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1.
N Engl J Med ; 383(13): 1204-1205, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32966721
2.
Clinics (Sao Paulo) ; 75: e1553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935821

RESUMO

OBJECTIVES: To assess the patterns of failure and prognostic factors in Brazilian patients with glioblastoma multiforme (GBM) treated with radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with diagnosed GBM post-resection received postoperative RT. TMZ was administered concurrently at 75 mg/m2/day for 28 consecutive days and adjuvant therapy at 150-200 mg/m2/day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement inside of the radiation field. When possible, patients with recurrence were salvaged with metronomic TMZ, either in combination with a local treatment or alone (surgery or re-irradiation). Several prognostic factors were evaluated for overall survival (OS). Univariate and multivariate analyses were performed to identify significant factors. A p-value <0.05 was considered significant. RESULTS: This study included 50 patients. The median follow-up time was 21 months. The median RT dose was 60 Gy and all patients received concomitant TMZ. During follow-up, 41 (83.6%) failures were observed, including 34 (83%) in-field, 4 (9.7%) marginal, and 3 (7.3%) distant failures. Metronomic TMZ was used as salvage treatment in 22 (44%) cases and in combination with local treatment in 12 (24%) cases. The median OS and progression-free survival times for the entire cohort were 17 and 9 months, respectively. In univariate analysis, the following factors were significant for better OS: maximal surgical resection (p=0.03), Karnofsky Performance Score (KPS)>70 at diagnosis (p=0.01), metronomic TMZ treatment (p=0.038), recursive partitioning analysis class III (p=0.03), and time to failure >9 months (p=0.0001). In multivariate analysis, the following factors remained significant for better OS: metronomic TMZ (p=0.01) and time to failure >9 months (p=0.0001). CONCLUSION: The median OS of Brazilian patients with GBM treated with RT and TMZ was satisfactory. Although TMZ therapy has become the standard of care for patients with newly diagnosed GBM, the recurrence rate is extremely high. Metronomic TMZ as salvage treatment improved survival in these patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/patologia , Brasil/epidemiologia , Quimioterapia Adjuvante , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Estudos Retrospectivos , Sobrevida , Resultado do Tratamento
3.
Cancer Treat Rev ; 89: 102083, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32736188

RESUMO

Melanoma brain metastases (MBM) are common and associated with a particularly poor prognosis; they directly cause death in 60-70% of melanoma patients. In the past, systemic treatments have shown response rates around 5%, whole brain radiation as standard of care has achieved a median overall survival of approximately three months. Recently, the combination of immune checkpoint inhibitors and combinations of MAP-kinase inhibitors both have shown very promising response rates of up to 55% and 58%, respectively, and improved survival. However, current clinical evidence is based on multi-cohort studies only, as prospectively randomized trials have been carried out rarely in MBM, independently whether investigating systemic therapy, radiotherapy or surgical techniques. Here, an interdisciplinary expert team reviewed the outcome of prospectively conducted clinical studies in MBM, identified evidence gaps and provided recommendations for the diagnosis, treatment, outcome evaluation and monitoring of MBM patients. The recommendations refer to four distinct scenarios: patients (i) with 'brain-only' disease, (ii) with oligometastatic asymptomatic intra- and extracranial disease, (iii) with multiple asymptomatic metastases, and (iv) with multiple symptomatic MBM or leptomeningeal disease. Changes in current management recommendations comprise the use of immunotherapy - preferably combined anti-CTLA-4/PD-1-immunotherapy - in asymptomatic MBM minus/plus stereotactic radiosurgery which remains the mainstay of local brain therapy being safe and effective. Adjuvant whole-brain radiotherapy provides no clinical benefit in oligometastatic MBM. Among the systemic therapies, combined MAPK-kinase inhibition provides, in BRAFV600-mutated patients with rapidly progressing or/and symptomatic MBM, an alternative to combined immunotherapy.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Melanoma/patologia , Melanoma/terapia , Animais , Neoplasias Encefálicas/diagnóstico , Ensaios Clínicos como Assunto , Estudos de Coortes , Terapia Combinada , Humanos , Melanoma/diagnóstico , Equipe de Assistência ao Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
4.
Ann Hematol ; 99(10): 2367-2375, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32816079

