Search

Intracerebral hemorrhage (ICH), accounting for 9-27% of all strokes, carries substantial rates of morbidity and mortality that have not shown much improvement in the past decades. The poor outcomes of ICH can be attributed to the primary and secondary brain injuries caused by mass effects and inflammatory mechanisms, respectively. Early ICH evacuation is a critical component of treatment, as it mitigates the effect of both the primary and secondary mechanisms of brain injury and is associated with significant improvement in patient outcomes. However, no standardized evacuation technique exists. This technical report introduces a novel stereotactic vacuum-assisted minimally invasive (MIS) aspiration of a hemorrhagic stroke with its effectiveness evidenced by excellent patient recovery.

Atypical central neurocytoma with extracranial metastases is a rare variant of benign central neurocytoma (CN). No definitive course of treatment exists for atypical CN. We report a unique case of atypical CN with concomitant pituitary macroadenoma and subsequent metastases to the spine. The patient received craniospinal radiation therapy. Close-follow up post tumor-resection may be advised to monitor for drop metastases. To the best of our knowledge, this is the only case reported of atypical CN with drop metastases to the spine concomitant with pathological-proven pituitary macroadenoma.

Brain abscesses are difficult to manage clinically and often result in a poor outcome. Although surgical and medical therapeutics have progressed, there are still challenges that make treating intracranial abscesses problematic. One of these treatment barriers is the poor penetration of intravenous antibiotics to the infection source through the blood-brain barrier. In this case report, we will discuss the use of a surgical drain as a conduit for direct antibiotic administration for a rare, recurrent Streptococcus intermedius infection. This technique allows us to bypass the blood-brain barrier while also reducing the systemic effects of antibiotics. When used in conjunction with craniotomy and resection, direct antibiotic administration via a surgical drain proved to be effective at treating our patient's abscess and preventing recurrence.

Olfactory groove meningiomas are slow-growing tumors that manifest with headaches, changes in vision, and personality changes. The anatomic location of these tumors makes psychiatric disturbances more common early in the stage of tumors than focal neurological deficits. The case study here describes a unique instance of an undiagnosed giant olfactory groove meningioma in a young mother who was charged with a felony of aggravated child abuse for the death of her toddler daughter. The patient underwent gross tumor resection and radiation therapy, which halted the visual decline, resolved the frontal headaches, and the patient showed improved mood. In this patient, the insidious onset of personality changes without obvious focal neurologic deficits until late as well as a history of depression likely contributed to the delayed diagnosis. Failure to notice these initial behavioral manifestations in these patients allows for further psychiatric and cognitive decline, which can result in devastating social consequences.

A 53-year-old female admitted to the hospital for generalized weakness, fever, and cough, tested positive for coronavirus disease 2019 (COVID-19). She experienced cardiac arrest and then developed a deep-venous thrombosis and pneumonia. She then developed new-onset paraplegia due to an epidural abscess found on thoracic-spine imaging. After surgical removal of the epidural abscess, the patient improved clinically. This is a unique case report of a patient developing paraplegia secondary to an epidural abscess as a serious complication of COVID-19 infection.

Pediatric glioblastoma (GBM) is a relatively rare brain tumor in children that has a dismal prognosis. Surgery followed by radiotherapy is the main treatment protocol used for older patients. The benefit of adjuvant chemotherapy is still limited due to a poor understanding of the underlying molecular and genetic changes that occur with irradiation of the tumor. In this study, we performed total RNA sequencing on an established stable radioresistant pediatric GBM cell line to identify mRNA expression changes following radiation. The expression of many genes was altered in the radioresistant pediatric GBM model. These genes have never before been reported to be associated with the development of radioresistant GBM. In addition to exhibiting an accelerated growth rate, radioresistant GBM cells also have overexpression of the DNA synthesis-rate-limiting enzyme ribonucleotide reductase, and pro-cathepsin B. These newly identified genes should be concertedly studied to better understand their role in pediatric GBM recurrence and progression after radiation. It was observed that the changes in multiple biological pathways protected GBM cells against radiation and transformed them to a more malignant form. These changes emphasize the importance of developing a treatment regimen that consists of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or a novel therapy that targets differentially expressed genes, such as metalloproteases, growth factors, and oncogenes and aim to minimize oncogenic changes following radiation is necessary to improve recurrent GBM survival.

// Ha Son Nguyen 1, 3 , Ninh B. Doan 1, 5 , Michael Gelsomino 1 , Saman Shabani 1 , Ahmed J. Awad 1, 4 , Mayank Kaushal 1 and Martin M. Mortazavi 2, 3 1 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA 2 National Skull Base Center, Thousand Oaks, California, USA 3 California Institute of Neuroscience, Thousand Oaks, California, USA 4 Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine 5 Department of Neurosurgery, University of South Alabama, Mobile, Alabama, USA Correspondence to: Ha Son Nguyen, email: Ha.son.nguyen@gmail.com Keywords: intracranial hemangioblastoma; SEER; surgery; radiation Received: March 28, 2018 Accepted: May 14, 2018 Published: June 15, 2018 ABSTRACT Introduction: Intracranial hemangioblastoma (HB) is a rare pathology. Limited data exist regarding its epidemiology. Methods: With the SEER-18 registry database, information from all patients diagnosed with intracranial HB from 2004 to 2013 were extracted, including age, gender, race, marital status, presence of surgery, extent of surgery, receipt of radiation, tumor size, tumor location, and follow-up data. Age-adjusted incidence rates and overall survival (OS). Cox proportional hazards model was employed for both univariate and multivariate analyses. Results: A total of 1307 cases were identified. The overall incidence of intracranial hemangioblastoma is 0.153 per 100,000 person-years [95% confidence interval (CI)=0.145–0.162]. Through univariate analysis, age < 40 [hazard ratio (HR)=0.277, p

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival.

