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1.  Sonographic localization of a nonpalpable shunt: Ultrasound-assisted ventricular shunt tap 
Background:
Patients frequently present to the emergency department (ED) for evaluation of cerebrospinal fluid (CSF) shunt malfunction, often requiring urgent management. A typical evaluation in the emergency room setting includes a thorough history and physical examination, noncontrasted head computed tomography (CT), shunt series, and occasionally a ventricular shunt tap.
Case Description:
We present the case of a 53-year-old male who initially presented to the ED in acute status epilepticus. His history was notable for seizures and multiple craniectomies and cranioplasties with subsequent placement of a ventriculoperitoneal shunt secondary to traumatic brain injury. Imaging in the ED suggested possible shunt failure. No previous imaging was available for comparison, and therefore a ventricular shunt tap was attempted. Initially, the tap could not be performed, as the shunt was not palpable secondary to the thickness of his scalp and location of the reservoir near his complex cranial reconstruction site. We report, for the first time, the utility of emergency ultrasound (EUS) to aid in such an encounter.
Conclusion:
EUS revealed the exact location of his shunt reservoir, and therefore enabled the shunt tap, which ultimately led to the discovery of the patient's proximal shunt failure in a setting that may have otherwise been missed. The patient underwent urgent shunt revision with a good outcome.
doi:10.4103/2152-7806.116151
PMCID: PMC3766327  PMID: 24032076
Hydrocephalus; shunt failure; ultrasound guidance; ventricular shunt tap
2.  Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells 
Cancer Biology & Therapy  2012;13(7):567-574.
The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was enhanced in multiple genetically disparate primary human glioblastoma isolates by the HDAC inhibitor sodium valproate (Depakote). Drug exposure reduced phosphorylation of p70 S6K and of mTOR. Similar data to that with valproate were also obtained using the HDAC inhibitor vorinostat (Zolinza). Sorafenib and valproate also interacted to kill medulloblastoma and PNET cell lines. Treatment with sorafenib and HDAC inhibitors radio-sensitized both GBM and medulloblastoma cell lines. Knock down of death receptor (CD95) expression protected GBM cells from the drug combination, as did overexpression of c-FLIP-s, BCL-XL and dominant negative caspase 9. Knock down of PDGFRα recapitulated the effect of sorafenib in combination with HDAC inhibitors. Collectively, our data demonstrate that the combination of sorafenib and HDAC inhibitors kills through activation of the extrinsic pathway, and could represent a useful approach to treat CNS-derived tumors.
doi:10.4161/cbt.19771
PMCID: PMC3679096  PMID: 22406992
HDAC inhibitor; Sorafenib; apoptosis; glioma
3.  Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death 
Cancer Biology & Therapy  2011;12(3):215-228.
The present studies were initiated to determine in greater molecular detail the regulation of CHK1 inhibitor lethality in transfected and infected breast cancer cells and using genetic models of transformed fibrobalsts. Multiple MEK1/2 inhibitors (PD184352, AZD6244 [ARRY-142886]) interacted with multiple CHK1 inhibitors (UCN-01 [7-hydroxystaurosporine], AZD7762) to kill mammary carcinoma cells and transformed fibroblasts. In transformed cells, CHK1 inhibitor-induced activation of ERK1/2 was dependent upon activation of SRC family non-receptor tyrosine kinases as judged by use of multiple SRC kinase inhibitors (PP 2, Dasatinib; AZD0530), use of SRC/FYN/YES deleted transformed fibroblasts or by expression of dominant negative SRC. Cell killing by SRC family kinase inhibitors and CHK1 inhibitors was abolished in BAX/BAK−/− transformed fibroblasts and suppressed by overexpression of BCL-XL. Treatment of cells with BCL-2/BCL-XL antagonists promoted SRC inhibitor + CHK1 inhibitor-induced lethality in a BAX/BAK-dependent fashion. Treatment of cells with [SRC + CHK1] inhibitors radio-sensitized tumor cells. These findings argue that multiple inhibitors of the SRC-RAS-MEK pathway interact with multiple CHK1 inhibitors to kill transformed cells.
doi:10.4161/cbt.12.3.16218
PMCID: PMC3230482  PMID: 21642769
CHK1; SRC; apoptosis; breast cancer; kinase; therapeutics; intrinsic; caspase
4.  Sorafenib enhances pemetrexed cytotoxicity through an autophagy -dependent mechanism in cancer cells 
Cancer research  2011;71(14):4955-4967.
Pemetrexed (ALIMTA) is a folate anti-metabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multi-kinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to Class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.
doi:10.1158/0008-5472.CAN-11-0898
PMCID: PMC3139015  PMID: 21622715
5.  Sorafenib inhibits STAT3 signaling associated with growth arrest and apoptosis of medulloblastomas 
Molecular cancer therapeutics  2008;7(11):3519-3526.
Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multi-kinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in both cell lines and the primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr705) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and MAPKs (ERK1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the anti-apoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data demonstrate that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.
doi:10.1158/1535-7163.MCT-08-0138
PMCID: PMC2592687  PMID: 19001435
sorafenib; medulloblastoma; STAT3; apoptosis; proliferation

Results 1-5 (5)