RESUMO

This study aimed to define the maximum tolerated dose (MTD) of temozolomide (TMZ) concurrent with radiotherapy (RT) after high-dose methotrexate (HD-MTX) for newly diagnosed primary central nervous system lymphoma (PCNSL). Adult patients with PCNSL were treated according to a response-adapted strategy. HD-MTX (3.5 g/m2) was followed by concomitant RT and escalating TMZ (50-60-75 mg/m2/day, 5 days/week). The total radiation dose was modulated according to the patient's response to HD-MTX. All patients received 30 Gy to the whole brain plus leptomeninges to C2, including the third posterior of the orbital cavity (clinical target volume 2; CTV2), plus 6, 10, or 16 Gy to the primary site, including the residual mass (CTV1), if a complete response (CR), partial response (PR)/stable disease (SD), or progressive disease (PD) was observed, respectively. Acute toxicities were graded according to the RTOG-EORTC criteria. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity or grade 3-4 hepatic toxicity, although 75 mg/m2/day was the maximum dose regardless of DLT. Neurocognitive function was evaluated using the Mini-Mental State Examination. Three patients were enrolled at each TMZ dose level (total = 9 patients). Twelve lesions were treated. Six patients received 2 cycles of HD-MTX, while 3 received only 1 cycle because of hepatic or renal toxicity. All patients completed chemoradiotherapy without interruptions. No DLT events were recorded. TMZ appears to be tolerable at a dose of 75 mg/m2/day when administered concomitantly with radiotherapy and after HD-MTX.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Irradiação Craniana , Linfoma não Hodgkin/terapia , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Quimioterapia Adjuvante , Transtornos Cognitivos/induzido quimicamente , Quimioterapia de Consolidação , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Masculino , Dose Máxima Tolerável , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Neoplasia Residual , Intervalo Livre de Progressão , Estudos Prospectivos , Temozolomida/efeitos adversos , Adulto Jovem
5.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
6.
Life Sci ; 258: 118152, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735881

RESUMO

AIMS: Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS: The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE: These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Nanofibras/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Glioma/patologia , Humanos , Hipertermia Induzida/métodos , Masculino , Camundongos Endogâmicos BALB C , Nanofibras/química , Nanotubos de Carbono/química , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/patologia , Poliésteres/química , Poliésteres/uso terapêutico , Tretinoína/administração & dosagem
7.
Nat Commun ; 11(1): 3288, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620753

RESUMO

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Isocitrato Desidrogenase/genética , Proteogenômica/métodos , Proteômica/métodos , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase/classificação , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Morfolinas/farmacologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
8.
Nat Commun ; 11(1): 3406, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641768

RESUMO

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Glioblastoma/genética , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Adulto , Animais , Antineoplásicos Alquilantes/farmacologia , Encéfalo/embriologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Feminino , Feto , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Análise de Célula Única/métodos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Crit Rev Oncol Hematol ; 153: 103062, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32717623

RESUMO

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.


Assuntos
Astrocitoma/diagnóstico , Astrocitoma/genética , Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Glioblastoma , Glioma , Humanos , Mutação , Recidiva Local de Neoplasia
10.
Nat Commun ; 11(1): 2978, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Monoacilglicerol Lipases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Células Cultivadas , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Monoacilglicerol Lipases/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Interferência de RNA , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Nat Commun ; 11(1): 3015, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541784

RESUMO

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6ß1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/ß-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/ß-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Sinalização Intercelular CCN/genética , Glioma/genética , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Sinalização Intercelular CCN/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Glioma/metabolismo , Glioma/terapia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Anticancer Res ; 40(6): 3453-3457, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487644

