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1.
Stem Cells ; 34(8): 2026-39, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27145382

RESUMO

Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. Stem Cells 2016;34:2026-2039.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Evasão da Resposta Imune , Fatores Inibidores da Migração de Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Arginase/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Glioblastoma/patologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/efeitos dos fármacos
2.
Stem Cells ; 33(7): 2114-2125, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25827713

RESUMO

Advanced cancers display cellular heterogeneity driven by self-renewing, tumorigenic cancer stem cells (CSCs). The use of cell lines to model CSCs is challenging due to the difficulty of identifying and isolating cell populations that possess differences in self-renewal and tumor initiation. To overcome these barriers in triple-negative breast cancer (TNBC), we developed a CSC system using a green fluorescent protein (GFP) reporter for the promoter of the well-established pluripotency gene NANOG. NANOG-GFP+ cells gave rise to both GFP+ and GFP(-) cells, and GFP+ cells possessed increased levels of the embryonic stem cell transcription factors NANOG, SOX2, and OCT4 and elevated self-renewal and tumor initiation capacities. GFP+ cells also expressed mesenchymal markers and demonstrated increased invasion. Compared with the well-established CSC markers CD24(-) /CD44(+) , CD49f, and aldehyde dehydrogenase (ALDH) activity, our NANOG-GFP reporter system demonstrated increased enrichment for CSCs. To explore the utility of this system as a screening platform, we performed a flow cytometry screen that confirmed increased CSC marker expression in the GFP+ population and identified new cell surface markers elevated in TNBC CSCs, including junctional adhesion molecule-A (JAM-A). JAM-A was highly expressed in GFP+ cells and patient-derived xenograft ALDH+ CSCs compared with the GFP(-) and ALDH(-) cells, respectively. Depletion of JAM-A compromised self-renewal, whereas JAM-A overexpression induced self-renewal in GFP(-) cells. Our data indicate that we have defined and developed a robust system to monitor differences between CSCs and non-CSCs in TNBC that can be used to identify CSC-specific targets for the development of future therapeutic strategies.


Assuntos
Genes Reporter/genética , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
3.
Stem Cells ; 32(7): 1746-58, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24737733

RESUMO

Glioblastoma (GBM) contains a self-renewing, tumorigenic cancer stem cell (CSC) population which contributes to tumor propagation and therapeutic resistance. While the tumor microenvironment is essential to CSC self-renewal, the mechanisms by which CSCs sense and respond to microenvironmental conditions are poorly understood. Scavenger receptors are a broad class of membrane receptors well characterized on immune cells and instrumental in sensing apoptotic cellular debris and modified lipids. Here, we provide evidence that CSCs selectively use the scavenger receptor CD36 to promote their maintenance using patient-derived CSCs and in vivo xenograft models. CD36 expression was observed in GBM cells in addition to previously described cell types including endothelial cells, macrophages, and microglia. CD36 was enriched in CSCs and was able to functionally distinguish self-renewing cells. CD36 was coexpressed with integrin alpha 6 and CD133, previously described CSC markers, and CD36 reduction resulted in concomitant loss of integrin alpha 6 expression, self-renewal, and tumor initiation capacity. We confirmed oxidized phospholipids, ligands of CD36, were present in GBM and found that the proliferation of CSCs, but not non-CSCs, increased with exposure to oxidized low-density lipoprotein. CD36 was an informative biomarker of malignancy and negatively correlated to patient prognosis. These results provide a paradigm for CSCs to thrive by the selective enhanced expression of scavenger receptors, providing survival, and metabolic advantages.


