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2.
J Neurol Surg A Cent Eur Neurosurg ; 81(1): 48-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31550737

RESUMO

BACKGROUND: World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking. METHODS: The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol. RESULTS: We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma. CONCLUSION: The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG. TRIAL REGISTRATION: NCT02686229 Clinical trials.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Isocitrato Desidrogenase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Progressão da Doença , Feminino , Glioma/genética , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Qualidade de Vida , Sistema de Registros , Adulto Jovem
3.
Cell Oncol (Dordr) ; 42(3): 287-301, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859392

RESUMO

PURPOSE: Anti-apoptotic and pro-migratory phenotypes are hallmarks of neoplastic diseases, including primary brain malignancies. In this work, we examined whether reprogramming of the apoptotic and migratory machineries through a multi-targeting approach would induce enhanced cell death and enhanced inhibition of the migratory capacity of glioblastoma cells. METHODS: Preclinical testing and molecular analyses of combined inhibition of Bcl-2/Bcl-xL and RAC1 were performed in established, primary cultured and stem-like glioblastoma cell systems. RESULTS: We found that the combined inhibition of Bcl-2/Bcl-xL and RAC1 resulted in synergistic pro-apoptotic and anti-migratory effects in a broad range of different glioblastoma cells. At the molecular level, we found that RAC1 inhibition led to a decreased expression of the deubiquitinase Usp9X, followed by a decreased stability of Mcl-1. We also found that the combined inhibition led to a significantly decreased migratory activity and that tumor formation of glioblastoma cells on chorion allantoic membranes of chicken embryos was markedly impaired following the combined inhibition. CONCLUSIONS: Our data indicate that concomitant inhibition of RAC1 and Bcl-2/Bcl-xL induces pro-apoptotic and anti-migratory glioblastoma phenotypes as well as synergistic anti-neoplastic activities. The clinical efficacy of this inhibitory therapeutic strategy warrants further evaluation.


Assuntos
Compostos de Anilina/farmacologia , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Sulfonamidas/farmacologia , Ubiquitina Tiolesterase/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genética , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
4.
Ther Adv Neurol Disord ; 11: 1756285617753597, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29403545

RESUMO

BACKGROUND: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. METHODS: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. RESULTS: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. CONCLUSIONS: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV.

5.
Neurosurg Rev ; 41(1): 207-219, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28265818

RESUMO

The objective of the present study is to assess the influence of extent of resection (EoR), use of intraoperative imaging, and awake surgery on health-related quality of life (HRQoL) in high-grade glioma (HGG) patients in a prospective multicenter study. We analyzed 170 surgeries of patients suffering from a HGG. During the first year after resection, HRQoL was evaluated using the European Organization of Research and Treatment of Cancer Core Questionnaire C30 and Brain Neoplasm 20 questionnaires. We assessed the influence of EoR; awake surgery; and use of 5-aminolevulinic acid (5-ALA), intraoperative MRI (iMRI), and their combination on sum scores for function and symptoms as well as several neurological single items. In mixed-model analyses, adjustments for age, Karnofsky performance status (KPS), and eloquent location were performed. In the mixed model, EoR generally did not significantly influence HRQoL (p = 0.10). Yet, patients receiving subtotal resection (STR) vs. patients with biopsy showed significantly better QoL and role and cognitive functions (p = 0.04, p = 0.02, and p < 0.01, respectively). The combination of iMRI and 5-ALA reached the highest EoR (95%) followed by iMRI alone (94%), 5-ALA alone (74%), and no imaging (73%). Thereby, neurological symptoms were lowest and functioning score highest after combined use of iMRI and 5-ALA, without reaching significance (p = 0.59). Despite lower scores in emotional function (59 vs. 46, p = 0.24), no significant impact of awake surgery on HRQoL was found (p = 0.70). In HGG patients, STR compared to biopsy was significantly associated with better HRQoL and fewer neurological symptoms in this series. An escalated use of intraoperative imaging increased EoR with stable or slightly better HRQoL and fewer neurological symptoms. Based on HRQoL, awake surgery was a well-tolerated and safe method in our series.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Qualidade de Vida , Adulto , Idoso , Ácido Aminolevulínico/uso terapêutico , Biópsia , Neoplasias Encefálicas/patologia , Cognição , Estudos Transversais , Feminino , Glioma/patologia , Humanos , Avaliação de Estado de Karnofsky , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Avaliação de Resultados da Assistência ao Paciente , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Prospectivos , Inquéritos e Questionários , Vigília
6.
Neurosurg Rev ; 38(3): 499-509; discussion 509, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25855197

