Overcoming chemotherapy resistance in low-grade gliomas: A computational approach.

Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients.

BACKGROUND: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. METHODS: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. RESULTS: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99-23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. CONCLUSIONS: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial.

BACKGROUND AND PURPOSE: Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke. We aimed to assess the safety, feasibility, and biological effects of autologous BM-MNC transplantation in patients with stroke. METHODS: A single-blind (outcomes assessor) controlled Phase I/II trial was conducted in patients with middle cerebral artery stroke. Autologous BM-MNCs were injected intra-arterially between 5 and 9 days after stroke. Follow-up was done for up to 6 months and blood samples were collected for biological markers. The primary outcome was safety and feasibility of the procedure. The secondary outcome was improvement in neurological function. RESULTS: Ten cases (BM-MNC-treated) and 10 control subjects (BM-MNC-nontreated) were consecutively included. Mean National Institutes of Health Stroke Scale before the procedure was 15.6. Mean BM-MNCs injected were 1.59×10(8). There was no death, stroke recurrence, or tumor formation during follow-up, although 2 cases had an isolate partial seizure at 3 months. After transplantation, higher plasma levels of beta nerve growth factor (ß-nerve growth factor) were found compared with control subjects (P=0.02). There were no significant differences in neurological function at 180 days. A trend to positive correlation between number of CD34+ cells injected and Barthel Index was found (r=0.56, P=0.09). CONCLUSIONS: Intra-arterial BM-MNC transplantation in subacute ischemic stroke is feasible and seems to be safe. Larger randomized trials are needed to confirm the safety and elucidate the efficacy of BM-MNC transplantation. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT00761982.

Mediterranean Diet and its Effects on Silent Brain Infarcts in a Cohort of Patients With Atrial Fibrillation.

Background and Aims: The benefits of Mediterranean Diet (MeDiet) in prevention of cardiovascular diseases (CVD) in general and ischemic stroke (IS) have been extensively studied and reported. We hypothesize that the consumption of nutrients typical of MeDiet would also reduce the rate of silent brain infarcts (SBI) among AF patients. Methods and Results: Patients with a history of AF who scored 0 to 1 in the CHADS2 score, ⩾50 years and with absence of neurological symptoms were selected from Seville urban area using the Andalusian electronic healthcare database. A 3T brain MRI was performed to all participants. Demographic and clinical data and food-frequency questionnaire (FFQ) were collected. Of the 443 scanned patients, 66 presented SBI. Of them 52 accepted to be scheduled for a clinical visit and were included in the diet sub study and 41 controls were matched per age and sex. There were no statistically significant differences in baseline characteristics. After logistic regression analysis, we found that a higher consumption of fiber from fruit was independently associated with a lower risk of SBI, while a higher consumption of high glycemic load (GL) foods was associated with a higher risk of SBI in a population with AF. Conclusion: Our findings support that MeDiet could be suggested as a prevention strategy for SBI in patients with AF.

Prevalence and risk factors of silent brain infarcts in patients with AF detected by 3T-MRI.

BACKGROUND: Silent brain infarcts (SBI), a finding on neuroimaging, are associated with higher risk of future stroke. Atrial Fibrillation (AF) has been previously identified as a cause of SBI. OBJECTIVES: The aim of this study is to determine the prevalence of and risk factors for SBI in patients with AF and low-to-moderate embolic risk according to CHADS2 and CHA2DS2VASc score. METHODS: Patients with a history of AF based on medical records who scored 0-1 in the CHADS2 score were selected from the Seville urban area using the Andalusian electronic healthcare database (DIRAYA). Demographic and clinical data were collected and a 3T brain MRI was performed on patients older than 50 years and with absence of neurological symptoms. RESULTS: 66 of the initial 443 patients (14.9%) and 41 of the 349 patients with low risk according to CHA2DS2VASc score (11.7%) presented at least 1 SBI. After adjusted multivariable analysis, an older age (OR 3.84, 95% CI 1.07-13.76) and left atrial (LA) enlargement (OR 3.13, 95% CI 1.15-8.55) were associated with SBI in the whole cohort, while only LA enlargement was associated with SBI in the low-risk cohort (OR 3.19, 95% CI 1.33-7.63). CONCLUSIONS: LA enlargement on echocardiogram was associated with SBI in patients with AF and low or moderate embolic risk according to CHADS2 and in the low-risk population according to CHA2DS2VASc. Although further studies are needed, a neuroimaging screening might be justified in these patients to guide medical therapies to improve stroke prevention.

