A Case of Scurvy Associated With Intracerebral Hemorrhage in a Patient With Alcohol Use Disorder.

Vitamin C deficiency, also known as scurvy, causes abnormalities in connective tissues and varied symptoms. We describe a patient with putaminal hemorrhage, a very rare presentation of scurvy. A 39-year-old man presented with weakness in the left arm and left leg. Right putaminal hemorrhage was initially diagnosed, and he underwent evacuation of the intracerebral hemorrhage. Scurvy was suspected when repeated physical examinations revealed a bleeding tendency and multiple untreated dental caries, missing teeth, and gingivitis. A diagnosis of scurvy was further supported by the patient's history of smoking, alcohol use disorder, poor diet, and low plasma vitamin C concentration. After receiving oral nutritional supplementation including vitamin C, the bleeding tendency quickly improved. This case highlights the importance of including scurvy in a differential diagnosis for patients with bleeding tendencies, especially those with a poor diet or unknown dietary history. Empirical administration of vitamin C is a reasonable treatment.

Evaluation of Brain Tumors Using Amide Proton Transfer Imaging: A Comparison of Normal Amide Proton Transfer Signal With Abnormal Amide Proton Transfer Signal Value.

OBJECTIVE: The aim of the study was to evaluate the relationship of amide proton transfer (APT) signal characteristics in brain tumors and uninvolved brain tissue for patients with glioblastoma and those with brain metastases. METHODS: Using the mDIXON 3D-APT sequence of the fast spin echo method, an APT image was obtained. The mean APT signal values of tumor core, peritumor edema, ipsilateral normal-appearing white matter (INAWM), and contralateral normal white matter (CNAWM) were obtained and compared between glioblastoma and brain metastases. Receiver operating characteristic curves were used to evaluate parameters for distinguishing between glioblastoma and brain metastases. In addition, the difference and change rate in APT signal values between tumor core and peritumoral edema (PE) and CNAWM were evaluated, respectively. RESULTS: The APT signal values of glioblastoma were the highest in tumor core (3.41% ± 0.49%), followed by PE (2.24% ± 0.29%), INAWM (1.35% ± 0.15%), and CNAWM (1.26% ± 0.12%, P < 0.001). The APT signal value of brain metastases was the highest in tumor core (2.74% ± 0.34%), followed by PE (1.86% ± 0.35%), INAWM (1.17% ± 0.13%), and CNAWM (1.2% ± 0.09%, P < 0.01). The APT change rate (between PE and CNAWM) was not significantly different at 78% and 56% for glioblastoma and brain metastases, respectively ( P > 0.05). CONCLUSIONS: Performing APT imaging under the same parameters used in this study may aid in the identification of brain tumors.

Cerebral hyperperfusion syndrome after endovascular covered stent grafting for a giant extracranial aneurysm of the internal carotid artery.

Symptomatic giant extracranial internal carotid artery (ICA) aneurysm is a rare and surgically intractable disease. Several authors have described successful treatments for extracranial ICA aneurysm. None, however, have described a perioperative evaluation of cerebral perfusion or a postoperative complication of cerebral hyperperfusion syndrome (CHS). We present a rare case of CHS after endovascular covered stent grafting for a giant extracranial ICA aneurysm. The CHS was successfully managed on the basis of hemodynamic monitoring. CHS can appear after endovascular reconstruction of an extracranial ICA aneurysm, and perioperative repeated evaluation of cerebral perfusion allows safe and effective management of CHS.

A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells.

Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, n-arachidonoyl dopamine, n-oleoyldopamine (OLDA), and n-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types.

Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway.

Glioblastoma multiforme (GBM) is a devastating disease, and the current therapies have only palliative effect. Evidence is mounting to indicate that brain tumor stem cells (BTSCs) are a minority of tumor cells that are responsible for cancer initiation, propagation, and maintenance. Therapies that fail to eradicate BTSCs may ultimately lead to regrowth of residual BTSCs. However, BTSCs are relatively resistant to the current treatments. Development of novel therapeutic strategies that effectively eradicate BTSC are, therefore, essential. In a previous study, we used patient-derived GBM sphere cells (stemlike GBM cells) to enrich for BTSC and identified maternal embryonic leucine-zipper kinase (MELK) as a key regulator of survival of stemlike GBM cells in vitro. Here, we demonstrate that a thiazole antibiotic, siomycin A, potently reduced MELK expression and inhibited tumor growth in vivo. Treatment of stemlike GBM cells with siomycin A resulted in arrested self-renewal, decreased invasion, and induced apoptosis but had little effect on growth of the nonstem cells of matched tumors or normal neural stem/progenitor cells. MELK overexpression partially rescued the phenotype of siomycin A-treated stemlike GBM cells. In vivo, siomycin A pretreatment abraded the sizes of stemlike GBM cell-derived tumors in immunodeficient mice. Treatment with siomycin A of mice harboring intracranial tumors significantly prolonged their survival period compared with the control mice. Together, this study may be the first model to partially target stemlike GBM cells through a MELK-mediated pathway with siomycin A to pave the way for effective treatment of GBM.