Brain abscesses are associated with high morbidity and mortality rates. In particular, patients with intraventricular rupture of brain abscess (IVROBA) exhibit mortality rates up to 85%. Treatment options are lacking for IVROBA, once patients become refractory to intravenous antibiotics and surgical drainage. Limited data exist regarding the risks and benefits of intraventricular therapy in such a scenario. We report a patient with IVROBA, who deteriorated while on systemic antibiotics; once intraventricular vancomycin was employed, the patient demonstrated remarkable improvement without perceivable side effects. This case suggests that intraventricular vancomycin may be a safe, effective, and viable option for the treatment of IVROBA, especially for patients becoming refractory to systemic antibiotics.

Dysregulated sphingolipid metabolism is associated with many cancers; allowing cells to evade apoptosis through increases in sphingosine-1-phosphate (S1P) and decreases in ceramides. Ceramides can be hydrolyzed by ceramidases to sphingosine, which can then be phosphorylated by sphingosine kinases to S1P. S1P allows cells to evade apoptosis and increase migration, while shifts toward ceramides favor cell death. Glioblastoma (GBM) exhibits shifts in the sphingolipid balance towards S1P, contributing to chemoresistance and migration. Understanding of sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target the dysregulation. Acid ceramidase (ASAH1), a key enzyme in the production of S1P, is highly expressed in GBM and is associated with worse survival of GBM patients, as per The Cancer Genome Atlas data. To address the altered sphingolipid metabolism and therapeutic resistance in GBM, we explored the efficacy of pharmacologic and genetic inhibition of ASAH1 in both parental and temozolomide (TMZ)-resistant patient-derived xenografts. Cells were infected with ASAH1 shRNA or treated with ASAH1 inhibitors and assessed for cell growth and migration. Our work suggests that pharmacologic inhibition of ASAH1 induces cell death and that this effect is maintained in TMZ-resistant cells. Furthermore, we find a novel role for carmofur, an ASAH1 inhibitor, in the inhibition of GBM migration. Together, these data suggest the potential utility of normalizing the sphingolipid balance in the context of GBM TMZ resistance.

// Ninh B. Doan 1, 2 , Hisham Alhajala 3 , Mona M. Al-Gizawiy 4 , Wade M. Mueller 2 , Scott D. Rand 4 , Jennifer M. Connelly 5 , Elizabeth J. Cochran 6 , Christopher R. Chitambar 3 , Paul Clark 7 , John Kuo 7 , Kathleen M. Schmainda 3, 8 and Shama P. Mirza 1, 9, 10 1 Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 2 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 3 Medicine, Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 4 Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 5 Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 6 Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 7 Department of Neurological Surgery and Human Oncology, University of Wisconsin, Madison, Wisconsin, 53792, USA 8 Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 9 Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 10 Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin, 53211, USA Correspondence to: Shama P. Mirza, email: mirza@uwm.edu Keywords: glioblastoma, acid ceramidase, carmofur, glioblastoma cancer stem cells (GSCs), overall survival Received: December 28, 2016 Accepted: September 30, 2017 Published: November 07, 2017 ABSTRACT Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50’s ranging from 11–104 μM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials.

Although the budgeting literature well documents managers' creation of budgetary slack in developed economies, lack of attention has been paid to this behaviour in emerging economies. It is doubtful that some unique characteristics, only existing in emerging economies, cause this behaviour to be different than the budgeting literature predicts. Since there is no study examining managers' creation of budgetary slack in emerging economies, such as Vietnam, to get insight into whether or not these characteristics cause the differences, the aim of this study is to replicate prior budgeting studies by using Vietnamese samples. Particularly, we investigated the impact of budgetary participation, budget emphasis, information asymmetry, and the interactions between these variables on managers' creation of budgetary slack. Data obtained from the questionnaire sent to 99 Vietnamese managers shows that the last two variables and the interaction between them induce managers' creation of budgetary slack. However, the results also indicate that the first variable and the interaction between this variable and the other two variables respectively have no impact on managers' creation of budgetary slack. These results provide some insight into the creation of budgetary slack of Vietnamese managers for future studies to extend the line of research.

Background Subependymomas are rare, slow-growing, benign tumors. Because they are scarce, knowledge relating to survival remains lacking. Consequently, we explore the SEER database to evaluate prognostic and treatment factors associated with intracranial subependymoma. Methods With the SEER-18 registry database, information from all patients with intracranial subependymoma diagnosed during 2004–2013 were extracted, including age, sex, race, occurrence of surgery, extent of primary surgery, receipt of radiation, tumor size, and follow-up data. Age-adjusted incidence rates, overall survival, and cause-specific survival were calculated. Cox proportional hazards model was used for both univariate and multivariate analyses. Results Four hundred sixty-six cases were identified. The overall incidence of intracranial subependymoma is 0.055 per 100,000 person-years (95% confidence interval, 0.05–0.06). Through multivariate analysis, age P = 0.03), female sex (HR, 0.34; P = 0.03), location within ventricles or near brainstem (HR, 0.49; P = 0.04), and occurrence of surgery (HR, 0.50; P = 0.02) were significant independent positive prognostic factors. Receipt of radiation did not show a significant relationship. Conclusion Clinical factors such as younger age, female sex, and location within ventricles or near brain stem demonstrated positive relationship with overall survival. For treatment options, surgery remains a mainstay option. No support for radiation therapy was identified.

