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1.
Epilepsy Behav ; 156: 109810, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38704985

RESUMO

OBJECTIVE: Laser interstitial thermal therapy (LITT) is an alternative to anterior temporal lobectomy (ATL) for the treatment of temporal lobe epilepsy that has been found by some to have a lower procedure cost but is generally regarded as less effective and sometimes results in a subsequent procedure. The goal of this study is to incorporate subsequent procedures into the cost and outcome comparison between ATL and LITT. METHODS: This single-center, retrospective cohort study includes 85 patients undergoing ATL or LITT for temporal lobe epilepsy during the period September 2015 to December 2022. Of the 40 patients undergoing LITT, 35 % (N = 14) underwent a subsequent ATL. An economic cost model is derived, and difference in means tests are used to compare the costs, outcomes, and other hospitalization measures. RESULTS: Our model predicts that whenever the percentage of LITT patients undergoing subsequent ATL (35% in our sample) exceeds the percentage by which the LITT procedure alone is less costly than ATL (7.2% using total patient charges), LITT will have higher average patient cost than ATL, and this is indeed the case in our sample. After accounting for subsequent surgeries, the average patient charge in the LITT sample ($103,700) was significantly higher than for the ATL sample ($88,548). A second statistical comparison derived from our model adjusts for the difference in effectiveness by calculating the cost per seizure-free patient outcome, which is $108,226 for ATL, $304,052 for LITT only, and $196,484 for LITT after accounting for the subsequent ATL surgeries. SIGNIFICANCE: After accounting for the costs of subsequent procedures, we found in our cohort that LITT is not only less effective but also results in higher average costs per patient than ATL as a first course of treatment. While cost and effectiveness rates will vary across centers, we also provide a model for calculating cost effectiveness based on individual center data.


Assuntos
Lobectomia Temporal Anterior , Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Terapia a Laser , Humanos , Epilepsia do Lobo Temporal/cirurgia , Epilepsia do Lobo Temporal/economia , Feminino , Masculino , Lobectomia Temporal Anterior/economia , Lobectomia Temporal Anterior/métodos , Adulto , Terapia a Laser/economia , Terapia a Laser/métodos , Estudos Retrospectivos , Epilepsia Resistente a Medicamentos/economia , Epilepsia Resistente a Medicamentos/cirurgia , Pessoa de Meia-Idade , Adulto Jovem , Resultado do Tratamento
2.
Ann Neurol ; 88(5): 970-983, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32827235

RESUMO

OBJECTIVE: Medial temporal lobe epilepsy (TLE) is the most common form of medication-resistant focal epilepsy in adults. Despite removal of medial temporal structures, more than one-third of patients continue to have disabling seizures postoperatively. Seizure refractoriness implies that extramedial regions are capable of influencing the brain network and generating seizures. We tested whether abnormalities of structural network integration could be associated with surgical outcomes. METHODS: Presurgical magnetic resonance images from 121 patients with drug-resistant TLE across 3 independent epilepsy centers were used to train feed-forward neural network models based on tissue volume or graph-theory measures from whole-brain diffusion tensor imaging structural connectomes. An independent dataset of 47 patients with TLE from 3 other epilepsy centers was used to assess the predictive values of each model and regional anatomical contributions toward surgical treatment results. RESULTS: The receiver operating characteristic area under the curve based on regional betweenness centrality was 0.88, significantly higher than a random model or models based on gray matter volumes, degree, strength, and clustering coefficient. Nodes most strongly contributing to the predictive models involved the bilateral parahippocampal gyri, as well as the superior temporal gyri. INTERPRETATION: Network integration in the medial and lateral temporal regions was related to surgical outcomes. Patients with abnormally integrated structural network nodes were less likely to achieve seizure freedom. These findings are in line with previous observations related to network abnormalities in TLE and expand on the notion of underlying aberrant plasticity. Our findings provide additional information on the mechanisms of surgical refractoriness. ANN NEUROL 2020;88:970-983.