BMPing off glioma stem cells.

Brain tumor stem cells (BTSC) bear some similarities to neural stem cells (NSC). Bone morphogenetic proteins (BMPs) have a proproliferative effect on early embryonic NSC, and a prodifferentiative effect on postnatal NSC. In this issue of Cancer Cell, Lee et al. demonstrate that BMPs have differing effects on different BTSC lines, either promoting or inhibiting an astrocytic-like differentiation program. This latter effect is the result of epigenetic silencing of the BMP receptor 1B (BMPR1B). These findings document the importance of the BMP signaling system in BTSC as well as that of taking heterogeneity into account when studying BTSC as potential targets for therapy.

Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells.

Emerging evidence suggests that neural stem cells and brain tumors regulate their proliferation via similar pathways. In a previous study, we demonstrated that maternal embryonic leucine zipper kinase (Melk) is highly expressed in murine neural stem cells and regulates their proliferation. Here we describe how MELK expression is correlated with pathologic grade of brain tumors, and its expression levels are significantly correlated with shorter survival, particularly in younger glioblastoma patients. In normal human astrocytes, MELK is only faintly expressed, and MELK knockdown does not significantly influence their growth, whereas Ras and Akt overexpressing astrocytes have up-regulated MELK expression, and the effect of MELK knockdown is more prominent in these transformed astrocytes. In primary cultures from human glioblastoma and medulloblastoma, MELK knockdown by siRNA results in inhibition of the proliferation and survival of these tumors. Furthermore, we show that MELK siRNA dramatically inhibits proliferation and, to some extent, survival of stem cells isolated from glioblastoma in vitro. These results demonstrate a critical role for MELK in the proliferation of brain tumors, including their stem cells, and suggest that MELK may be a compelling molecular target for treatment of high-grade brain tumors.

Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas.

To better understand the pathogenesis of glioblastoma multiforme (GBM) and to increase the accuracy of predicting outcomes for patients with this disease, we performed genome-wide screening for DNA copy-number aberrations in 22 glioma-derived cell lines using a custom-made comparative genomic hybridization-array. Copy-number gains were frequently detected at 3q, 7p, 7q, 20q, Xp and Xq, and losses at 4q, 9p, 10p, 10q, 11q, 13q, 14q, 18q, and 22q. Among several non-random chromosomal aberrations, the gain/amplification of DNA at 5p, which has never been reported before in GBM, was detected with a relatively high ratio (log2 ratio = 0.41-1.19) in four cell lines. Amplification and subsequent overexpression of SKP2, a possible target of amplification within 5p, were detected in four of the 22 cell lines. We also investigated the expression of the gene product in primary GBM by immunohistochemistry, which revealed increased levels of Skp2 in 11 of the 35 tumors examined (31.4%). Heightened expression of Skp2 was associated with shorter overall survival (P = 0.001, logrank test), especially in patients younger than 65 years. These results suggest that overexpression of Skp2 through gene amplification may contribute to the pathogenesis of GBM, and that overabundance of the protein might be a useful prognostic tool in patients with this disease.

[Benign intracranial hypertension resulting from corticosteroid withdrawal: case report].

We report a case of benign intracranial hypertension (BIH) resulting from corticosteroid withdrawal. A 36-year-old woman was admitted to hospital because of an intractable headache. A neurological examination on admission showed no abnormalities other than a headache and nausea. CT, MRI, and angiogram examinations showed no abnormalities. Hematological and laboratory data were also normal. Continuous monitoring of her cerebrospinal fluid (CSF) pressure showed a value of over 25 mmHg during sleep, but papilledema was not observed. A diagnosis of BIH was made, with corticosteroid withdrawal considered to be the most probable cause. The patient was given isosorbide solution for 3 months. However, her clinical condition continued to deteriorate; she eventually began to develop visual loss, photopsia, and memory disturbances. She underwent lumboperitoneal shunt surgery, which immediately eliminated the headache, photopsia, and memory disturbances. She regained her vision over a five-month period. BIH should be considered as a differential diagnosis when an intractable headache develops after corticosteroid withdrawal, especially in young women.