William A. Vandergrift

Drug resistance in glioblastoma: a mini review.

Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated.

Spontaneous CSF Leaks

Spontaneous cerebrospinal fluid rhinorrhea represents a distinct clinic entity that is likely a variant of idiopathic intracranial hypertension (IIH). Patients with spontaneous cerebrospinal fluid (CSF) leaks are generally middle-aged obese women with radiographic evidence of skull base defects, associated meningoencephaloceles, and empty sella syndrome, a common sign of increased intracranial pressure. Significant overlap exists in the characteristics of patients with spontaneous CSF leak and IIH. Endoscopic repair of the CSF fistula is the gold standard treatment for this condition, but emerging evidence supports the reduction of CSF pressure as an important adjuvant treatment in this patient population.

Cost‐effectiveness of the endoscopic versus microscopic approach for pituitary adenoma resection

To evaluate the cost‐effectiveness of an endoscopic versus microscopic approach to pituitary adenoma resection.

A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway

Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.

RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK′872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma

Metastatic Hepatocellular Carcinoma With Associated Spinal Cord Compression

Metastatic hepatocellular carcinoma is a rare occurrence in the United States. The prognosis is poor, with a survival time of months from the time of diagnosis. This article reports a case of myelopathy that developed from metastases in a patient with no significant medical history. The patient was treated with decompressive laminectomy followed by adjuvant radiotherapy. A review of the literature demonstrated that most cases from hepatocellular carcinoma metastasizing to the spinal cord involve either the thoracic or lumbar levels and arise from the right liver lobe or both lobes. Major risk factors included positive hepatitis B virus serologies. This article also discusses current trends in management of epidural spinal cord compression. Although treatment with chemotherapy has not shown any benefit, surgical management has been shown to decrease morbidity and mortality in some patients.

Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma

Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the management of human GBs.

Percutaneous ethanol embolization and cement augmentation of aggressive vertebral hemangiomas at two adjacent vertebral levels

This report describes a case of successful percutaneous direct-puncture ethanol embolization, followed by vertebroplasty, of an aggressive vertebral hemangioma (VH) involving two adjacent thoracic vertebral levels. In this case, the 78-year-old male patient presented with a 6-month history of progressive paraparesis due to spinal cord compression by a T8-T9 VH with an extensive epidural component. Follow-up demonstrated epidural component shrinkage with complete regression of symptoms at 3 months. This case suggests that exclusive percutaneous treatment may be considered for symptomatic VH even when two adjacent vertebral levels are affected.

Intracranial Angiomatoid Fibrous Histiocytoma: Case Report and Literature Review.

BACKGROUND Angiomatoid fibrous histiocytoma (AFH) is a rare and low-grade soft tissue lesion that typically arises from subcutaneous and deep dermal tissue of extremities. The first case was reported in 1979 by Enzinger and has since become known as a distinct entity. AFH has been increasingly reported in different organ systems, with rare reports of primary intracranial AFH. To date there have been 3 reports of intracranial AFH and 1 report of metastasis to the brain, most of which were in young adults. CASE DESCRIPTION In this paper, we present a case of an older patient with a large, petrous apex AFH that was clinically mistaken for a trigeminal nerve schwannoma. We discuss radiographic and histologic features initially found and the findings that ultimately led to the diagnosis of AFH. We also discuss the findings noted in all other reports of intracranial AFH. CONCLUSION We present a rare case of intracranial AFH in a patient relatively old for onset of diagnosis. To date, only 3 prior cases of AFH have been reported. The radiographic findings were nonspecific and initially pointed toward a diagnosis of schwannoma, whereas histopathology seemed to initially suggest meningioma. Further pathologic consultation finally confirmed AFH as the diagnosis. We suspect there are more cases of intracranial AFH that are misdiagnosed due to variability of findings on pathology. The behavior of this tumor remains in question as 1 of the 3 reported cases demonstrated significant recurrence. As such, gross total resection of this lesion is preferable.

Deep learning applied to whole-brain connectome to determine seizure control after epilepsy surgery

We evaluated whether deep learning applied to whole‐brain presurgical structural connectomes could be used to predict postoperative seizure outcome more accurately than inference from clinical variables in patients with mesial temporal lobe epilepsy (TLE).