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine-1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.

// Ninh B. Doan 1, 2 , Ha S. Nguyen 2 , Andrew Montoure 2 , Mona M. Al-Gizawiy 3 , Wade M. Mueller 2 , Shekar Kurpad 2 , Scott D. Rand 3 , Jennifer M. Connelly 4 , Christopher R. Chitambar 4 , Kathleen M. Schmainda 3, 6 , Shama P. Mirza 1, 7, 8 1 Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 2 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 3 Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 4 Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 5 Department of Medicine, Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 6 Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 7 Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 8 Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin, 53211, USA Correspondence to: Ninh B. Doan, email: ndoan@mcw.edu Keywords: pediatric glioblastoma, acid ceramidase inhibitors, carmofur, glioblastoma, medulloblastoma Received: September 12, 2016 Accepted: February 15, 2017 Published: March 01, 2017 ABSTRACT Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC 50 values (4.6–50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.

Background The authors present a case of delayed acute subdural hematoma and review all reported cases in the literature. The focus of this paper is to identify the subset of the population who are at risk, and determine whether they should be admitted for observation in the setting of mild traumatic brain injury. Case Description A 75-year-old woman taking daily aspirin (81 mg) had a fall with loss of consciousness. Her Glasgow Coma Scale (GCS) score was 15 at the time of presentation to the emergency department. However, because of her postconcussive symptoms, computed tomography (CT) of the head was obtained, and the results were negative for any intracranial hemorrhage or fractures. She was admitted for workup. The next day, she neurologically deteriorated to a GCS score of 6. CT of the head was reobtained and showed acute, left-sided subdural hematoma with shift and herniation. She was taken to operating room for emergent decompressive craniotomy. Postoperatively, she developed left-sided temporal and occipital intraparenchymal hemorrhage. She died after being placed on comfort care. Conclusion Delayed acute subdural hematoma occurs mainly in the middle-aged or older population who are taking anticoagulation or antiplatelet therapy. Most patients have a GCS score of 15 with no loss of consciousness. Neurological deterioration occurs within the first 24 hours for 70% of the patients. Therefore, we recommend admission and observation of these selected group of patients. Due to small reported population of patients, we could not determine whether the patients taking anticoagulant, antiplatelet, or both anticoagulant and antiplatelet medication are at higher risk. In addition, the role of delayed CT of the head without change in the examination result needs to be explored further.

Background Spontaneous resolution of acute subdural hematomas (SDHs), occurring as the result of a traumatic injury, is well reported in the literature and rapidly resolving SDHs have been reported as well. Although the mechanism behind the rapid resolution of a SDH has not been well understood, there are postulated mechanisms for this phenomenon. The aim of this report is to present a patient who experienced the rapid resolution of a traumatic SDH, which was replaced by a subdural hygroma. Case Description This 25-year-old man presented to the hospital with an acute left-sided SDH after a head-on motor vehicle collision. At the time of presentation, the patient had an acute SDH with 11 mm of midline shift. The hematoma resolved spontaneously within 48 hours and was replaced by a thin subdural hygroma. Conclusions Rapidly resolving SDHs represent a phenomenon that has been well described, although is not entirely understood. The imaging findings of this patient suggest that cerebrospinal fluid washout is a mechanism that promotes acute SDH resolution.

Background: Chronic subdural hematoma (cSDH) is a common neurosurgical pathology associated with older age and complicated by antiplatelet/anticoagulant therapies. With improving medical care in an aging population, the incidence of cSDH will likely increase over the next 25 years, placing a burden on health care costs. Aims: A simple and inexpensive treatment option for cSDH is desirable. Material and methods: We report a basic, but novel, technique to drain cSDH with an Integra Camino bolt. Results: This technique was employed in two patients, where the significant resolution of cSDH and associated clinical symptoms were observed without complications. Conclusions: Our technique is simple and effective. It incorporates readily available materials, which reduces costs. Such characteristics are necessary, given the increasing incidence of cSDH.

Medulloblastomas are categorized as the World Health Organization Grade IV neoplasms. Only 33 cases have been reported of extra-axial, mostly in the cerebellar pontine angle and lateral cerebellar hemisphere, medulloblastomas in the current literature. Our study showcases the first case of an extremely rare presentation of an extra-axial midline tentorial adult medulloblastoma with the dural-tail sign mimicking a meningioma. To achieve the best possible outcome, a high index of suspicion for medulloblastoma is critical especially in young patient with an atypical posterior fossa mass as treatment regimens drastically different between a medulloblastoma and a meningioma.

Methotrexate (MTX) is a common antimetabolite agent that is widely used today in treating leukemia, lymphoma, and osteosarcoma. Its use has been associated with leukoencephalopathy causing seizures, paralysis, and even coma. To achieve the best possible outcome, it is important to be able to make a prompt diagnosis. Studies reported restricted diffusion on diffusion-weighted imaging (DWI) which is a reliable early sign of acute MTX-induced leukoencephalopathy. However, we report here the first case of MTX-induced leukoencephalopathy without typical restricted diffusion on DWI and the utility magnetic resonance spectroscopy to support this diagnosis in the difficult case such as the one being presented here.

