.