Assuntos
Neoplasias Encefálicas/metabolismo , Antígenos CD36/metabolismo , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Antígenos CD36/genética , Proliferação de Células , Progressão da Doença , Feminino , Expressão Gênica , Glioblastoma/mortalidade , Glioblastoma/patologia , Estimativa de Kaplan-Meier , Lipoproteínas LDL/fisiologia , Camundongos Nus , Transplante de Neoplasias , Células Tumorais Cultivadas
4.
Neurosurg Focus ; 36(4): E3, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24684336

RESUMO

In 1919, it was observed that intravascular osmolar shifts could collapse the thecal sac and diminish the ability to withdraw CSF from the lumbar cistern. This led to the notion that hyperosmolar compounds could ameliorate brain swelling. Since then, various therapeutic interventions have been used for the reduction of intracranial pressure and brain volume. Urea was first used as an osmotic agent for the reduction of brain volume in 1950. It was associated with greater efficacy and consistency than alternatives such as hyperosmolar glucose. Its use became the standard of clinical practice by 1957, in both the intensive care unit and operating room, to reduce intracranial pressure and brain bulk and was the first hyperosmolar compound to have widespread use. However, the prime of urea was rather short lived. Reports of side effects and complications associated with urea emerged. These included coagulopathy, hemoglobinuria, electrocardiography changes, tissue necrosis with extravasation, and a significant potential for rebound intracranial hypertension. Mannitol was introduced in 1961 as a comparable and potentially superior alternative to urea. However, mannitol was initially purported to be less effective at rapidly reducing intracranial pressure. The debate over the two compounds continued for a decade until mannitol eventually replaced urea by the late 1960s and early 1970s as the hyperosmolar agent of choice due to the ease of preparation, chemical stability, and decreased side effect profile. Although urea is not currently the standard of care today, its rise and eventual replacement by mannitol played a seminal role in both our understanding of cerebral edema and the establishment of strategies for its management.


Assuntos
Edema Encefálico/tratamento farmacológico , Pressão Intracraniana/efeitos dos fármacos , Ureia/história , Ureia/uso terapêutico , Edema Encefálico/história , Diuréticos Osmóticos/história , Diuréticos Osmóticos/uso terapêutico , História do Século XX , História do Século XXI , Humanos , Manitol/uso terapêutico
5.
J Stroke Cerebrovasc Dis ; 23(5): 1242-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24103673

RESUMO

Moyamoya disease is a rare cerebrovascular anomaly involving the intracranial carotid arteries that can present clinically with either ischemic or hemorrhagic disease. Moyamoya syndrome, indistinguishable from moyamoya disease at presentation, is associated with multiple clinical conditions including neurofibromatosis type 1, autoimmune disease, prior radiation therapy, Down syndrome, and Turner syndrome. We present the first reported case of an adult patient with previously unrecognized mosaic Turner syndrome with acute subarachnoid and intracerebral hemorrhage as the initial manifestation of moyamoya syndrome. A 52-year-old woman was admitted with a subarachnoid hemorrhage with associated flame-shaped intracerebral hemorrhage in the left frontal lobe. Physical examination revealed short stature, pectus excavatum, small fingers, micrognathia, and mild facial dysmorphism. Cerebral angiography showed features consistent with bilateral moyamoya disease, aberrant intrathoracic vessels, and an unruptured 4-mm right superior hypophyseal aneurysm. Genetic analysis confirmed a diagnosis of mosaic Turner syndrome. Our case report is the first documented presentation of adult moyamoya syndrome with subarachnoid and intracerebral hemorrhage as the initial presentation of mosaic Turner syndrome. It illustrates the utility of genetic evaluation in patients with cerebrovascular disease and dysmorphism.


Assuntos
Hemorragia Cerebral/etiologia , Mosaicismo , Doença de Moyamoya/complicações , Acidente Vascular Cerebral/etiologia , Hemorragia Subaracnóidea/etiologia , Síndrome de Turner/complicações , Doenças Assintomáticas , Angiografia Cerebral/métodos , Hemorragia Cerebral/diagnóstico , Feminino , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Doença de Moyamoya/diagnóstico , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Hemorragia Subaracnóidea/diagnóstico , Tomografia Computadorizada por Raios X , Síndrome de Turner/diagnóstico , Síndrome de Turner/genética
6.
World Neurosurg ; 181: e399-e404, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37852472