Corrigendum to "Increasing Dose of Autologous Bone Marrow Mononuclear Cells Transplantation Is Related to Stroke Outcome: Results from a Pooled Analysis of Two Clinical Trials".

[This corrects the article DOI: 10.1155/2016/8657173.].

Increasing Dose of Autologous Bone Marrow Mononuclear Cells Transplantation Is Related to Stroke Outcome: Results from a Pooled Analysis of Two Clinical Trials.

Background and Purpose. BM-MNC transplantation improves recovery in experimental models of ischemic stroke. Clinical trials are ongoing to test efficacy in stroke patients. However, whether cell dose is related to outcomes is not known. Methods. We performed a pooling data analysis of two pilot clinical trials with autologous BM-MNCs transplantation in ischemic stroke patients. Cell dose and route were analyzed to evaluate their relation to good outcome (m-Rankin scale [mRS] score 0-2) at 6 months. Results. Twenty-two patients were included. A median of 153 × 10(6) (±121 × 10(6)) BM-MNCs was injected. Intra-arterial route was used in 77.3% of cases. A higher number of cells injected were associated with better outcomes at 180 days (390 × 10(6) [320-422] BM-MNCs injected in those patients with mRS of 0-2 at 6 months versus 130 × 10(6) [89-210] in those patients with mRS 3-6, p = 0.015). In the intra-arterially treated patients, a strong correlation between dose of cells and disability was found (r = -0.63, p = 0.006). A cut point of 310 × 10(6) injected cells predicted good outcome with 80% sensitivity and 88.2% specificity. Conclusions. Similar to preclinical studies, a higher dose of autologous BM-MNC was related to better outcome in stroke patients, especially when more than 310 × 10(6) cells are injected. Further interventional studies are warranted to confirm these data.

Silent cerebral ischemic lesions after carotid artery stenting with distal cerebral protection.

OBJECTIVE: To evaluate by MR diffusion weighted image (DWI-MR) the presence of new ischemic cerebral lesions after carotid artery stenting (CAS) and distal cerebral protection, in patients with internal carotid artery (ICA) stenosis >70. METHODS: Sixty-seven CAS were performed under cerebral protection with a distal filter. Mean age of the patients was 68.3 years (range 37-86) and 42 patients (62.7%) were symptomatic. An EZ filter device was used in all cases. The mean length of the procedure was 22.2 minutes (range 8-110). All patients had a cerebral MRI done in the 3 days before CAS and a DW-MR (eco planar single shot, b=1000 mm2/seconds) was done the day after. RESULTS: As a consequence of the CAS, three transient ischemic attacks were observed. There was one minor stroke (1.5%) on day 21, but no major stroke, death or myocardial infarction in a 30-day period. DW-MRI after CAS showed 26 new silent ischemic lesions in 11 asymptomatic patients (16.4%). In six, they were multiple (range 2-5). Lesions were mainly seen in the ipsilateral medial cerebral artery (21); four in the posterior fossa, and one in the contralateral medial cerebral artery. DISCUSSION: Although the use of distal cerebral protection was safe, new cerebral ischemic lesions, supposedly embolic, were observed in 16.4% of the patients. Although without clinical consequences in our series, their moderate high incidence should promote the investigation of safer techniques and devices.

Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): protocol of a phase II, randomized, dose-finding, controlled multicenter trial.

RATIONALE: No neuroprotective or neurorestorative therapies have been approved for ischemic stroke. Bone marrow mononuclear cell intra-arterial transplantation improves recovery in experimental models of ischemic stroke. AIMS: This trial aims to test safety and efficacy of intra-arterial injection of autologous bone marrow mononuclear cell in ischemic stroke patients. DESIGN: Multicenter, prospective, phase II, randomized, controlled (non-treated group as control), assessor-blinded clinical trial. Seventy-six stroke patients will be enrolled. Patients fulfilling clinical and radiological criteria (e.g. age between 18 and 80 years, middle cerebral artery ischemic stroke with a National Institutes of Health Stroke Scale score of 6-20 within one- to seven-days from stroke onset and no lacunar stroke) will be randomized to intervention or control group (1 : 1). Bone marrow harvest and intra-arterial injection of autologous bone marrow mononuclear cell will be done in the intervention group with two different doses (2 × 10(6) /kg or 5 × 10(6) /kg in 1 : 1 proportion). Patients will be stratified at randomization by National Institutes of Health Stroke Scale score. Patients will be followed up for two-years. STUDY OUTCOMES: The primary outcome is the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days. Secondary outcomes include National Institutes of Health Stroke Scale and Barthel scores at six-months, infarct volume, mortality, and seizures. DISCUSSION: This is the first trial to explore efficacy of different doses of intra-arterial bone marrow mononuclear cell in moderate-to-severe acute ischemic stroke patients. The trial is registered as NCT02178657.