Assuntos
Conectoma , Epilepsia do Lobo Temporal/cirurgia , Aprendizado de Máquina , Procedimentos Neurocirúrgicos/métodos , Adulto , Imagem de Tensor de Difusão , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Giro Para-Hipocampal/diagnóstico por imagem , Curva ROC , Resultado do Tratamento
3.
Cancer Invest ; 38(6): 349-355, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32441531

RESUMO

Background: Meningiomas represent ∼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.


Assuntos
Benzimidazóis/farmacologia , Quinase do Ponto de Checagem 2/genética , Meningioma/tratamento farmacológico , Neurofibromina 2/genética , Quinolonas/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Meningioma/genética , Meningioma/patologia , Mutação/genética , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína bcl-X/genética
4.
Epilepsia ; 59(9): 1643-1654, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30098002

RESUMO

OBJECTIVE: 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). METHODS: Fifty patients with unilateral TLE were classified either as having persistent disabling seizures (SZ) or becoming seizure-free (SZF) at least 1 year after epilepsy surgery. Their presurgical structural connectomes were reconstructed from whole-brain diffusion tensor imaging. A deep network was trained based on connectome data to classify seizure outcome using 5-fold cross-validation. RESULTS: Classification accuracy of our trained neural network showed positive predictive value (PPV; seizure freedom) of 88 ± 7% and mean negative predictive value (NPV; seizure refractoriness) of 79 ± 8%. Conversely, a classification model based on clinical variables alone yielded <50% accuracy. The specific features that contributed to high accuracy classification of the neural network were located not only in the ipsilateral temporal and extratemporal regions, but also in the contralateral hemisphere. SIGNIFICANCE: Deep learning demonstrated to be a powerful statistical approach capable of isolating abnormal individualized patterns from complex datasets to provide a highly accurate prediction of seizure outcomes after surgery. Features involved in this predictive model were both ipsilateral and contralateral to the clinical foci and spanned across limbic and extralimbic networks.


Assuntos
Encéfalo/fisiopatologia , Conectoma/métodos , Aprendizado Profundo , Epilepsia/cirurgia , Avaliação de Resultados em Cuidados de Saúde/métodos , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais , Avaliação de Resultados em Cuidados de Saúde/classificação , Estudos Retrospectivos , Adulto Jovem
5.
Tumour Biol ; 37(6): 7525-34, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26684801

RESUMO

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.


Assuntos
Raios gama/efeitos adversos , Glioblastoma/radioterapia , Necrose/metabolismo , Necrose/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Western Blotting , Caspases , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Técnicas Imunoenzimáticas , Masculino , Necrose/etiologia , Lesões por Radiação/etiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Tumour Biol ; 36(9): 7027-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25864108

RESUMO

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 ß (GSK3ß) via inhibition of the Wnt5/ß-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.


Assuntos
Catecóis/administração & dosagem , Álcoois Graxos/administração & dosagem , Flavonas/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Lanosterol/análogos & derivados , Limoninas/administração & dosagem , Meningioma/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Triterpenos/administração & dosagem , Apoptose/efeitos dos fármacos , Catecóis/química , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Álcoois Graxos/química , Flavonas/química , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Ácidos Heptanoicos/química , Humanos , Lanosterol/administração & dosagem , Lanosterol/química , Limoninas/química , Meningioma/genética , Meningioma/patologia , Sesquiterpenos/química , Triterpenos/química , Via de Sinalização Wnt/efeitos dos fármacos
7.
J Neuroradiol ; 41(4): 269-74, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23419714

RESUMO

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.


Assuntos
Cimentos Ósseos/uso terapêutico , Embolização Terapêutica/métodos , Etanol/uso terapêutico , Hemangioma/terapia , Neoplasias da Coluna Vertebral/terapia , Vértebras Torácicas , Vertebroplastia/métodos , Idoso , Terapia Combinada/métodos , Hemangioma/diagnóstico , Humanos , Masculino , Neoplasias da Coluna Vertebral/diagnóstico , Resultado do Tratamento
8.
J Neurosurg Case Lessons ; 5(22)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37249138