RESUMO

BACKGROUND: Transradial access is an important tool for many neuroendovascular procedures. Occlusion of the radial or ulnar artery is not uncommon after transradial or transulnar access and can present a challenge for patients requiring repeat angiography. METHODS: Between March 2022 and June 2023, patients undergoing transradial or transulnar angiography who were found to have a radial artery occlusion or ulnar artery occlusion were identified. Repeat catheterization of the occluded artery was attempted using a 21-gauge single wall puncture needle and a 0.021-inch wire to traverse the occlusion and insert a 23-cm sheath into the brachial artery. RESULTS: A total of 25 patients undergoing 26 angiograms during the study period were found to have a radial artery occlusion or ulnar artery occlusion. Successful repeat catheterization of the occluded artery was achieved in 21 of 26 cases (80.7%). Outer diameter sheath size ranged from 5 Fr (0.0655 inch) to 8 Fr (0.1048 inch). No access complications were encountered. Number of prior angiograms, time since prior angiogram, and prior angiogram procedure time were associated with lower likelihood of successful access. CONCLUSIONS: Transradial or transulnar neuroangiography through an occluded radial or ulnar artery is safe and feasible by traversing the occlusion into the brachial artery with a 23-cm sheath. Repeat catheterization is most successful in patients with an arterial occlusion <6 months old. This technique is important in patients who have limited options for arterial access, avoiding access site complications inherent in transfemoral access, and in patients who specifically require radial or ulnar artery access.


Assuntos
Arteriopatias Oclusivas , Artéria Ulnar , Humanos , Lactente , Artéria Ulnar/diagnóstico por imagem , Artéria Ulnar/cirurgia , Artéria Braquial/cirurgia , Angiografia , Artéria Radial/cirurgia , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/cirurgia , Arteriopatias Oclusivas/etiologia , Angiografia Coronária/métodos
7.
Gynecol Oncol ; 131(3): 503-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24060416

RESUMO

OBJECTIVE: Ovarian cancer accounts for 50% of deaths from gynecologic malignancies. We sought to determine the cost of common methods of surveillance of women with ovarian cancer in first clinical remission. The current standard for post treatment surveillance is the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: We retrospectively determined how recurrence was initially detected at our institution and a cost model was created and applied to the United States population to calculate surveillance costs using the Surveillance Epidemiology & End Results (SEER) database. RESULTS: 57% (n=60) of first recurrences were identified by increasing CA 125 level. Routine office visit identified 27% (n=29) of recurrences, and 15% (n=16) were diagnosed initially with CT scan. In 5% (5/105), CT abnormality was the only finding. 95% (100/105) of patients had either elevated CA 125 or office visit findings at time of recurrence. Of the 22,000 women diagnosed with ovarian cancer yearly, 60% (n=13,266) will have advanced disease and are likely to recur. The surveillance cost for this population for 2 years using our model is $32,500,000 using NCCN guidelines and $58,000,000 if one CT scan is obtained. CONCLUSIONS: Our data suggests that following NCCN guidelines will detect 95% of recurrences. An additional $26 million will be needed to identify the 5% of women with recurrence seen on CT only. Post treatment surveillance of ovarian cancer patients contributes significantly to health care costs. Use of CT scan to follow these patients largely increases cost with only a small increase in recurrence detection.


Assuntos
Antígeno Ca-125/análise , Proteínas de Membrana/análise , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/economia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Diagnóstico por Imagem/economia , Diagnóstico por Imagem/métodos , Intervalo Livre de Doença , Feminino , Custos de Cuidados de Saúde , Humanos , Pessoa de Meia-Idade , Modelos Econômicos , Exame Físico/economia , Exame Físico/métodos , Vigilância da População , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Programa de SEER , Estados Unidos
8.
J Neurointerv Surg ; 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38124221

RESUMO

Transvenous access is a necessary tool for numerous cerebrovascular pathologies.Transvenous access in the arm offers several benefits compared with transfemoral access, including patient comfort, the avoidance of transfemoral access complications, and the ability to close both radial arterial access and distal arm venous access with a single transradial compression band.1In this video we describe the indications, technical nuances, benefits, and limitations of transvenous access in the arm.neurintsurg;jnis-2023-020996v1/V1F1V1Video 1- Combined venous and arterial access in the arm for treatment of a complex dural arteriovenous fistulaWe present the case of a young patient who presented with pulsatile tinnitus and was found to have a Cognard type IIa dural arteriovenous fistula near the left transverse sigmoid junction.The patient was treated with transvenous embolization via the distal right basilic vein, and a single radial compression band served to close both the arterial and venous access sites.