Magnetic resonance spectroscopy of normal appearing white matter in early relapsing-remitting multiple sclerosis: correlations between disability and spectroscopy.

BACKGROUND: What currently appears to be irreversible axonal loss in normal appearing white matter, measured by proton magnetic resonance spectroscopy is of great interest in the study of Multiple Sclerosis. Our aim is to determine the axonal damage in normal appearing white matter measured by magnetic resonance spectroscopy and to correlate this with the functional disability measured by Multiple Sclerosis Functional Composite scale, Neurological Rating Scale, Ambulation Index scale, and Expanded Disability Scale Score. METHODS: Thirty one patients (9 male and 22 female) with relapsing remitting Multiple Sclerosis and a Kurtzke Expanded Disability Scale Score of 0-5.5 were recruited from four hospitals in Andalusia, Spain and included in the study. Magnetic resonance spectroscopy scans and neurological disability assessments were performed the same day. RESULTS: A statistically significant correlation was found (r = -0.38 p < 0.05) between disability (measured by Expanded Disability Scale Score) and N-Acetyl Aspartate (NAA/Cr ratio) levels in normal appearing white matter in these patients. No correlation was found between the NAA/Cr ratio and disability measured by any of the other disability assessment scales. CONCLUSIONS: There is correlation between disability (measured by Expanded Disability Scale Score) and the NAA/Cr ratio in normal appearing white matter. The lack of correlation between the NAA/Cr ratio and the Multiple Sclerosis Functional Composite score indicates that the Multiple Sclerosis Functional Composite is not able to measure irreversible disability and would be more useful as a marker in stages where axonal damage is not a predominant factor.

Progressive changes in cerebral perfusion after carotid stenting: a dynamic susceptibility contrast perfusion weighted imaging study.

BACKGROUND: We aimed to assess baseline inter-hemispheric perfusion differences, before carotid artery stenting (CAS), of severe internal carotid artery (ICA) stenosis, and to evaluate perfusion changes over time after CAS by means of perfusion weighted imaging (PWI). METHODS: Dynamic susceptibility contrast PWI was performed in 33 patients with severe ICA stenosis 1 day before and 1 day after CAS, and repeated in 23 patients 30 days after CAS. Cerebral blood volume, cerebral blood flow, arrival time (T0), mean transit time, and time to peak (TTP) relative values comparing symptomatic and asymptomatic hemispheres before CAS were obtained. Pre- and post-CAS values were also compared in the treated hemisphere and middle cerebral artery (MCA) territories. The influence of collateral circulation and contralateral ICA stenosis were evaluated. RESULTS: Before CAS, TTP was significantly increased in the affected hemisphere and MCA territory in all patients (p=0.007 and p=0.021, respectively). After treatment, normalization was observed for TTP and T0 30 days after CAS in all patients, mainly in patients with any grade of contralateral stenosis and with one or both functioning communicating arteries (42.4% of patients had both, and 42.4% showed only one-anterior communicating artery=11 patients (78.6%) and posterior communicating artery=3 patients (21.4%)). CONCLUSIONS: Inter-hemispheric perfusion differences in patients with severe ICA stenosis normalize after CAS in the long term, up to 30 days after the procedure.

Intra-arterial bone marrow mononuclear cell transplantation correlates with GM-CSF, PDGF-BB, and MMP-2 serum levels in stroke patients: results from a clinical trial.

Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke through secretion of cytokines and growth factors (GFs), enhancing neoangiogenesis, and enhancing neuroplasticity. In this study, we tested whether BM-MNC transplantation in stroke patients induces changes in serum levels of cytokines and GFs. A phase I/II trial was conducted in middle cerebral artery (MCA) stroke patients with autologous intra-arterial BM-MNC transplantation between 5 and 9 days after stroke. Follow-up was done for up to 6 months. Eight cases and nine controls were included, and the serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), ß nerve growth factor (ß-NGF), and matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) were measured before and 4, 8, and 90 days after transplantation. The correlation of these serum levels with dose of cells and clinical outcomes was studied. A total of 1.59 × 10(8) (±1.21 × 10(8)) BM-MNCs were injected in cases; of them 3.38 × 10(6) (±2.33 × 10(6)) were CD34(+) cells. There was a positive correlation between total BM-MNCs injected and levels of GM-CSF and PDGF-BB at 90 days after transplantation (r = 0.929, p = 0.001 and r = 0.714, p = 0.047, respectively), and a negative correlation between total CD34(+) cells injected and MMP-2 levels at 4 days after transplantation (r = -0.786, p = 0.036). Lower plasma levels of MMP-2 at 4 days and higher levels of PDGF-BB at 90 days were associated with better functional outcomes during follow-up (p = 0.019 and p = 0.037, respectively). When administered intra-arterially in subacute MCA stroke patients, BM-MNCs seem to induce changes in serum levels of GM-CSF, PDGF-BB, and MMP-2, even 3 months after transplantation, which could be associated with better functional outcomes. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Influence of psychological stress on headache in patients with systemic lupus erythematosus.

OBJECTIVE: To compare the prevalence and disability of headache in patients with systemic lupus erythematosus (SLE) with the general population and to assess the role of chronic psychological stress (CPS) in headache development. METHODS: One hundred seventy patients with SLE and 102 control subjects matched for age, sex, and level of education were included in this multicenter, cross-sectional study. CPS, headache-related disability, and chronic analgesic intake (CAI) were evaluated in all participants. RESULTS: No statistical differences in the prevalence of headache between both groups were observed but headache disability was significantly higher in patients with SLE. In addition, a higher average score in the Cohen Perceived Stress Scale (CPSS) and a higher prevalence of patients with CAI were observed in patients with SLE. In multivariate analysis, CPSS score was positively (OR 1.09; 95% CI: 1.03-1.14; p = 0.001) and CAI negatively (OR 0.43; 95% CI: 0.19-0.99; p = 0.049) associated with headache in patients with SLE. CONCLUSION: Despite the prevalence of headache in patients with SLE and the general population being similar, headache-related disability may be higher in patients with SLE. Moreover, CPS might play a role in the pathogenesis of SLE headache, whereas CAI might have a protective effect against it.

Degeneración walleriana bilateral de haces pontocerebelosos secundaria a infarto protuberancial / Bilateral Wallerian degeneration of pontocerebellar fibres secondary to pontine infarction

No disponible

Appropriateness of lumbar spine magnetic resonance imaging in Spain.

OBJECTIVES: To determine the minimum percentage of lumbar spine magnetic resonance imaging (LSMRI) which are inappropriately prescribed in routine practice. METHODS: LSMRI performed prospectively on 602 patients in 12 Radiology Services across 6 regions in Spain, were classified as "appropriate", "uncertain" or "inappropriate" based on the indication criteria established by the National Institute for Clinical Excellence, the American College of Physicians and Radiology, and current evidence-based clinical guidelines. Studies on patients reporting at least one "red flag" were classified as "appropriate". A logistic regression model was developed to identify factors associated with a higher likelihood of inappropriate LSMRI, including gender, reporting of referred pain, health care setting (private/public), and specialty of prescribing physician. Before performing the LSMRI, the radiologists also assessed the appropriateness of the prescription. RESULTS: Eighty-eight percent of LSMRI were appropriate, 1.3% uncertain and 10.6% inappropriate. The agreement of radiologists' assessment with this classification was substantial (k=0.62). The odds that LSMRI prescriptions were inappropriate were higher for patients without referred pain [OR (CI 95%): 13.75 (6.72; 28.16)], seen in private practice [2.25 (1.20; 4.22)], by orthopedic surgeons, neurosurgeons or primary care physicians [2.50 (1.15; 5.56)]. CONCLUSION: Efficiency of LSMRI could be improved in routine practice, without worsening clinical outcomes.