RESUMO
BACKGROUND: This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma. METHODS: In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion. RESULTS: Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4. CONCLUSION: Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT02869243.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Qualidade de Vida , Proteína Morfogenética Óssea 4/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Encefálicas/patologia , Dose Máxima TolerávelRESUMO
The application and interpretation of P values have caused debate for several decades, and this debate has become particularly relevant in the past few years. The P value represents the probability of seeing results as extreme or more extreme than those observed in a data analysis, were the null hypothesis and other underlying assumptions to be true. While P values are useful in pointing out where an effect may be present, they have often been misused in an attempt to oversell "statistically significant" findings. As P values rely on the spread and number of measurements, a smaller P value does not necessarily imply a larger effect size, which is better assessed via an effect estimate and confidence interval interpreted in the context of the study. The clinical relevance of a computed P value is context dependent. We investigated the current use of P values in a small sample of recent neurosurgical literature. Only a minority of manuscripts that reported statistical significance described confounder adjustment, or effect sizes. A common, incorrect assumption often observed was that statistical significance equals clinical relevance. To enable correct interpretation of clinical significance, it is crucial that authors describe the clinical implications of their findings.
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Análise de Dados , Publicações , Humanos , ProbabilidadeRESUMO
BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4. METHODS: Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures. RESULTS: High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4. CONCLUSION: The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Proliferação de Células , Perfilação da Expressão Gênica , Biomarcadores/metabolismo , RNA/metabolismo , Células-Tronco Neoplásicas/metabolismo , Diferenciação Celular , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/farmacologia , Proteína Morfogenética Óssea 4/metabolismoRESUMO
BACKGROUND: Little is known about the results of young vascular neurosurgeons who perform only microsurgical clip reconstruction in the era since the International Subarachnoid Aneurysm Trial (ISAT) or about the training and caseload required to equivocate the results of senior, more experienced colleagues. The aim of this study was to compare clinical outcomes of patients treated by young and senior vascular neurosurgeons at Erasmus MC University Medical Center Rotterdam, adjusting for case mix. METHODS: A partially prospective and partially retrospective database was used. Hierarchical mixed models with a random intercept for surgeon were used for confounder adjustment, and propensity score matching for complexity was used to create comparable groups. RESULTS: The study included 609 patients harboring 767 aneurysms. Most (86%) of the aneurysms had at least 1 complexity characteristic, with the majority having 3 characteristics. The most often encountered complexity characteristics were the presence of a broad neck and the presence of branches emerging from the aneurysm. Use of temporary clipping and skull base approaches was significantly higher in the young vascular neurosurgeons group (P < 0.0001). The complexity score differed significantly between senior and young vascular neurosurgeons (P < 0.001). After propensity score matching for complexity, multivariable logistic regression showed young vascular neurosurgeons to be significantly associated with better outcomes for ruptured aneurysms (propensity score weighted odds ratio 0.55 [95% confidence interval 0.35-0.88], P = 0.01). CONCLUSIONS: In a high-volume neurovascular center where both endovascular and microsurgical treatment options are available, young vascular neurosurgeons can be trained to achieve at least the same results as their senior colleagues despite increased complexity.
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Procedimentos Endovasculares/educação , Microcirurgia/educação , Neurocirurgia/educação , Procedimentos Neurocirúrgicos/educação , Procedimentos de Cirurgia Plástica/educação , Adulto , Competência Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Prospectivos , Procedimentos de Cirurgia Plástica/instrumentação , Estudos Retrospectivos , Instrumentos Cirúrgicos , Resultado do TratamentoRESUMO
BACKGROUND: Frameless stereotactic neuronavigation has proven to be a feasible technology to acquire brain biopsies with good accuracy and little morbidity and mortality. New systems are constantly introduced into the neurosurgical armamentarium, although few studies have actually evaluated and compared the diagnostic yield, morbidity, and mortality of various manufacturer's frameless neuronavigation systems. The present study reports our experience with brain biopsy procedures performed using both the Medtronic Stealth Treon(TM) Vertek® and BrainLAB® Varioguide frameless stereotactic brain biopsy systems. PATIENTS AND METHODS: All 247 consecutive biopsies from January 2008 until May 2013 were evaluated retrospectively. One hundred two biopsies each were performed using the Medtronic (2008-2009) and BrainLAB® system (2011-2013), respectively. The year 2010 was considered a transition year, in which 43 biopsies were performed with either system. Patient demographics, perioperative characteristics, and histological diagnosis were reviewed, and a comparison was made between the two brain biopsy systems. RESULTS: The overall diagnostic yield was 94.6 %, i.e., 11 biopsies were nondiagnostic, 5 (4.9 %) with the Medtronic and 6 (5.9 %) with the BrainLAB® system. No differences besides the operating time (108 vs 120 min) were found between the two biopsy methods. On average, 6.6 tissue samples were taken with either technique. Peri- and postoperative complications were seen in 5.3 % and 12.9 %, consisting of three symptomatic hemorrhages (1.2 %). Biopsy-related mortality occurred in 0.8 % of all biopsies. CONCLUSIONS: Regarding diagnostic yield, complication rate, and biopsy-related mortality, there seems to be no difference between the frameless biopsy technique from Medtronic and BrainLAB®. In contemporary time, the neurosurgeon has many tools to choose from, all with a relatively fast learning curve and ever improving feasibility. Thus, the issue of choice involves not the results, but the familiarity, end-user friendliness, and overall comfort when operating the system.