9.
JCI Insight ; 8(13)2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37252795

RESUMO

Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.


Assuntos
Glioblastoma , Fatores Inibidores da Migração de Macrófagos , Humanos , Lactoferrina/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Glioblastoma/genética , Regiões Promotoras Genéticas , Microambiente Tumoral/genética , Oxirredutases Intramoleculares/genética
10.
Neurosurgery ; 90(6): 684-690, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35311745

RESUMO

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. OBJECTIVE: To compare LITT vs medical management (MM) in the treatment of RN. METHODS: A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. RESULTS: Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). CONCLUSION: These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.


Assuntos
Neoplasias Encefálicas , Terapia a Laser , Lesões por Radiação , Radiocirurgia , Biópsia , Neoplasias Encefálicas/patologia , Humanos , Terapia a Laser/efeitos adversos , Terapia a Laser/métodos , Lasers , Necrose/etiologia , Necrose/cirurgia , Recidiva Local de Neoplasia/cirurgia , Estudos Prospectivos , Lesões por Radiação/terapia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Estudos Retrospectivos , Esteroides/uso terapêutico , Resultado do Tratamento
11.
Neurooncol Adv ; 4(1): vdac086, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795470

RESUMO

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

12.
Neurosurg Clin N Am ; 32(1): 105-115, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33223019

RESUMO

The previous decade has seen an expansion in the use of laser interstitial thermal therapy (LITT) for a variety of pathologies. LITT has been used to treat both newly diagnosed and recurrent glioblastoma (GBM), especially in deep-seated, difficult-to-access lesions where open resection is otherwise infeasible or in patients who would not tolerate craniotomy. This review aims to describe the current state of the technology and operative technique, as well as summarize the outcomes data and future research regarding LITT as a treatment of GBM.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Terapia a Laser/métodos , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Técnicas Estereotáxicas , Resultado do Tratamento
13.
Cancers (Basel) ; 13(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572751

RESUMO

Glioblastoma (GBM) is the most common primary brain tumor in adults, with few available therapies and a five-year survival rate of 7.2%. Hence, strategies for improving GBM prognosis are urgently needed. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. High TSPO gene expression is associated with reduced survival in GBM patients; however, the relation between the most frequent TSPO genetic variant and GBM pathogenesis is not known. The present study retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. TSPO rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort of 441 patients. We observed similar trends in two other independent cohorts. These observations suggest that the TSPO rs6971 polymorphism could be a significant predictor of poor prognosis in GBM, with a potential for use as a prognosis biomarker in GBM patients. These results reveal for the first time a biological sex-specific relation between rs6971 TSPO polymorphism and GBM.

14.
Clin Cancer Res ; 27(7): 2038-2049, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33542075

RESUMO

PURPOSE: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment-including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment-has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined. EXPERIMENTAL DESIGN: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM. RESULTS: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles. CONCLUSIONS: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Idoso , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Carga Tumoral
15.
Front Immunol ; 11: 1191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32625208