RESUMO

BACKGROUND/AIM: Gliomas present a uniquely challenging clinical situation in the context of pregnancy, with no standard recommendations. This case series aimed to describe the treatment regimen and outcomes of five pregnant patients with gliomas. PATIENTS AND METHODS: This is a retrospective study. A patient database from electronic medical records was evaluated to identify pregnant patients with gliomas treated at our institution between 2008-2018. RESULTS: Five study patients who were pregnant with gliomas were identified. Of these, 4 were diagnosed during pregnancy, while 1 was diagnosed prior to her pregnancy. One patient had grade 2 astrocytoma, 1 had grade 3 anaplastic astrocytoma, and 3 had grade 4 glioblastomas (GBM). All patients received surgery, and one patient received radiation therapy without concurrent chemotherapy during her pregnancy. All delivered healthy babies. Three of the 5 patients remain alive, and 2 of the 5 were progression-free at the last follow-up. CONCLUSION: Treatment plans must be specifically tailored to the individual patient based on the glioma grade, the mother's desire to continue the pregnancy, and the risks of delaying treatment until after pregnancy. Additional studies need to be performed to definitively establish uniform guidelines for the treatment of pregnant patients with glioma.


Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Biomarcadores , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/terapia , Terapia Combinada , Feminino , Glioma/etiologia , Glioma/terapia , Humanos , Imagem por Ressonância Magnética , Mutação , Gradação de Tumores , Gravidez
13.
Anticancer Res ; 40(6): 3231-3237, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487617

RESUMO

BACKGROUND/AIM: We previously established a novel type of epidermal growth factor receptor variant III (EGFRvIII)-specific chimeric antigen receptor (CAR)-expressing natural killer (NK) cell line, designated EvCAR-KHYG-1, which inhibited the growth of glioblastoma (GBM) cells in vitro via apoptosis. MATERIALS AND METHODS: We investigated the cytokine-producing effect of EvCAR-KHYG-1 cells on GBM-like cell lines and their antitumour effect using in vivo xenograft assays. RESULTS: EvCAR-KHYG-1 cells produced interleukin-2, interferon-γ, and tumour necrosis factor-α on EGFRvIII-expressing U87MG cells. In vivo xenograft assays showed that EvCAR-KHYG-1 cells did not reduce the volume of subcutaneous tumours derived from EGFRvIII-expressing U87MG cells but did reduce tumour cell occupancy. CONCLUSION: EvCAR-KHYG-1 cells led to expression of cellular immunity-related cytokines on EGFRvIII-expressing U87MG in vitro but did not inhibit tumour progression due to the induction of a pseudo progression-like pathological feature. Future studies investigating the effect of different conditions in vivo are required to study the inhibition of tumour progression in GBM.


Assuntos
Neoplasias Encefálicas/terapia , Receptores ErbB/imunologia , Glioblastoma/terapia , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Citocinas/imunologia , Progressão da Doença , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Células HEK293 , Humanos , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Distribuição Aleatória , Receptores de Antígenos Quiméricos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Medicine (Baltimore) ; 99(24): e20223, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541449

RESUMO

INTRODUCTION: At present, there is no uniform consensus on the treatment of brain metastases from esophageal cancer. The studies on the treatment of brain metastases from esophageal cancer by radiotherapy combined with temozolomide (TMZ) are even rarer. PATIENT CONCERNS: A 69-year-old woman was admitted to our hospital for brain metastases from esophageal cancer after thoracic irradiation. DIAGNOSES: Magnetic resonance imaging of the head showed a round, heterogeneous metastatic tumor in the left parietal lobe. Brain magnetic resonance imaging showed edema around brain metastasesInterventions: After radiotherapy plus TMZ in this patient's head, the brain metastatic tumor was significantly decreased. OUTCOMES: At the end of radiotherapy, and 1 and 2 months after the end of radiotherapy, the metastatic tumor continued to shrink, and no obvious side effects were observed. LESSONS: This study suggests that radiotherapy plus TMZ might be a feasible option for brain metastases from esophageal cancer.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Esofágicas/patologia , Temozolomida/uso terapêutico , Administração Oral , Assistência ao Convalescente , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Terapia Combinada/métodos , Neoplasias Esofágicas/radioterapia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Metástase Neoplásica/patologia , Radioterapia/métodos , Temozolomida/administração & dosagem , Resultado do Tratamento
15.
Arch Biochem Biophys ; 689: 108462, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32590068