RESUMO

BACKGROUND: The Responsive Neurostimulation (RNS) system is an implantable device for patients with drug-resistant epilepsy who are not candidates for resection of a seizure focus. As a relatively new therapeutic, the full spectrum of adverse effects has yet to be determined. A literature review revealed no previous reports of cerebral vasospasm following RNS implantation. OBSERVATIONS: A 35-year-old man developed severe angiographic and clinical vasospasm following bilateral mesial temporal lobe RNS implantation. He initially presented with concerns for status epilepticus 8 days after implantation. On hospital day 3, a decline in his clinical examination prompted imaging studies that revealed a left middle cerebral artery (MCA) stroke with angiographic evidence of severe vasospasm of the left internal carotid artery (ICA), MCA, anterior cerebral artery (ACA), and right ICA and ACA. Despite improvements in angiographic vasospasm after appropriate treatment, a thrombus developed in the posterior M2 branch, requiring mechanical thrombectomy. Ultimately, the patient was stabilized and discharged to a rehabilitation facility with residual cognitive and motor deficits. LESSONS: Cerebral vasospasm as a cause of ischemic stroke after uneventful RNS implantation is exceedingly rare, yet demands particular attention given the potential for severe consequences and the growing number of patients receiving RNS devices.

9.
Neurochem Res ; 37(6): 1192-200, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22228201

RESUMO

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.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/metabolismo , Compostos Alílicos/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Terapia Combinada , Metilases de Modificação do DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/efeitos dos fármacos , Flavonoides/uso terapêutico , Alho/química , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , MicroRNAs/uso terapêutico , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , RNA Interferente Pequeno/uso terapêutico , Retinoides/uso terapêutico , Sulfetos/uso terapêutico , Proteínas Supressoras de Tumor/efeitos dos fármacos
10.
J Clin Neurosci ; 105: 122-128, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36182812

RESUMO

OBJECTIVE: Vagus Nerve Stimulation (VNS) paired with rehabilitation delivered by the Vivistim® Paired VNS™ System was approved by the FDA in 2021 to improve motor deficits in chronic ischemic stroke survivors with moderate to severe arm and hand impairment. Vagus nerve stimulators have previously been implanted in over 125,000 patients for treatment-resistant epilepsy and the surgical procedure is generally well-tolerated and safe. In this report, we describe the Vivistim implantation procedure, perioperative management, and complications for chronic stroke survivors enrolled in the pivotal trial. METHODS: The pivotal, multisite, randomized, triple-blind, sham-controlled trial (VNS-REHAB) enrolled 108 participants. All participants were implanted with the VNS device in an outpatient procedure. Thrombolytic agents were temporarily discontinued during the perioperative period. Participants were discharged within 48 hrs and started rehabilitation therapy approximately 10 days after the Procedure. RESULTS: The rate of surgery-related adverse events was lower than previously reported for VNS implantation for epilepsy and depression. One participant had vocal cord paresis that eventually resolved. There were no serious adverse events related to device stimulation. Over 90% of participants were taking antiplatelet drugs (APD) or anticoagulants and no adverse events or serious adverse events were reported as a result of withholding these medications during the perioperative period. CONCLUSIONS: This study is the largest, randomized, controlled trial in which a VNS device was implanted in chronic stroke survivors. Results support the use of the Vivistim System in chronic stroke survivors, with a safety profile similar to VNS implantations for epilepsy and depression.


Assuntos
Epilepsia , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Estimulação do Nervo Vago , Anticoagulantes , Epilepsia/etiologia , Epilepsia/cirurgia , Fibrinolíticos , Humanos , Inibidores da Agregação Plaquetária , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral/métodos , Resultado do Tratamento , Nervo Vago , Estimulação do Nervo Vago/métodos
11.
J Neurol Sci ; 418: 117102, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32866816

RESUMO

Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Preparações Farmacêuticas , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Benzamidas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Imidazóis , Fosfatidilinositol 3-Quinases , Pirimidinas , Sulfonas , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Triazinas , Proteínas Supressoras de Tumor/genética
12.
Oncolytic Virother ; 7: 107-116, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538967