RESUMO

The application of tumor immunotherapy to glioblastoma (GBM) is limited by an unprecedented degree of immune suppression due to factors that include high numbers of immune suppressive myeloid cells, the blood brain barrier, and T cell sequestration to the bone marrow. We previously identified an increase in immune suppressive myeloid-derived suppressor cells (MDSCs) in GBM patients, which correlated with poor prognosis and was dependent on macrophage migration inhibitory factor (MIF). Here we examine the MIF signaling axis in detail in murine MDSC models, GBM-educated MDSCs and human GBM. We found that the monocytic subset of MDSCs (M-MDSCs) expressed high levels of the MIF cognate receptor CD74 and was localized in the tumor microenvironment. In contrast, granulocytic MDSCs (G-MDSCs) expressed high levels of the MIF non-cognate receptor CXCR2 and showed minimal accumulation in the tumor microenvironment. Furthermore, targeting M-MDSCs with Ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, reduced MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. These findings demonstrate the MDSC subsets differentially express MIF receptors and may be leveraged for specific MDSC targeting.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Células Supressoras Mieloides/imunologia , Receptores Imunológicos/imunologia , Evasão Tumoral/imunologia , Animais , Humanos , Imunoterapia/métodos , Fatores Inibidores da Migração de Macrófagos/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Piridinas/farmacologia , Receptores Imunológicos/metabolismo , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Cancer Discov ; 10(8): 1210-1225, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32300059

RESUMO

Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1ß blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1ß gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.See related commentary by Gabrilovich et al., p. 1100.This article is highlighted in the In This Issue feature, p. 1079.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células Supressoras Mieloides , Caracteres Sexuais , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Imunoterapia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Supressoras Mieloides/efeitos dos fármacos , Linfócitos T/imunologia , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
17.
JCI Insight ; 4(22)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31600167

RESUMO

BACKGROUNDMyeloid-derived suppressor cells (MDSCs) are elevated in the circulation of patients with glioblastoma (GBM), present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.METHODSA phase 0/I dose-escalation clinical trial was conducted in patients with recurrent GBM treated 5-7 days before surgery with low-dose chemotherapy via capecitabine, followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multiparameter flow cytometry, and tumor tissue immune profiles were assessed via time-of-flight mass cytometry.RESULTSEleven patients total were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared with pretreatment baseline, circulating MDSCs were found to be higher after surgery in the 150-mg treatment arm and lower in the 300-mg and 450-mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared with untreated GBM patients in the 300-mg and 450-mg treatment arms.CONCLUSIONSLow-dose, metronomic capecitabine in combination with bevacizumab was well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.TRIAL REGISTRATIONClinicalTrials.gov NCT02669173.FUNDINGThis research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, the Musella Foundation, B*CURED, the NIH, the National Cancer Institute, the Sontag Foundation, Blast GBM, the James B. Pendleton Charitable Trust, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Capecitabine was provided in kind by Mylan Pharmaceuticals.


Assuntos
Antineoplásicos Imunológicos , Capecitabina , Glioblastoma/tratamento farmacológico , Células Supressoras Mieloides/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/efeitos dos fármacos
18.
Int J Surg Case Rep ; 23: 47-51, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27086272

RESUMO

INTRODUCTION: Haemangioblastoma has been uncommonly reported to occur in coexistence either temporally or spatially with the development of an arteriovenous malformations (AVM). We present a case of a delayed AVM following haemangioblastoma resection. PRESENTATION OF CASE: 44 year old female initially presented with a several week history of headaches, vertigo and nausea and emesis and was found to have a cystic lesion with a solid enhancing component on Magnetic Resonance Imaging (MRI) in the superior aspect of the vermis. She underwent gross total resection and final pathology was consistent with WHO grade I haemangioblastoma. One year later, patient re-presented with headaches, dizziness and left trochlear nerve palsy with rotary nystagmus. Imaging revealed a left posterior tentorial paramedian cerebellar vascular nidus with venous drainage into the left transverses sinus suspicious for arteriovenous malformation. She underwent gross total resection of the lesion. Final pathology confirmed the diagnosis of an arteriovenous malformation. DISCUSSION: Recent research supports both haemangioblastoma and AVM are of embryologic origin but require later genetic alterations to develop into symptomatic lesions. It is unclear in our case if the AVM was present at the time of the initial haemangioblastoma resection or developed de novo after tumor resection. However, given the short time between tumor resection and presentation of AVM, de novo AVM although possible, appears less likely. CONCLUSION: AVM and haemangioblastoma rarely presents together either temporally or spatially. We present a case of a delayed AVM following haemangioblastoma resection. More research is needed to elucidate the rare intermixture of these lesions.

