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1.
Mol Ther Oncolytics ; 22: 232-244, 2021 Sep 24.
Article in English | MEDLINE | ID: mdl-34514102

ABSTRACT

The difficulty of glioblastoma treatment makes it a good candidate for novel therapies, such as oncolytic viruses. Vesicular stomatitis virus expressing Lassa virus glycoprotein (Lassa-VSV) showed significant promise in animal models using established glioblastoma cell lines. These experiments were to determine the susceptibility of low-passage, patient-derived cell lines to Lassa-VSV oncolysis. Four patient-derived glioblastoma cell lines were infected with Lassa-VSV that expresses green fluorescent protein (GFP) and analyzed by fluorescence microscopy, flow cytometry, and cell viability assays. Cells were also analyzed as tumorspheres containing primarily glioma stem-like cells. Three low-passage, patient-derived cells were further analyzed with RNA sequencing (RNA-seq). Individual cell lines varied somewhat in their levels of viral gene expression and time course of Lassa-VSV-induced cell death, but each was susceptible to Lassa-VSV. Brain Tumor Center of Excellence (BTCOE) 4765 cells had the highest level of expression of interferon-stimulated genes but were most susceptible to Lassa-VSV-induced cell death, indicating that more susceptible cells do not necessarily have lower interferon pathway activation. Cells cultured as tumorspheres and infected with Lassa-VSV also showed variable susceptibility to Lassa-VSV, but BTCOE 4765 cells were least susceptible. Thus, patient-derived brain tumor cells show variable responses to Lassa-VSV infection, but each of the lines was susceptible to VSV oncolysis.

2.
J Neurosurg Pediatr ; 27(4): 446-451, 2021 Jan 29.
Article in English | MEDLINE | ID: mdl-33513575

ABSTRACT

Until recently, cerebral arteriopathy due to heterozygous mutations of the ACTA2 gene was considered a variant of moyamoya disease. However, radiographic analysis of patients with these mutations reveals a distinctive angiographic appearance from that seen in moyamoya disease. Several heterozygous missense ACTA2 mutations have been implicated in the development of this distinct cerebrovascular entity; however, the penetrance and systemic manifestations of these mutations vary based on the location of the amino acid replacement within the α-smooth muscle actin protein. The severity of the phenotype may also differ among patients within a single mutation type. There is limited literature on the safety and efficacy of revascularization procedures for ACTA2 arteriopathy, which have been limited to those patients with known Arg179His mutations. The authors provide a review of the breadth of mutations within the ACTA2 literature and report a case of two siblings with de novo ACTA2 Arg258Cys mutations with differing clinical courses, highlighting the utility of indirect revascularization with 8-year follow-up data. This case highlights the importance of early recognition of the angiographic appearance of ACTA2 cerebral arteriopathy and performance of genetic testing, as the location of the mutation impacts clinical presentation and outcomes.


Subject(s)
Actins/genetics , Cerebral Arterial Diseases/genetics , Adolescent , Child , Humans , Male , Mutation, Missense , Penetrance , Siblings
3.
Neurosurgery ; 87(2): 166-175, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32097466

ABSTRACT

Marijuana is increasingly utilized for the treatment of multiple medical problems, including back pain, in the United States. Although there is strong preclinical evidence supporting the promise of cannabinoids in the treatment of back pain, there is a paucity of clinical data supporting their use in clinical practice. Opioids are an important medication for the treatment of acute and chronic back pain, but utilization of opioid-based regimens have likely contributed to the growing opioid epidemic. The significant risk of morbidity, mortality, and dependence secondary to opioid medications have increased the interest in nonopioid medications, including cannabinoid-based pain regimens, in treating back pain. This review will provide an overview on the pharmacology, drug delivery methods, clinical evidence, and safety considerations critical to understanding the potential role of cannabinoids in the treatment of back pain.


Subject(s)
Back Pain/drug therapy , Cannabinoids/therapeutic use , Pain Management/methods , Humans
4.
J Neurointerv Surg ; 10(3): 235-239, 2018 Mar.
Article in English | MEDLINE | ID: mdl-28600482

ABSTRACT

INTRODUCTION: There are few published data evaluating the incidence of mechanical thrombectomy among stroke centers or the times at which they occur. METHODS: A multicenter retrospective study was performed to identify all patients undergoing emergent thrombectomy for acute ischemic stroke during a 3-month period (June through August 2016). Consultations that did not undergo thrombectomy were not included. RESULTS: Ten institutions participated in the study. During the 92-day study period, a total of 189 patients underwent mechanical thrombectomy. The average number of procedures per hospital over the study period was 18.9 (average of 0.2 cases per day per or 75.6 cases per year). This ranged from 0.09 cases per day at the lowest volume center to 0.49 cases per day at the highest volume center. Procedures were more common on weekdays (p<0.001) and during non-work hours (p<0.001). The most common period for thrombectomy procedures was between 20:00 and 21:00 hours. The median time from notification to groin puncture was 84 min (IQR 56-145 min) and from puncture to closure was 57 min (IQR 33-80 min). The median time from imaging completion to procedural start was 52 min longer for non-work hours than during work hours (p<0.001). There were no differences in procedural length based on day of the week or time of day. CONCLUSIONS: These findings indicate that the majority of mechanical thrombectomy cases occur during non-work hours, with associated off-hours delays, which has important operational implications for hospitals implementing stroke call coverage.