RESUMO

Silver nanoparticles (AgNP) emerged as a promising reagent for cancer therapy with oxidative stress implicated in the toxicity. Meanwhile, studies reported cold atmospheric plasma (CAP) generation of reactive oxygen and nitrogen species has selectivity towards cancer cells. Gold nanoparticles display synergistic cytotoxicity when combined with CAP against cancer cells but there is a paucity of information using AgNP, prompting to investigate the combined effects of CAP using dielectric barrier discharge system (voltage of 75 kV, current is 62.5 mA, duty cycle of 7.5kVA and input frequency of 50-60Hz) and 10 nm PVA-coated AgNP using U373MG Glioblastoma Multiforme cells. Cytotoxicity in U373MG cells was >100-fold greater when treated with both CAP and PVA-AgNP compared with either therapy alone (IC50 of 4.30 µg/mL with PVA-AgNP alone compared with 0.07 µg/mL after 25s CAP and 0.01 µg/mL 40s CAP). Combined cytotoxicity was ROS-dependent and was prevented using N-Acetyl Cysteine. A novel darkfield spectral imaging method investigated and quantified AgNP uptake in cells determining significantly enhanced uptake, aggregation and subcellular accumulation following CAP treatment, which was confirmed and quantified using atomic absorption spectroscopy. The results indicate that CAP decreases nanoparticle size, decreases surface charge distribution of AgNP and induces uptake, aggregation and enhanced cytotoxicity in vitro.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Gases em Plasma/farmacologia , Prata/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Nanopartículas Metálicas/análise , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacocinética
16.
ESMO Open ; 4(Suppl 2)2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-360021

RESUMO

The COVID-19 pandemic has created major insecurities regarding whether we can and should maintain the current standards of diagnosis and treatment and access to care for patients with cancer. This is particularly true in the field of neuro-oncology, where the perceived benefit of therapeutic interventions is often low, although this notion is partially incorrect. We acknowledge that the recommendations for care of patients with cancer have become a moving target and that all recommendations are subject to modification based on national and institutional regulations. Still, some important considerations and proposals may apply broadly. First, it is important to note that old age and cardiovascular and pulmonary co-morbidities are the major risk factors for experiencing a severe course of and for dying of COVID-19, not chronic immunosuppression and cancer. Second, many of the considerations on how we should adapt clinical practice in neuro-oncology in view of COVID-19 that are now dominating discussions at local tumour boards, as well as on the institutional level and within societies of neuro-oncology, are not novel but have been valid before and only now have become a priority. More than ever, it seems to be mandatory to adhere to evidence-based medicine and not to prescribe potentially toxic, notably immunsuppresssive systemic therapy where evidence for efficacy is low. Furthermore, it is more obvious now that oncologists must not miss the right time for advance care planning, that is, supporting patients in understanding and sharing their personal values, life goals and preferences regarding future medical care. The major psychological impact of transforming oncology care to teleconferences and videoconferences and of the important strict recommendation of social distancing must not be overlooked in a patient population that is characterised by significant prevalence of cognitive decline and by the general perception that their life span may not exceed the life span of the COVID-19 pandemic.


Assuntos
Neoplasias Encefálicas/terapia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus/isolamento & purificação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/virologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Humanos , Oncologia/métodos , Oncologia/normas , Pandemias , Pneumonia Viral/complicações , Guias de Prática Clínica como Assunto
18.
ESMO Open ; 4(Suppl 2)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32409298