Glioblastoma (GB) and its variants portend a poor prognosis. The predominant cause of death (COD) is related to the cancer diagnosis, but a significant subset is related to other causes. As GB is a systemic disease requiring systemic treatment, focus regarding all COD provides a comprehensive illustration of the disease.The SEER-18 was queried for patients with cranial GB and its variants. Age, gender, race, marital status, tumor characteristics, treatment details, and follow-up data were acquired. The patients were classified into group A (death attributed to this cancer diagnosis) or group B (death attributed to causes other than this cancer diagnosis).From 1973 to 2013, 36,632 deaths (94%) constituted group A, and 2,324 deaths (5.9%) constituted group B. The latter significantly exhibited lower proportions of age60, Caucasians, married status, frontal/brain stem/ventricle tumor locations, and receipt of radiation. From logistic regression, age60, male gender, race, not married, tumor location, and no radiation were significant independent predictors for group B. The top known CODs in group B are diseases of heart, pneumonia and influenza, cerebrovascular diseases, accidents and adverse effects, and infections.CODs not attributed to GB remains a significant subset of all CODs. Many of these, particularly diseases of heart, are frequent comorbidities. Moreover, infection-related CODs after GB diagnosis appear more salient compared to CODs in the general population. Consideration of these CODs, and vigilant treatment aimed at these CODs, may improve overall care for GB patients.

BACKGROUND For gliomas, metropolitan status has not been heavily explored in the context of short-term mortality or long-term observed survival. Larger populations are associated with proximity to academic universities/high-volume hospitals. METHODS The SEER-18 registry was queried for patients with gliomas. The patients were further classified into two population groups based on rural-urban continuum codes: metropolitan or non-metropolitan. Demographics and clinical factors were compared between both groups. For observed survival, univariate and multivariate analyses occurred with Cox proportional hazards model. RESULTS The non-metropolitan group constituted approximately 10.8% of all patients. Age at diagnosis of glioma was older for the non-metropolitan group compared to metropolitan group (51.60 years vs. 49.06 years). Relative to the metropolitan group, the non-metropolitan group exhibited a larger proportion of Caucasian, married, grade I and IV gliomas, no surgery, no GTR (for those who had surgery), and temporal/parietal/occipital locations. Other covariates (sex, tumor size, laterality, and radiation status) did not exhibit significant differences in proportions. From analysis of observed survival, independent predictors include population group, as well as age, gender, marital status, tumor location, tumor grade, laterality, GTR, and receipt of radiation. Short-term mortality was 11.68% and 13.04% for Metropolitan and non-metropolitan groups, respectively. Median survival was 15 months and 12 months for Metropolitan and non-metropolitan groups, respectively. CONCLUSIONS About one-tenth of gliomas are treated at non-metropolitan sites. Key differences exist among patient/glioma characteristics based on metropolitan status. Overall, metropolitan status appears to influence short-term mortality and long-term observed survival for gliomas.

Human acid ceramidase (AC) is a lysosomal cysteine amidase, which has received a great deal of interest in recent years as a potential target for the development of new therapeutics against melanoma and glioblastoma tumors. Despite the strong interest in obtaining structural information, only the structures of the apo-AC enzyme in its zymogen and activated conformations are available. In this work, the crystal structure of AC in complex with the covalent carmofur inhibitor is presented. Carmofur is an antineoplastic drug containing an electrophilic carbonyl reactive group that targets the catalytic cysteine. This novel structural data explains the basis of the AC inhibition, provides insights into the enzymatic properties of the protein, and is a great aid toward the structure-based drug design of potent inhibitors for AC, providing the detailed mechanism, which has eluded the scientific community for more than 30 years, of carmofur’s mysterious 5-fluorouracil-independent anti-tumor activity.

Objective Endometrial cancer is the most common gynecologic cancer and yet much is still unknown about this disease. Our goal was to identify unique biomarkers of disease by performing a comprehensive proteomic analysis of early stage, low-grade endometrial cancer through analysis of serum collected from patients pre- and post-definitive surgery. Methods We used mass spectrometry (MS)-based proteomics to identify serum proteins from these patients. Serum samples from women undergoing hysterectomy with bilateral salpingo-oophorectomy for benign reasons served as control samples for the correlative studies. We then correlated our findings with The Cancer Genome Atlas (TCGA) database for additional confirmation. Results The Ingenuity Pathway Analysis of proteins that were differentially expressed in endometrial cancer showed increased cell survival and decreased organismal death, the most common hallmarks of cancer. We identified over expression of FAM83D (family with sequence similarity 83, member D) in the serum of patients with early stage low-grade endometrial cancer and verified the same in the endometrial cancer cell lines and patient tumors. We also confirmed our hypothesis that FAM83D may serve as a biomarker for endometrial cancer in a cohort of patients with endometrial cancer from The Cancer Genome Atlas (TCGA) project. Conclusion Comprehensive proteomic analysis is a feasible strategy for potential biomarker identification. Using this technique, FAM83D was identified as a candidate biomarker in early endometrial cancer in our patient samples and was not present in benign control samples. FAM83D has been associated with poor clinical outcomes in several human malignancies. Significance Our manuscript describes an alternative approach to comprehensive protein analysis in a model pre and post tumor removal for a sample of patients with early endometrial cancer. The model is innovative and the findings of over expression FAM83D in this population of early cancer may be useful in the study of a disease where there are few biomarkers or targetable therapies.