RESUMO

INTRODUCTION: Linear array intraoperative ultrasound (lioUS) is an emerging technology for intracranial use. We evaluated sensitivity and specificity of lioUS to detect residual tumor in patients harboring a glioblastoma. METHODS: After near total resection in 20 patients, residual tumor detection using lioUS, conventional intraoperative ultrasound (cioUS), and gadopentetic-diethylenetriamine penta-acetic acid (Gd-DTPA)-enhanced intraoperative MRI (iMRI) were compared. Sensitivity and specificity were calculated based on 68 navigated biopsies. Receiver operator characteristic (ROC) curves and correlation with histopathological findings of each imaging modality were calculated. Additionally, results were evaluated in the subgroup of recurrent disease (23 biopsies in 8 patients). RESULTS: Sensitivity of lioUS (76 %) was significantly higher compared with iMRI (55 %) and cioUS (24 %). Specificity of lioUS (58 %) was significantly lower than in cioUS (96 %), while there was no significant difference to iMRI (74 %). All imaging modalities correlated significantly with histopathological findings. In the subgroup of recurrent disease, sensitivity and specificity decreased in all modalities. However, cioUS showed significant lower values than iMRI and lioUS. In ROC curves, lioUS showed a higher area und the curve (AUC) in comparison with iMRI and cioUS. We found similar results in the subgroup of recurrent disease. CONCLUSION: Tumor detection using a lioUS is significantly superior to cioUS. Overall test performance in lioUS is comparable with results of iMRI. While, the latter has a higher specificity and a significantly lower sensitivity in comparison with lioUS.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Imageamento por Ressonância Magnética/métodos , Procedimentos Neurocirúrgicos/métodos , Cirurgia Assistida por Computador/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Biópsia , Feminino , Gadolínio DTPA , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Recidiva Local de Neoplasia , Neuronavegação , Estudos Prospectivos , Reprodutibilidade dos Testes
7.
Acta Neurochir (Wien) ; 157(2): 195-206, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25559430

RESUMO

INTRODUCTION: In low-grade glioma (LGG) surgery, intraoperative differentiation between tumor and most likely tumor-free brain tissue can be challenging. Intraoperative ultrasound can facilitate tumor resection. The aim of this study is to evaluate the accuracy of linear array ultrasound in comparison to conventional intraoperative ultrasound (cioUS) and intraoperative high-field MRI (iMRI). METHODS: We prospectively enrolled 13 patients harboring a LGG of WHO Grade II. After assumed near total removal, a resection control was performed using navigated cioUS, navigated lioUS, and iMRI. We harvested 30 navigated biopsies from the resection cavity and compared the histopathological findings with the respective imaging results. Spearman's rho was calculated to test for significant correlations. Sensitivity and specificity as well as receiver operating characteristics (ROC) were calculated to assess test performance of each imaging modality. RESULTS: Imaging results of lioUS correlated significantly (p < 0.009) with iMRI. Both iMRI and lioUS correlated significantly with final histopathological diagnosis (p < 0.006, p < 0.014). cioUS did not correlate with other imaging findings or with final diagnosis. The highest sensitivity for residual tumor detection was found in iMRI (83 %), followed by lioUS (79 %). The sensitivity of cioUS was only 21 %. Specificity was highest in cioUS (100 %), whereas iMRI and lioUS both achieved 67 %. ROC curves showed fair results for iMRI and lioUS and a poor result for cioUS. CONCLUSIONS: Intraoperative resection control in LGGs using lioUS reaches a degree of accuracy close to iMRI. Test results of lioUS are superior to cioUS. cioUS often fails to discriminate solid tumors from "normal" brain tissue during resection control. Only in lesions <10 cc cioUS does show good accuracy.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Imageamento por Ressonância Magnética/normas , Neuronavegação/normas , Ultrassonografia/normas , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuronavegação/métodos , Sensibilidade e Especificidade , Ultrassonografia/métodos , Adulto Jovem
8.
Int J Cancer ; 136(4): E173-87, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25123598