RESUMO

The COVID-19 pandemic has created major insecurities regarding whether we can and should maintain the current standards of diagnosis and treatment and access to care for patients with cancer. This is particularly true in the field of neuro-oncology, where the perceived benefit of therapeutic interventions is often low, although this notion is partially incorrect. We acknowledge that the recommendations for care of patients with cancer have become a moving target and that all recommendations are subject to modification based on national and institutional regulations. Still, some important considerations and proposals may apply broadly. First, it is important to note that old age and cardiovascular and pulmonary co-morbidities are the major risk factors for experiencing a severe course of and for dying of COVID-19, not chronic immunosuppression and cancer. Second, many of the considerations on how we should adapt clinical practice in neuro-oncology in view of COVID-19 that are now dominating discussions at local tumour boards, as well as on the institutional level and within societies of neuro-oncology, are not novel but have been valid before and only now have become a priority. More than ever, it seems to be mandatory to adhere to evidence-based medicine and not to prescribe potentially toxic, notably immunsuppresssive systemic therapy where evidence for efficacy is low. Furthermore, it is more obvious now that oncologists must not miss the right time for advance care planning, that is, supporting patients in understanding and sharing their personal values, life goals and preferences regarding future medical care. The major psychological impact of transforming oncology care to teleconferences and videoconferences and of the important strict recommendation of social distancing must not be overlooked in a patient population that is characterised by significant prevalence of cognitive decline and by the general perception that their life span may not exceed the life span of the COVID-19 pandemic.


Assuntos
Neoplasias Encefálicas/terapia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus/isolamento & purificação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/virologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Humanos , Oncologia/métodos , Oncologia/normas , Pandemias , Pneumonia Viral/complicações , Guias de Prática Clínica como Assunto
19.
Pediatr Blood Cancer ; 67(7): e28379, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32383818

RESUMO

BACKGROUND: Hypothalamic obesity causes unrelenting weight gain for childhood brain tumor survivors. No single therapy has proven effective for treatment. We aimed to evaluate effectiveness of long-term methylphenidate therapy on body mass index (BMI) change in children with hypothalamic obesity. METHODS: A retrospective analysis included children with a history of brain tumor and hypothalamic obesity receiving methylphenidate (10-60 mg/day) for hypothalamic obesity. Subjects were evaluated for BMI trajectory before and after methylphenidate start. Given that z-scores can be skewed in severely obese children, we calculated BMI as a percent of the BMI at the 95th percentile for the child's age and gender (BMI% 95th). RESULTS: Twelve patients with hypothalamic obesity completed methylphenidate therapy for at least 6 months (median 3.1 years, range 1.0-5.8 years). All subjects had a suprasellar tumor (nine [75%] with craniopharyngioma) and pituitary dysfunction. Pretreatment median BMI percent of the 95th percentile was 125.6% (interquartile range [IQR] 25-75: 115.3-138.3%) with BMI z-score of 2.4 (IQR 25-75: 2.1-2.6). Following methylphenidate treatment, there was a 69.9% reduction in the median slope of BMI change. Eleven of 12 patients (92%) had a reduction in the slope of their BMI change on methylphenidate treatment. Postmethylphenidate median BMI percent of the 95th percentile decrease to 115.2% (IQR 25-75: 103.6-121.2%) with median BMI z-score of 2.1 (IQR 25-75: 1.8-2.2). Mild side effects were noted in six patients. CONCLUSIONS: Methylphenidate use reduced and sustained BMI change in children with hypothalamic obesity. Stimulant therapy is an effective first-line agent for treatment of hypothalamic obesity.


Assuntos
Neoplasias Encefálicas/complicações , Sobreviventes de Câncer/estatística & dados numéricos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Doenças Hipotalâmicas/tratamento farmacológico , Metilfenidato/uso terapêutico , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/etiologia , Masculino , Obesidade/diagnóstico , Obesidade/etiologia , Prognóstico , Estudos Retrospectivos
20.
BMC Neurol ; 20(1): 178, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393192

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. CASE PRESENTATION: Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. CONCLUSIONS: Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Glioblastoma/secundário , Gliossarcoma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Coluna Vertebral/secundário , Antineoplásicos Alquilantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Craniotomia , Evolução Fatal , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Terapia com Prótons , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Temozolomida/uso terapêutico , Tomografia Computadorizada por Raios X
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