Background. Synovial sarcoma is an aggressive soft tissue sarcoma with uncertain histological origin. The pathology frequently presents as a localized disease, especially near large joints around the knee and thigh. Intracranial disease, which is rare, has been reported as metastasis from synovial sarcoma. We report a case with no obvious primary extracranial pathology, suggesting primary intracranial disease; this has not been reported in the literature.Case Description. A 21-year-old male, with a prior right skull lesion resection for atypical spindle cell neoplasm, presented with headaches, gait instability, left arm weakness, and left homonymous hemianopsia. CT of head demonstrated a right parietal hemorrhagic lesion with mass effect, requiring surgical decompression. Histopathology revealed synovial sarcoma. FISH analysis noted the existence of the t(X;18)(p11.2;q11.2) chromosomal translocation. PET scan did not show other metastatic disease. He underwent stereotactic radiotherapy and adjuvant chemotherapy. At 2-year follow-up, he remained nonfocal without recurrence.Conclusion. We report the first known case of primary intracranial synovial sarcoma. Moreover, we stress that intracranial lesions may have a tendency for hemorrhage, requiring urgent lifesaving decompression.

Background Secondary brain stem injury is associated with transtentorial herniation, and manifests as "Duret" hemorrhages. Such an injury has been considered a terminal brain stem event with a high morbidity and mortality, sometimes discouraging continuation of care. However, there have been rare instances where patients have had reasonable recovery. We report another case, emphasizing that such an injury by itself should not deter aggressive measures, as good outcomes remain a possibility. Case presentation A 37-year-old male sustained a right subdural hematoma after a mechanical fall while intoxicated. He presented initially with a Glasgow Coma Scale 15. Three days later, he exhibited acute neurological deterioration to Glasgow Coma Scale 4, requiring intubation and mannitol. Repeat scan demonstrated enlarging right subdural hematoma with worsening shift; brain stem hemorrhage was noted at pontomesencephalic junction. Patient was immediately taken for subdural hematoma evacuation. The following day, patient was able to sluggishly follow commands in all four extremities. He had a short stay for inpatient rehabilitation and underwent autologous cranioplasty at 3 months. On examination, he was awake, alert, and oriented to self, time, and location; he exhibited dysarthric speech, right ptosis, but followed commands in all four extremities with no focal motor weakness. Conclusion In contrast to the common belief, patients suffering from a "Duret" hemorrhage can still have a good outcome. "Duret" hemorrhages may not represent a fatal injury. The finding from this paper suggests the finding of "Duret" hemorrhages on imaging should not deter aggressive measures especially in patients with lesions causing significant mass effects. Overall clinical status should drive surgical options and clinical course.

Lumbar endplate fractures were investigated in different experimental scenarios, however the biomechanical effect of segmental alignment was not outlined. The objectives of this study were to quantify effects of spinal orientation on lumbar spine injuries during single-cycle compressive loads and understand lumbar spine endplate injury tolerance. Twenty lumbar motion segments were compressed to failure. Two methods were used in the preparation of the lumbar motion segments. Group 1 (n = 7) preparation maintained pre-test sagittal lordosis, whereas Group 2 (n = 13) specimens had a free-rotational end condition for the cranial vertebra, allowing sagittal rotation of the cranial vertebra to create parallel endplates. Five Group 1 specimens experienced posterior vertebral body fracture prior to endplate fracture, whereas two sustained endplate fracture only. Group 2 specimens sustained isolated endplate fractures. Group 2 fractures occurred at approximately 41% of the axial force required for Group 1 fracture (p < 0.05). Imaging and specimen dissection indicate endplate injury consistently took place within the confines of the endplate boundaries, away from the vertebral periphery. These findings indicate that spinal alignment during compressive loading influences the resulting injury pattern. This investigation identified the specific mechanical conditions under which an endplate breach will take place. Development of endplate injuries has significant clinical implication as previous research identified internal disc disruption (IDD) and degenerative disc disease (DDD) as long-term consequences of the axial load-shift that occurs following a breach of the endplate. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1084-1091, 2016.

INTRODUCTION: Recurrent glioblastoma (GBM) is known to be more aggressive and resistant to therapy when compared to the de-novo GBM tumor. Our previous in vivo studies showed that irradiated SJ-GBM2 cells exhibit greater radiological differences in angiogenesis and biological aggressiveness when compared with untreated (control) SJ-GBM2 cells. This may be explained by biological changes that occur after treatment with radiation and chemotherapy. Herein, we present evidence of changes in 21 gene expression and invasion protein markers between irradiated and non-irradiated cells. METHODS: Pediatric GBM cells (SJ-GBM2) were irradiated with a total dose of 10Gy (SJGBM2-10gy). Irradiated and untreated control cells were tested for viability and changes in microRNA (miRNA) expression using miRNA microarrays that analyze more than 2000 genes. Samples were analyzed in duplicate. Western blots of the irradiated and control cell lysates and dot blots of the cell conditioned serum-free media were immunostained for pro-cathepsin B and VEGF. RESULTS: Only a relatively small set of miRNAs exhibited differential expression; 21 miRNAs genes were downregulated and none were upregulated in SJGBM2-10gy compared with SJ-GBM2 cells. Many of these down-regulated miRNAs were found to be tumor suppressor genes. This study also identified multiple novel downregulated miRNAs that have not yet been characterized. VEGF secretion was increased in the irradiated cells. DISCUSSION: Our study demonstrates increased biological aggressiveness in irradiated SJGBM2-10gy cells and suggests that this is due to multiple mechanisms that are activated following irradiation. These mechanisms include down-regulation of tumor suppressors’ miRNA genes and changes in the secretion of VEGF.