RESUMO

Glioblastoma is a highly aggressive, common brain tumor with poor prognosis. Therefore, this study examines a new therapeutic approach targeting oncogenic and survival pathways combined with common chemotherapeutics. The RIST (rapamycin, irinotecan, sunitinib, temozolomide) and the variant aRIST (alternative to rapamycin, GDC-0941) therapy delineate growth inhibiting effects in established glioblastoma cell lines and primary cultured patient material. These combinations significantly decreased cell numbers and viability compared to inhibitors and chemotherapeutics alone with aRIST being superior to RIST. Notably, RIST/aRIST appeared to be apoptogenic evoked by reduction of anti-apoptotic protein levels of XIAP and BCL-2, with concomitant up-regulation of pro-apoptotic protein levels of p53 and BAX. The treatment success of RIST therapy was confirmed in an orthotopic mouse model. This combination treatment revealed significantly prolonged survival time and drastically reduced the tumor burden by acting anti-proliferative and pro-apoptotic. Surprisingly, in vivo, aRIST only marginally extended survival time with tumor volumes comparable to controls. We found that aRIST down-regulates the microvessel density suggesting an insufficient distribution of chemotherapy. Further, alterations in different molecular modes of action in vivo than in vitro suggest, that in vivo RIST therapy may mimic the superior aRIST protocol's pro-apoptotic inhibition of pAKT in vitro. Of note, all substances were administered in therapeutically relevant low doses with no adverse side effects observed. We also provide evidence of the potential benefits of the RIST therapy in a clinical setting. Our data indicates RIST therapy as a novel treatment strategy for glioblastoma achieving significant anti-tumorigenic activity avoiding high-dose chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adolescente , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Criança , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Humanos , Indóis/administração & dosagem , Irinotecano , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos NOD , Terapia de Alvo Molecular , Pirróis/administração & dosagem , Sirolimo/administração & dosagem , Sunitinibe , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
9.
World Neurosurg ; 82(3-4): 366-75, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24878624

RESUMO

OBJECTIVE: Conventional curved or sector array ultrasound (cioUS) is the most commonly used intraoperative imaging modality worldwide. Although highly beneficial in various clinical applications, at present the impact of linear array intraoperative ultrasound (lioUS) has not been assessed for intracranial use. We provide a technical description to integrate an independent lioUS probe into a commercially available neuronavigation system and evaluate the use of navigated lioUS as a resection control in glioblastoma surgery. METHODS: We performed a prospective study assessing residual tumor detection after complete microsurgical resection using either cioUS or lioUS in 15 consecutive patients. We compared the imaging findings of both ultrasound modalities in 44 sites surrounding the resection cavity. The respective findings were correlated with the histopathologic findings of tissue specimen obtained from those sites. RESULTS: Use of cioUS leaded to an additional resection in 9 patients, whereas lioUS detected residual tumor during all surgeries. A further resection was performed at 33 of 44 intraoperative sites (75%) based on results of lioUS alone. Resected tissue was solid tumor in 66% and infiltration zone in 34%. No false-positive or false-negative findings were seen using lioUS. There was no case of a tumor detection in cioUS combined with a negative finding in lioUS. The difference of imaging results between cioUS and lioUS was significant (sign test, P<0.001). CONCLUSIONS: lioUS can be used as a safe and precise tool for intracranial image-guided resection control of glioblastomas. It can be integrated in a commercially available navigation system and shows a significant higher detection rate of residual tumor compared with conventional cioUS.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Monitorização Neurofisiológica Intraoperatória/métodos , Neuronavegação/métodos , Procedimentos Neurocirúrgicos/métodos , Idoso , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcirurgia/métodos , Pessoa de Meia-Idade , Imagem Multimodal , Neoplasia Residual/diagnóstico por imagem , Neuronavegação/instrumentação , Procedimentos Neurocirúrgicos/instrumentação , Resultado do Tratamento , Ultrassonografia
10.
Neurosurg Focus ; 36(2): E3, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24484256