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive form of brain cancer which is associated with poor prognosis. A variety of oncolytic viruses have previously shown positive efficacy against GBM, potentially offering new treatment options for patients. One such oncolytic virus is Myxoma virus (MYXV), a rabbit-specific poxvirus that has been shown to be efficacious against a variety of tumor models including GBM. PURPOSE: The purpose of this study was to test the efficacy of MYXV combined with current treatment regimens for GBM in both established cell lines as well as patient biopsy samples. MATERIALS AND METHODS: U118 gliobastoma cell lines were treated under various standard of care combinations (untreated, radiation and chemotherapeutic) prior to infection with MYXV. Infection was then monitored for differences in rate of infection, titer and rate of spread. Cellular death was measured by MTT assay and Caspase-3 colorimetric assay. Patient biopsies were harvested and treated under similar treatment conditions. RESULTS: The addition of GBM standard of care to MYXV infection resulted in an increased rate of spread compared to single treatment with either radiation or chemotherapeutic alone. SOC did not alter viral replication or infection rates. Similar effects were seen in ex vivo patient biopsies. Cellular viability was significantly decreased with the combination therapy of SOC and MYXV infection compared to any other treatment outcome. Caspase-3 activity was also significantly increased in samples treated with combination therapy when compared to any other treatment combination. CONCLUSION: Our results show that the combination of MYXV with current SOC results in both increased killing of GBM cells compared to either treatment regime alone as well as increased spread of MYXV infection. These findings lay the foundation for future in vivo studies on combining MYXV with GBM SOC.

13.
Cancer Chemother Pharmacol ; 82(6): 945-952, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209569

RESUMO

PURPOSE/INTRODUCTION: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models. METHODS: Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS. RESULTS: Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. CONCLUSIONS: DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.


Assuntos
Compostos Alílicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Sulfetos/uso terapêutico , Compostos Alílicos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioblastoma/enzimologia , Glioblastoma/patologia , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Masculino , Camundongos SCID , Neurônios/efeitos dos fármacos , Neurônios/patologia , Sulfetos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Neurosurg Focus ; 20(4): E13, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16709018

RESUMO

The treatment of malignant gliomas has advanced significantly in the past 15 years. The simultaneous development of new targeting agents and techniques to deliver these high-molecular-weight compounds has led to improved efficacy and promising results in Phase III trials. Convection-enhanced delivery (CED) of macromolecules has emerged as the leading delivery technique for the treatment of malignant gliomas. A summary of the basic principles of CED and a review of the current human trials of protein targeting agents are provided.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioma/tratamento farmacológico , Glioma/radioterapia , Imunotoxinas/administração & dosagem , Radioisótopos/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Terapia Combinada/métodos , Terapia Combinada/tendências , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Humanos , Bombas de Infusão/tendências
15.
World Neurosurg ; 96: 403-409, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27667574

RESUMO

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.


Assuntos
Craniotomia/métodos , Histiocitoma Fibroso Maligno/diagnóstico por imagem , Histiocitoma Fibroso Maligno/cirurgia , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Fossa Craniana Média/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Receptores de Superfície Celular/metabolismo , Sindecana-1/metabolismo , Lobo Temporal/diagnóstico por imagem
16.
Laryngoscope ; 125(1): 16-24, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24938934

RESUMO

OBJECTIVES/HYPOTHESIS: To evaluate the cost-effectiveness of an endoscopic versus microscopic approach to pituitary adenoma resection. STUDY DESIGN: Markov decision tree economic evaluation. METHODS: An economic evaluation using a Markov decision tree model was performed. The economic perspective was that of the healthcare third-party payer. Effectiveness and probability data were obtained from a single meta-analysis of 38 studies. Costs were obtained from the Healthcare Cost and Utilization Project database and wholesale pharmaceutical pricing. Multiple sensitivity analyses were performed including a probabilistic sensitivity analysis. Comparative treatment groups were: 1) endoscopic approach and 2) microscopic approach to pituitary adenoma resection. The primary outcome was cost per quality-adjusted life year (QALY). The time horizon was 25 years, and costs were discounted at a rate of 3.5%. RESULTS: The endoscopic approach cost a total of $17,244.63 and produced a total of 24.30 QALYs. The microscopic approach cost a total of $23,756.60 and produced a total of 24.20 QALYs. In the reference case, the endoscopic approach was a dominant intervention (both less costly and more effective); therefore, an incremental cost-effectiveness ratio was not calculated. The sensitivity analysis demonstrated 79% certainty that the endoscopic approach is the cost-effective decision, at a willingness to pay threshold of $50,000 per QALY. CONCLUSIONS: This economic evaluation suggests that the endoscopic approach is the more cost-effective intervention compared to the microscopic approach for patients requiring a pituitary adenoma resection.