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the treatment of GBM maybe a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. A comprehensive understanding of these markers is mandatory for the development of treatments against therapy-resistant GBMs. This review also provides an overview of a novel marker called acid ceramidase and its implication in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given these global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment for radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving the overall GBM survival.

Background Subependymal giant cell astrocytoma (SEGA) is a rare, benign neoplasm predominantly associated with tuberous sclerosis complex. Clinical outcomes have largely been conveyed via small- and medium-sized case series. Methods With the Surveillance, Epidemiology, and End Results Program (SEER)–18 registry database, information from all patients diagnosed with SEGA from 2004 to 2013 was obtained (age, sex, race, marital status, tumor size, tumor location, occurrence of surgery, receipt of radiation, and follow-up data). Age-adjusted incidence rates and overall survival (OS) were determined. Cox proportional hazards model was used for both univariate and multivariate analyses. Results The overall incidence of SEGA within the SEER-18 database is 0.027 per 100,000 person-years (95% confidence interval, 0.024–0.031). A total of 226 cases were identified. For OS, univariate analysis revealed age younger than 18 years (hazard ratio [HR], 0.214; P = 0.004) and occurrence of surgery (HR, 0.328; P = 0.039) were significant positive prognostic factors. Sex, marital status, race, tumor size, tumor location, and receipt of radiation did not exhibit significant relationships. Interestingly, subanalysis for extent of resection to gross total resection did not show benefit. Multivariate analysis revealed that both age younger than 18 years (HR, 0.193; P = 0.002) and occurrence of surgery (HR, 0.286; P = 0.021) remained significant. Conclusions Based on our analysis, younger age and occurrence of surgery are significant independent factors associated with better OS. There was no support for radiation.

Glioblastoma is the most common, malignant primary tumor of the central nervous system. The average prognosis for life expectancy after diagnosis, with the triad of surgery, chemotherapy, and radiation therapy, is less than 1.5 years. Chemotherapy treatment is mostly limited to temozolomide. In this paper, the authors review an emerging, novel drug called acid ceramidase, which targets glioblastoma. Its role in cancer treatment in general, and more specifically, in the treatment of glioblastoma, are discussed. In addition, the authors provide insights on acid ceramidase as a potential druggable target for glioblastoma.

Background: Granulomatous amebic encephalitis (GAE) is rare, but often fatal. The infection has been documented predominantly among the immunocompromised population or among those with chronic disease. To date, however, there have only been eight cases regarding the infection following hematopoietic stem cell transplantation (HSCT). Case Description: A 62-year-old female with a history of relapsed diffuse large B-cell lymphoma, recently underwent peripheral blood autologous stem cell transplant after BEAM conditioning (day 0). On day +15, she began to exhibit worsening fatigue, generalized weakness, and fever. Symptoms progressed to nausea, emesis, somnolence, confusion, and frontal headaches over the next few days. Imaging demonstrated multifocal ill-defined vasogenic edema with patchy enhancement. The patient was started on broad antibiotics, antifungals, and seizure prophylaxis. Evaluation for bacterial, fungal, mycobacterial, and viral etiologies was fruitless. Her mental status progressively deteriorated. On day +22, she exhibited severe lethargy and went into pulseless electrical activity arrest, requiring chest compressions. The episode lasted

Dural ectasia is frequently associated with connective tissue disorders or inflammatory conditions. Presentation in a patient without known risk factors is rare. Moreover, the literature regarding the treatment options for symptomatic dural ectasia is controversial, variable, and limited. A 62-year-old female presents with intractable, postural headaches for years. A lumbar puncture revealed opening pressure 3 cm of water. A computed tomography myelogram of the spine demonstrated erosion of her sacrum due to a large lumbosacral dural ectasia. An initial surgery was attempted to reduce the size of the expansile dura, and reconstruct the dorsal sacrum with a titanium plate (Depuy Synthes, Westchester, PA, USA) to prevent recurrence of thecal sac dilatation. Her symptoms initially improved, but shortly thereafter recurred. A second surgery was then undertaken to obliterate the thecal sac distal to the S2 nerve roots. This could not be accomplished through simple ligation of the thecal sac circumferentially as the ventral dura was noted to be incompetent and attempts to develop an extradural tissue plane were unsuccessful. Consequently, an abundance of fibrin glue was injected into the thecal sac distal to S2, and the dural ectasia was marsupialized rostrally, effectively obliterating the distal thecal sac while further reducing the size of the expansile dura. This approach significantly improved her symptoms at 5 months follow-up. Treatment of dural ectasia is not well-defined and has been variable based on the underlying manifestations. We report a rare patient without risk factors who presented with significant lumbosacral dural ectasia. Moreover, we present a novel method to treat postural headaches secondary to dural ectasia, where the thecal sac is obliterated distal to the S2 nerve roots using an abundance of fibrin glue followed by marsupialization of the thecal sac rostally. This method may offer an effective therapy option as it serves to limit the expansile dura, reducing the cerebrospinal fluid sump and the potential for intracranial hypotension.

