Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.
Praveen K. Belur, Jason J. Chang, Shuhan He, Benjamin A. Emanuel and William J. Mack
Shuhan He, Martin H. Pham, Matthew Pease, Gabriel Zada, Steven L. Giannotta, Kai Wang and William J. Mack
A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide useful targets for molecular classification and development of targeted therapies for meningiomas.
The authors performed a review of the current literature to identify the epigenetic modifications associated with the formation and/or progression of meningiomas.
Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with meningiomas. Hypermethylation of TIMP3 inactivates its tumor suppression activity while CDKN2 (p14[ARF]) and TP73 gene hypermethylation and HIST1H1c upregulation interact with the p53 regulation of cell cycle control. Other factors such as HOX, IGF, WNK2, and TGF-β epigenetic modifications allow either upregulation or downregulation of critical pathways for meningioma development, progression, and recurrence.
Genome-wide methylation profiling demonstrated that global hypomethylation correlates with tumor grades and severity. Identification of additional epigenetic changes, such as histone modification and higher-order chromosomal structure, may allow for a more thorough understanding of tumorigenesis and enable future individualized treatment strategies for meningiomas.
Timothy Wen, Shuhan He, Frank Attenello, Steven Y. Cen, May Kim-Tenser, Peter Adamczyk, Arun P. Amar, Nerses Sanossian and William J. Mack
As health care administrators focus on patient safety and cost-effectiveness, methodical assessment of quality outcome measures is critical. In 2008 the Centers for Medicare and Medicaid Services (CMS) published a series of “never events” that included 11 hospital-acquired conditions (HACs) for which related costs of treatment are not reimbursed. Cerebrovascular procedures (CVPs) are complex and are often performed in patients with significant medical comorbidities.
This study examines the impact of patient age and medical comorbidities on the occurrence of CMS-defined HACs, as well as the effect of these factors on the length of stay (LOS) and hospitalization charges in patients undergoing common CVPs.
The HACs occurred at a frequency of 0.49% (1.33% in the intracranial procedures and 0.33% in the carotid procedures). Falls/trauma (n = 4610, 72.3% HACs, 357 HACs per 100,000 CVPs) and catheter-associated urinary tract infections (n = 714, 11.2% HACs, 55 HACs per 100,000 CVPs) were the most common events. Age and the presence of ≥ 2 comorbidities were strong independent predictors of HACs (p < 0.0001). The occurrence of HACs negatively impacts both LOS and hospital costs. Patients with at least 1 HAC were 10 times more likely to have prolonged LOS (≥ 90th percentile) (p < 0.0001), and 8 times more likely to have high inpatient costs (≥ 90th percentile) (p < 0.0001) when adjusting for patient and hospital factors.
Improved quality protocols focused on individual patient characteristics might help to decrease the frequency of HACs in this high-risk population. These data suggest that risk adjustment according to underlying patient factors may be warranted when considering reimbursement for costs related to HACs in the setting of CVPs.
Xiao Chang, Lingling Shi, Fan Gao, Jonathan Russin, Liyun Zeng, Shuhan He, Thomas C. Chen, Steven L. Giannotta, Daniel J. Weisenberger, Gabriel Zada, Kai Wang and William J. Mack
Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%–5% display malignant pathological features. The key molecular pathways involved in malignant transformation remain to be determined.
Illumina expression microarrays were used to assess gene expression levels, and Illumina single-nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant meningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones). A weighted gene coexpression network approach was used to identify coexpression modules associated with malignancy.
At the genomic level, malignant meningiomas had more chromosomal losses than atypical and benign meningiomas, with average length of 528, 203, and 34 megabases, respectively. Monosomic loss of chromosome 22 was confirmed to be one of the primary chromosomal level abnormalities in all subtypes of meningiomas. At the transcriptome level, the authors identified 23 coexpression modules from the weighted gene coexpression network. Gene functional enrichment analysis highlighted a module with 356 genes that was highly related to tumorigenesis. Four intramodular hubs within the module (GAB2, KLF2, ID1, and CTF1) were oncogenic in other cancers such as leukemia. A putative meningioma tumor suppressor MN1 was also identified in this module with differential expression between malignant and benign meningiomas.
The authors' genomic and transcriptome analysis of meningiomas provides novel insights into the molecular pathways involved in malignant transformation of meningiomas, with implications for molecular heterogeneity of the disease.