Assuntos
Adenoma/cirurgia , Endoscopia/economia , Hipofisectomia/economia , Microcirurgia/economia , Neoplasias Hipofisárias/cirurgia , Análise Custo-Benefício , Árvores de Decisões , Feminino , Humanos , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econômicos , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/etiologia , Anos de Vida Ajustados por Qualidade de Vida
17.
Anticancer Res ; 35(2): 615-25, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25667438

RESUMO

Glioblastoma is the most common and deadliest of malignant primary brain tumors (Grade IV astrocytoma) in adults. Current standard treatments have been improving but patient prognosis still remains unacceptably devastating. Glioblastoma recurrence is linked to epigenetic mechanisms and cellular pathways. Thus, greater knowledge of the cellular, genetic and epigenetic origin of glioblastoma is the key for advancing glioblastoma treatment. One rapidly growing field of treatment, epigenetic modifiers; histone deacetylase inhibitors (HDACis), has now shown much promise for improving patient outcomes through regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. HDAC inhibitors have been shown, in a pre-clinical setting, to be effective anticancer agents via multiple mechanisms, by up-regulating expression of tumor suppressor genes, inhibiting oncogenes, inhibiting tumor angiogenesis and up-regulating the immune system. There are many HDAC inhibitors that are currently in pre-clinical and clinical stages of investigation for various types of cancers. This review will explain the theory of epigenetic cancer therapy, identify HDAC inhibitors that are being investigated for glioblastoma therapy, explain the mechanisms of therapeutic effects as demonstrated by pre-clinical and clinical studies and describe the current status of development of these drugs as they pertain to glioblastoma therapy.


Assuntos
Epigênese Genética , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Oligopeptídeos/uso terapêutico
18.
J Neurosurg Pediatr ; 14(6): 662-4, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25303158

RESUMO

Placement of a ventriculoperitoneal shunt (VPS) is a procedure comprising many small steps. Difficulties and delays can arise when passing the distal shunt tubing down the distal tunneling sheath during surgery. The authors of this report describe a simple technique for quickly passing the distal catheter of a VPS through the tunneler sheath, whereby the sheath is used as a fluid tube to allow the distal catheter to be drawn through the fluid tube under suction pressure. The plastic sheath that surrounds the shunt tunneler device is used as a fluid tube, or "straw," with the proximal aperture submerged into a bucket of sterile irrigation liquid containing the distal catheter. Suction pressure is placed against the distal aperture of the tunneler, and the shunt catheter is quickly drawn through the sheath. No special equipment is required. In time trials, the bucket and straw technique took an average of 0.43 seconds, whereas traditional passage methods took 32.3 seconds. The "bucket and straw" method for passing distal shunt tubing through the tunneler sheath is a technique that increases surgical efficiency and reduces manual contact with shunt hardware.


Assuntos
Hidrocefalia/cirurgia , Duração da Cirurgia , Derivação Ventriculoperitoneal/instrumentação , Derivação Ventriculoperitoneal/métodos , Catéteres , Humanos
19.
Am J Med Sci ; 341(2): 148-52, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21107234

RESUMO

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.


Assuntos
Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas , Compressão da Medula Espinal/etiologia , Neoplasias da Medula Espinal/secundário , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico , Evolução Fatal , Humanos , Laminectomia , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Compressão da Medula Espinal/diagnóstico , Compressão da Medula Espinal/cirurgia , Neoplasias da Medula Espinal/complicações , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/cirurgia
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