19.
Neuro Oncol ; 18(5): 656-66, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26374689

RESUMO

BACKGROUND: Cancer stem cells (CSCs) provide an additional layer of complexity for tumor models and targets for therapeutic development. The balance between CSC self-renewal and differentiation is driven by niche components including adhesion, which is a hallmark of stemness. While studies have demonstrated that the reduction of adhesion molecules, such as integrins and junctional adhesion molecule-A (JAM-A), decreases CSC maintenance. The molecular circuitry underlying these interactions has yet to be resolved. METHODS: MicroRNA screening predicted that microRNA-145 (miR-145) would bind to JAM-A. JAM-A overexpression in CSCs was evaluated both in vitro (proliferation and self-renewal) and in vivo (intracranial tumor initiation). miR-145 introduction into CSCs was similarly assessed in vitro. Additionally, The Cancer Genome Atlas dataset was evaluated for expression levels of miR-145 and overall survival of the different molecular groups. RESULTS: Using patient-derived glioblastoma CSCs, we confirmed that JAM-A is suppressed by miR-145. CSCs expressed low levels of miR-145, and its introduction decreased self-renewal through reductions in AKT signaling and stem cell marker (SOX2, OCT4, and NANOG) expression; JAM-A overexpression rescued these effects. These findings were predictive of patient survival, with a JAM-A/miR-145 signature robustly predicting poor patient prognosis. CONCLUSIONS: Our results link CSC-specific niche signaling to a microRNA regulatory network that is altered in glioblastoma and can be targeted to attenuate CSC self-renewal.


Assuntos
Neoplasias Encefálicas/patologia , Moléculas de Adesão Celular/metabolismo , Adesão Celular/fisiologia , Glioblastoma/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores de Superfície Celular/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Immunoblotting , Camundongos , Células-Tronco Neoplásicas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
20.
Neuro Oncol ; 17(3): 361-71, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25416826

RESUMO

BACKGROUND: Malignant gliomas are complex systems containing a number of factors that drive tumor initiation and progression, including genetic aberrations that lead to extensive cellular heterogeneity within the neoplastic compartment. Mouse models recapitulate these genetic aberrations, but readily observable heterogeneity remains challenging. METHODS: To interrogate cellular heterogeneity in mouse glioma models, we utilized a replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS-tva) system to generate spontaneous mouse gliomas that contained a Sox2-enhanced green fluorescent protein (EGFP) reporter. Glial fibrillary acidic protein-tva mice were crossed with Sox2-EGFP mice, and tumors were initiated that contained a subpopulation of Sox2-EGFP-high cells enriched for tumor-initiating cell properties such as self-renewal, multilineage differentiation potential, and perivascular localization. RESULTS: Following implantation into recipient mice, Sox2-EGFP-high cells generated tumors containing Sox2-EGFP-high and Sox2-EGFP-low cells. Kinomic analysis of Sox2-EGFP-high cells revealed activation of known glioma signaling pathways that are strongly correlated with patient survival including platelet-derived growth factor receptor beta, phosphoinositide-3 kinase, and vascular endothelial growth factor. Our functional analysis identified active feline sarcoma (Fes) signaling in Sox2-EGFP-high cells. Fes negatively correlated with glioma patient survival and was coexpressed with Sox2-positive cells in glioma xenografts and primary patient-derived tissue. CONCLUSIONS: Our RCAS-tva/Sox2-EGFP model will empower closer examination of cellular heterogeneity and will be useful for identifying novel glioma pathways as well as testing preclinical treatment efficacy.


Assuntos
Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Genes Reporter , Glioma/patologia , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição SOXB1/genética , Animais , Vírus da Leucose Aviária/genética , Vírus do Sarcoma Aviário/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/virologia , Vetores Genéticos , Glioma/genética , Glioma/metabolismo , Glioma/virologia , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
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