Induction of differentiation inhibits the tumorigenic potential of glioblastoma cancer stem cells

The outcome of the patients with newly diagnosed glioblastoma remains dismal, despite the use of surgery, radiotherapy and adjuvant temozolomide and while new agents like anti-angiogenic agents seem to offer some promise, a new approach is needed. Recent studies suggest that cancer stem cells (CSCs) may play an important role in malignant gliomas invasion and proliferation. Therefore, CSCs became new therapeutical targets, and one of the main experimental therapies which could be used against CSCs is the differentiation therapy.The purpose of this study was to characterize the CSCs isolated from glioblastoma samples, to assess in vivo the tumorigenic potential of these cells and to induct the differentiation of the CSCs. The changes in invasive markers (matrixmetalloproteases-MMPs, cadherins and cathenins) expression were assessed. CSCs exposed to differentiation inductor factors have been inoculated in nude mice and their tumorigenic potential has been evaluated. The stemness biological feature was correlated with increased of MMPs, cadherins, catenin expression and with tumour contra-lateral invasion. The expression of MMPs, cadherins and cadherins decreased after exposure of the CSCs cultures to the differentiation inductor factors. In vivo experiments demonstrated the inhibition of tumorigenic potential of differentiated CSCs cultures.In conclusion, differentiated CSCs showed a decreased expression of invasive markers in vitro and lost their tumorigenic potential in vivo

Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study

BACKGROUND: Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies. OBJECTIVE: To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches. METHODS: This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20 000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months. EXPECTED OUTCOMES: Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research. DISCUSSION: Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management

Global Perspectives on Task Shifting and Task Sharing in Neurosurgery.

BACKGROUND: Neurosurgical task shifting and task sharing (TS/S), delegating clinical care to non-neurosurgeons, is ongoing in many hospital systems in which neurosurgeons are scarce. Although TS/S can increase access to treatment, it remains highly controversial. This survey investigated perceptions of neurosurgical TS/S to elucidate whether it is a permissible temporary solution to the global workforce deficit. METHODS: The survey was distributed to a convenience sample of individuals providing neurosurgical care. A digital survey link was distributed through electronic mailing lists of continental neurosurgical societies and various collectives, conference announcements, and social media platforms (July 2018-January 2019). Data were analyzed by descriptive statistics and univariate regression of Likert Scale scores. RESULTS: Survey respondents represented 105 of 194 World Health Organization member countries (54.1%; 391 respondents, 162 from high-income countries and 229 from low- and middle-income countries [LMICs]). The most agreed on statement was that task sharing is preferred to task shifting. There was broad consensus that both task shifting and task sharing should require competency-based evaluation, standardized training endorsed by governing organizations, and maintenance of certification. When perspectives were stratified by income class, LMICs were significantly more likely to agree that task shifting is professionally disruptive to traditional training, task sharing should be a priority where human resources are scarce, and to call for additional TS/S regulation, such as certification and formal consultation with a neurosurgeon (in person or electronic/telemedicine). CONCLUSIONS: Both LMIC and high-income countries agreed that task sharing should be prioritized over task shifting and that additional recommendations and regulations could enhance care. These data invite future discussions on policy and training programs

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: A survey in 66 neurotrauma centers participating in the CENTER-TBI study

The distributions of species are not only determined by where they can survive – they must also be able to reproduce. Although immigrant inviability is a well-established concept, the fact that immigrants also need to be able to effectively reproduce in foreign environments has not been fully appreciated in the study of adaptive divergence and speciation. Fertilization and reproduction are sensitive life-history stages that could be detrimentally affected for immigrants in non-native habitats. We propose that “immigrant reproductive dysfunction” is a hitherto overlooked aspect of reproductive isolation caused by natural selection on immigrants. This idea is supported by results from experiments on an externally fertilizing fish (sand goby, Pomatoschistus minutus). Growth and condition of adults were not affected by non-native salinity whereas males spawning as immigrants had lower sperm motility and hatching success than residents. We interpret these results as evidence for local adaptation or acclimation of sperm, and possibly also components of paternal care. The resulting loss in fitness, which we call “immigrant reproductive dysfunction,” has the potential to reduce gene flow between populations with locally adapted reproduction, and it may play a role in species distributions and speciation.</p

Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: A survey in 66 neurotrauma centers participating in the CENTER-TBI

Background: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI. Methods: A 29-item survey on ICP monitoring and treatment was developed based on literature and expert opinion, and pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research (CENTER-TBI) study. Results: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately ninety percent of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomography abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as having a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%). Conclusions: Substantial variation was found regarding monitoring and treatment policies in patients with traumatic brain injury and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research

Variation in structure and process of care in traumatic brain injury: Provider profiles of European Neurotrauma Centers participating in the CENTER-TBI study

Introduction: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Methods: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions.Results: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. Conclusion: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches.</p

Controversies in multimodal treatment of pineal tumors: Experience of 84 cases

The pineal tumors represent one of the most difficult and challenging disease from all brain pathology due to the complex anatomy of the area and because of the diverse pathology of this type of tumors. The management of these tumors is multi modal and comprises the surgical approach followed by radiotherapy and chemotherapy. The authors present a large series of 84 consecutive operated cases of pineal tumors. All these cases have undergone one of the two main surgical approaches (occipito-transtentorial approach and supracerebellar - infratentorial approach). In 22 cases (26,1%) the tumor was totally removed, in 18 cases (21,4%) near total removal was obtained, in 33 cases (39,2%) partial removal and biopsy was performed in 11 cases (13,1%). From all 84 cases, 39 cases (46%) were germ cells tumors, 16 cases (19%) were pineal parenchyma tumors, in 27 cases (32%) were glial cell tumors and in 2 cases (3%) were miscellaneous tumors. As adjuvant therapy, radiotherapy played an important role within the multimodal management of pineal tumors. Therefore 61 cases have undergone the radiotherapy, which have been indicated for all sensitive tumors. The chemotherapy was applied in 41 cases, and consisted in a combination of cisplatin, bleomycin and actinomycin D. The outcome was good recovery in 56 cases (66%), moderate disability in 12 cases (14.7%), severe disability in 9 cases (10.2%) and death in 7 cases (8.8%).&nbsp

Isolation and characterization of a human glioblastoma cell line

The characterization of a glioblastoma cells line represents an important achievement in the field of brain tumor research activity, which enables the researchers to obtain strong results with a wide recognition by the scientific community. The objective of this study was to develop a standardized glioblastoma cells line using the resources obtained entirely from the national research projects. The tumor samples was initially obtained intraoperative from a 58 years-old female patient, with the preoperative written consent of the patient. The histopathological exam showed a grad IV WHO glioma (glioblastoma). The sample was prepared by manual fragmentation into pieces up to few millimeters each, followed by enzymatic digestions using different concentration of trypsin. Then, the cellular line was cultivated for more then 100 passages using Dulbecco Modified Eagle's medium enrich with 10% fetal bovine serum. The characterization of the glioblastoma line was made by the evaluation of cells proliferation (growth curve), by morphological studies, by studying the karyotype of the cells and by immunohistochemistry studies for the identification of the specific markers (glial fibrillary acidic proteins - GFAP, vimentin) of the tumor cells. The determination of the expression/amplification of the receptors tyrosine kinases (PDGFR and more important EGFR) is in progress. The characterization of a glioblastoma cells line represents an essential step in order to obtain a better in vitro and in vivo experimental model for glioblastoma