RESUMO

OBJECT: High-grade gliomas (HGGs) and metastasis (MET) are the most common intracranial lesions in neurosurgical routine. Both of them show an invasive growth pattern extending into neural tissue beyond the margins of contrast enhancement on MRI. These "undetected" areas might be the origin of early tumor recurrence. The aim of the present study was to evaluate whether 5-aminolevulinic acid (5-ALA) fluorescence provides an additional benefit in detection of invasive tumor compared with intraoperative MRI (iMRI). METHODS: The authors prospectively enrolled 45 patients harboring contrast-enhancing lesions, in whom gross-total resection was intended. All patients had surgery in which iMRI and 5-ALA-guided resection were used following a specific protocol. First, a typical white light tumor resection was performed. Then, spatial location of residual fluorescence was marked. After that, an iMRI was performed and residual uptake of contrast was marked. Navigated biopsy samples were taken from all marked areas and from additional sites according to the surgeon's judgment. Cross tables and receiver operating characteristic curves were calculated, assessing performance of the imaging methods for tumor detection alone and for combined detection of infiltration zone and solid tumor (pathological tissue). Also, correlations of histopathological findings with imaging results were tested using Spearman rho. RESULTS: Thirty-four patients with HGGs and 11 with METs were enrolled. Three patients harboring a MET showed no 5-ALA enhancement and were excluded; 127 histopathological samples were harvested in the remaining patients. In HGG, sensitivity for tumor detection was significantly higher (p < 0.001) in 5-ALA (0.85) than in iMRI (0.41). Specificity was significantly lower (p < 0.001) in 5-ALA (0.43) than in iMRI (0.70). For detection of pathological tissue, 5-ALA significantly exceeded iMRI in specificity (0.80 vs 0.60) and sensitivity (0.91 vs 0.66) (p < 0.001). Imaging results of iMRI and 5-ALA did not correlate significantly; only 5-ALA showed a significant correlation with final histopathological diagnosis of the specimen and with typical histopathological features of HGGs. In METs, sensitivity and specificity for tumor detection were equal in 5-ALA and iMRI. Both techniques showed high values for sensitivity (0.75) and specificity (0.80). The odds ratio for detection of tumor tissue was 12 for both techniques. Concerning pathological tissue, no statistically significant difference was found either. Imaging results of iMRI and 5-ALA correlated significantly (p < 0.022), as with final histopathological diagnosis in METs. CONCLUSIONS: In METs, due to the rate of nonenhancing lesions, the authors found no additional benefit of 5-ALA compared with iMRI. In HGG, imaging results of 5-ALA and iMRI are significantly different at the border zone; 5-ALA has a higher sensitivity and a lower specificity for tumor detection than Gd-DTPA-enhanced iMRI. For detection of infiltrating tumor at the border of the resection cavity, 5-ALA is superior to Gd-DTPA-enhanced iMRI concerning both sensitivity and specificity. Thus, use of 5-ALA in addition to iMRI might be beneficial to maximize extent of resection. Clinical synergistic effects will be evaluated in a prospective randomized trial.


Assuntos
Ácido Aminolevulínico , Neoplasias Encefálicas/diagnóstico , Gadolínio DTPA , Glioblastoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neuronavegação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Meios de Contraste , Feminino , Corantes Fluorescentes , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Estudos Prospectivos
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