Background Pure subdural hematoma (without subarachnoid, intraventricular, or intraparenchymal hemorrhage) due to a ruptured intracranial aneurysm is rare. Most reported cases involve an aneurysm along the internal carotid artery, posterior communicating artery, or middle cerebral artery. No reports have described an aneurysm along the transmastoid branches of the occipital artery. Case description A 70-year-old female presented with sudden-onset, excruciating headaches, associated with dizziness, nausea, and emesis. There was no history of trauma. Computed tomography (CT) head demonstrated a pure tentorial subdural hematoma. Vascular imaging revealed bilateral aneurysms along the transmastoid branches of the intracranial portion of both the occipital arteries. Consequently, these branches were embolized, with no residual filling of the aneurysms. After the procedure, the patient remained neurologically well. The patient was monitored appropriately for vasospasm, and was discharged home 10 days after presentation. Conclusion Rupture of aneurysms along intracranial branches of the occipital artery can lead to pure subdural hematoma along the tentorium.

Quantification of biomechanical tolerance is necessary for injury prediction and protection of vehicular occupants. This study experimentally quantified lumbar spine axial tolerance during accelerative environments simulating a variety of military and civilian scenarios. Intact human lumbar spines (T12-L5) were dynamically loaded using a custom-built drop tower. Twenty-three specimens were tested at sub-failure and failure levels consisting of peak axial forces between 2.6 and 7.9 kN and corresponding peak accelerations between 7 and 57 g. Military aircraft ejection and helicopter crashes fall within these high axial acceleration ranges. Testing was stopped following injury detection. Both peak force and acceleration were significant (p < 0.0001) injury predictors. Injury probability curves using parametric survival analysis were created for peak acceleration and peak force. Fifty-percent probability of injury (95%CI) for force and acceleration were 4.5 (3.9-5.2 kN), and 16 (13-19 g). A majority of injuries affected the L1 spinal level. Peak axial forces and accelerations were greater for specimens that sustained multiple injuries or injuries at L2-L5 spinal levels. In general, force-based tolerance was consistent with previous shorter-segment lumbar spine testing (3-5 vertebrae), although studies incorporating isolated vertebral bodies reported higher tolerance attributable to a different injury mechanism involving structural failure of the cortical shell. This study identified novel outcomes with regard to injury patterns, wherein more violent exposures produced more injuries in the caudal lumbar spine. This caudal migration was likely attributable to increased injury tolerance at lower lumbar spinal levels and a faster inertial mass recruitment process for high rate load application. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 36:1747-1756, 2018.

Background Dysembryoplastic neuroectodermal tumor (DNT) is a rare neoplasm. Though the pathology is commonly considered benign, there have been various reports documenting rapid growth, recurrence/progression, sudden death, and malignant transformation. Most studies have addressed outcomes regarding seizure control, but limited data exist regarding incidence and survival. Consequently, we explore the Surveillance, Epidemiology, and End Results (SEER) database to explore the epidemiology of DNT. Methods From the SEER-18 registry database, information from all patients diagnosed with intracranial DNT between 2004 and 2013 was extracted, including age, sex, race, marital status, tumor location, tumor size, receipt of surgery, extent of primary surgery, receipt of radiation, and follow-up data. Age-adjusted incidence rates and overall survival (OS) were calculated. A Cox proportional hazards model was used to assess relationships between various demographic/treatment variables and OS. Results A total of 381 cases were identified in the SEER-18 database. The incidence of DNT within the large subset of the United States population represented by SEER was 0.033 per 100,000 person-years (95% confidence interval [CI], 0.030–0.037). The median duration of follow-up was 50 months. The median OS was not attained. The 3-, 5-, and 9-year OS was 99.363% (95% CI, 97.428%–99.844%), 97.993% (95% CI, 95.168%–99.174%), and 96.296% (95% CI, 91.834%–98.341%), respectively. Seven of the 381 patients passed at their last follow up. Of all demographic/treatment factors, only receipt of radiation demonstrated a significant relationship with OS (hazard ratio, 0.051; 95% CI, 0.01–0.267; P Conclusions Although the prognosis for DNT is generally favorable, the pathology can lead to poor outcomes in rare cases. Common demographic factors, treatment with surgery, and the extent of surgical resection did not show significant associations with OS. In contrast, treatment with radiation was associated with poorer OS.

Background In the setting of trauma, the cause of intracranial hemorrhage (ICH) is frequently attributed to the physical, traumatic event. Caution should still be directed toward nontraumatic (or spontaneous) causes responsible for the trauma, such as hypertension, cerebral amyloid angiopathy, aneurysms, vascular malformation, and hemorrhagic infarcts. The role for immediate computed tomography angiography remains controversial to evaluate for nontraumatic causes. Methods A systematic review of the available literature in the Medline PubMed database. Results In the available literature, only 12 patients with traumatic brain injury underwent computed tomography angiography of the head that either showed a vascular malformation and/or altered clinical management because of concerns of a vascular malformation. The ICH in 11 patients was attributed to rupture of a cerebral aneurysm; the other patient received a diagnostic angiogram that was negative. Conclusions ICH in patients with traumatic brain injury seems to be vastly associated with the traumatic event. Only rare cases have been attributed to aneurysmal rupture. None has been associated with arteriovenous malformation. Nevertheless, clinical vigilance remains reasonable, especially in younger patients and those with hemorrhage within the subarachnoid cisterns or sylvian fissure.