Subject(s)
Brain Ischemia/surgery , Operative Time , Stroke/surgery , Thrombectomy/methods , Thrombectomy/standards , Adult , Aged , Brain Ischemia/epidemiology , Female , Humans , Male , Middle Aged , Retrospective Studies , Stroke/epidemiology , Treatment Outcome
5.
J Neurooncol ; 128(1): 119-128, 2016 05.
Article in English | MEDLINE | ID: mdl-26948673

ABSTRACT

With escalating focus on cost containment, there is increasing scrutiny on the practice of multiple stereotactic radiosurgeries (SRSs) for patients with cerebral metastases distant to the initial tumor site. Our goal was to determine the survival patterns of patients with cerebral metastasis who underwent multiple SRSs. We retrospectively analyzed survival outcomes of 801 patients with 3683 cerebral metastases from primary breast, colorectal, lung, melanoma and renal histologies consecutively treated at the University of California, San Diego/San Diego Gamma Knife Center (UCSD/SDGKC), comparing the survival pattern of patients who underwent a single (n = 643) versus multiple SRS(s) (n = 158) for subsequent cerebral metastases. Findings were recapitulated in an independent cohort of 2472 patients, with 26,629 brain metastases treated with SRS at the Katsuta Hospital Mito GammaHouse (KHMGH). For the UCSD/SDGKC cohort, no significant difference in median survival was found for patients undergoing 1, 2, 3, or ≥4 SRS(s) (median survival of 167, 202, 129, and 127 days, respectively). Median intervals between treatments consistently ranged 140-178 days irrespective of the number of SRS(s) (interquartile range 60-300; p = 0.25). Patients who underwent >1 SRSs tend to be younger, with systemic disease control, harbor lower cumulative tumor volume but increased number of metastases, and have primary melanoma (p < 0.001, <0.001, <0.001, 0.02, and 0.009, respectively). Comparable results were found in the KHMGH cohort. Using an independent validation study design, we demonstrated comparable overall survival between judiciously selected patients who underwent a single or multiple SRS(s).


Subject(s)
Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Radiosurgery , Retreatment , Age Factors , Aged , Brain/diagnostic imaging , Brain/radiation effects , Brain Neoplasms/diagnostic imaging , Disease Management , Humans , Magnetic Resonance Imaging , Middle Aged , Retrospective Studies , Survival Analysis , Treatment Outcome , Tumor Burden
6.
Surg Neurol Int ; 3: 97, 2012.
Article in English | MEDLINE | ID: mdl-23061013

ABSTRACT

BACKGROUND: Between 2005 and 2010, we treated patients with hydrocephalus related to cerebral metastases, who were not good candidates for surgical resection by either endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunting (VPS). Patients were excluded from ETV if they had a clinical history suggestive of non-obstructive hydrocephalus, including: (1) history of infection or ventricular hemorrhage and (2) leptomeningeal carcinomatosis. The rest of the patients were treated with VPS. METHODS: We analyzed the clinical outcome of these patient cohorts, to determine whether the efficacy of VPS was compromised due to a history of infection, ventricular hemorrhage, or leptomeningeal carcinomatosis, and compared these results to those patients who underwent ETV. RESULTS: Sixteen patients were treated with ETV and 36 patients were treated with VPS. The overall efficacy of symptomatic palliation was comparable in the ETV and VPS patients (ETV = 69%, VPS = 75%). In both groups, patients with more severe hydrocephalic symptoms such as nausea, vomiting, and lethargy were more likely to benefit from the procedure. The overall complication rate for the two groups was comparable (ETV = 12.6%, VPS = 19.4%), although the spectrum of complications differed. The overall survival, initial Karnofsky performance status (KPS), and three-month KPS, were similarly comparable (median survival: ETV 3 months, VPS 5.5 months; initial KPS: ETV = 66 ± 7, VPS = 69 ± 12; 3 months KPS: ETV = 86 ± 7, KPS = 84 ± 12). CONCLUSION: VPS remains a reasonable option for poor RPA grade metastasis patients with hydrocephalus, even in the setting of a previous infection, hemorrhage, or in those with leptomeningeal disease. Optimal treatment of this population will involve the judicious consideration of the relative merits of VPS and ETV.

7.
Science ; 327(5970): 1223-8, 2010 Mar 05.
Article in English | MEDLINE | ID: mdl-20203043

ABSTRACT

Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.


Subject(s)
Aging , Drosophila Proteins/physiology , Drosophila melanogaster/physiology , Heat-Shock Proteins/physiology , Protein Kinases/metabolism , AMP-Activated Protein Kinases/metabolism , Amino Acid Sequence , Animals , Autophagy , Cell Size , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/chemistry , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/cytology , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Fat Body/metabolism , Feedback, Physiological , Forkhead Transcription Factors/metabolism , Gene Expression Regulation , Heart/physiology , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Mitochondria, Muscle/physiology , Mitochondria, Muscle/ultrastructure , Models, Animal , Molecular Sequence Data , Muscles/physiology , Oxidative Stress , Reactive Oxygen Species/metabolism , Signal Transduction , TOR Serine-Threonine Kinases , Transcription, Genetic , Triglycerides/metabolism , Wings, Animal/cytology , Wings, Animal/growth & development , Wings, Animal/metabolism
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