Surgery for meningioma is associated with significant blood loss. Preoperative embolization has been associated with reduction of blood loss and has been noted to decrease intensity on T1 + contrast sequences. We investigate potential relationships between blood loss and the extent of T1 + contrast intensity.Forty-two patients who underwent surgical resection of intracranial meningioma were retrospectively reviewed from August 2009 to May 2016. Clinical data were extracted (age, gender, location of meningioma, grade of meningioma, need for blood transfusion during surgery, preoperative and postoperative hematocrit level, estimated blood loss [EBL], and duration of surgery). Using OsiriX MD, the tumor volume, sinus involvement, peritumoral edema, extent of resection, and T1 index (average T1+C intensity across the tumor normalized to value at basilar artery) were assessed.With EBL, univariate analysis for gender, tumor volume, and T1 index showed correlations with P value0.1. A logistic regression to predict EBL300 mL and ≥300 mL using the 3 variables yielded T1 index (odds ratio [OR], 31.22; 95% confidence interval [CI], 1.14-855.65), gender (OR, 0.17; 95% CI, 0.03-0.96), and tumor volume (OR, 1.05; 95% CI, 1.00-1.10) as significant predictors (all P 0.05). With duration for surgery, gender, tumor volume, need for blood transfusion, and preoperative hematocrit exhibited P value0.05; multivariate analysis did not show a significant model.Along with gender and tumor volume, extent of T1+C intensity is also an independent predictor of EBL. This finding may be helpful for surgical management of meningioma.

Chronic subdural hematoma (CSDH) is a relatively common condition encountered in a neurosurgical practice. There have been increased efforts in creating different treatment regimens for CSDH to improve patients' outcomes, including the addition of tissue plasminogen activator (tPA) in drains to reduce recurrences. Here, we present the first case report of the safe use of tPA in conjunction with an Integra Camino bolt for maximized drainage of CSDH with a successful neurological recovery and the complete resolution of the hematoma.

BACKGROUND: Chemo- and radioresistance are characteristic features of post-treatment high-grade glioma (HGG). The cell populations responsible for this treatment-resistant phenotype are glioma stem cells (GSCs). These GSCs have a high requirement for iron which is essential for tumor cell viability. Intriguingly, the transferrin receptors that play a crucial role in iron uptake by both adult and pediatric astrocytomas exhibit a high affinity for gallium maltolate (GaM), a novel iron mimetic. Given the added commonality between adult and pediatric glioma stem cell signatures, especially post-treatment, we believe targeting treatment-resistant cell populations via their inherent iron metabolism is a viable approach to combat treatment-resistant HGG in adults and children. Here, we demonstrate the profound effects of GaM in a novel in vivo model of recurrent glioblastoma. METHODS: Irradiated human GBM cells (adult or pediatric) were stereotactically implanted into the right striatum of male athymic rats. Following confirmation of in vivo tumor growth by MRI at 9.4T, animals received GaM (50 mg/kg/day) in an oral preparation for voluntary ingestion. Tumor growth was monitored weekly by MRI, and lesion volume and associated advanced MRI parameter maps were determined using enhancing tumor ROIs. RESULTS: In a first set of animals, the mean weekly tumor growth rates of enhancing lesions were 65.8% and 156% in GaM-treated and control rats, respectively (p=0.002). Median disease-specific survival was 51 days in GaM-treated animals and 28 days in controls (p=0.004). Complete response was observed in 20% of the animals, with complete resolution of the disease confirmed histologically. A partial response was observed in 40% of the animals. Follow-up data is being collected in a second set of animals for verification and updated results will be discussed. CONCLUSION: We present compelling evidence that iron-targeted therapy using the novel iron mimetic GaM is highly effective in treatment-resistant HGG.

Intracranial subdural empyema (ISDE) is a life-threatening condition. The risk for ISDE increases in patients that have undergone prior intracranial procedures. The non-specificity in its clinical presentation often makes ISDE difficult to diagnose. Here, we present a rare case of ISDE mimicking a recurrent chronic subdural hematoma, emphasizing the significance of obtaining early magnetic resonance images of the brain for early diagnosis and treatment to achieve the optimal outcome.

The gunshot wound to the head (GSWH) is associated with a mortality rate of 20–90% in adults and 20–65% in the pediatric population. Due to the high rates of mortality and morbidity, the management of these patients has been a topic of high interest in the neurosurgical community. We present an 18-year-old male suffering a GSWH with the bullet following a transventricular trajectory and crossing the midsagittal plane, creating extensive intracranial injuries. Despite a calculated mortality rate of >97% from these devastating injuries, the patient survived the GSWH and made a remarkable recovery. The young adult brain still maintains a high potential for neurological plasticity. This may partially explain why the young adult population with a severe GSWH can have a better than expected recovery course. Bifrontal GSW injuries may have much better outcomes than more posterior injuries as has been demonstrated in this patient in this case.