Bogdan Pintea

Engrailed-2 regulates genes related to vesicle formation and transport in cerebellar Purkinje cells.

Engrailed transcription factors regulate survival, cell fate decisions and axon pathfinding in central neurons. En-2 can also attenuate Purkinje cell (PC) maturation. Here, we use array analysis to scrutinize gene expression in developing PCs overexpressing Engrailed-2 (L7En-2). The majority (70%) of regulated genes was found down-regulated in L7En-2 cerebella, consistent with the known repressive function of Engrailed-2. Differential gene expression, verified by in situ hybridization or Western blotting, was particularly evident during the first postnatal week, when L7En-2 PCs display conspicuous deficits in dendritogenesis. Functional classification revealed clusters of genes linked to vesicle formation and transport. Consistently, Golgi stacks located at the axonal pole of wild type PC somata were rarely detected in L7En-2 PCs. In addition, long continuous stretches of endoplasmic reticulum typically found around the axonal pole of wild type PCs were less frequently observed in transgenic cells. Engrailed-2 might therefore orchestrate PC survival and process formation as a regulator of subcellular organization.

Is Spinal Cord Stimulation Useful and Safe for the Treatment of Chronic Pain of Ischemic Origin? A Review.

Objectives:The scope of this literature review was to assess the safety and the efficacy of spinal cord stimulation (SCS) for the treatment of chronic pain syndromes originating from refractory angina pectoris and peripheral vascular disease compared with conservative management. Materials and Methods:A literature review was performed, which included randomized controlled trials and prospective controlled trials. PubMed searches were performed using terms such as SCS, RCT, vascular, VAS, heart, legs, limbs, and angina pectoris. Conservative management consisted of antihypertensive, vasodilator, or anticoagulant medications, analgesics, and local wound care. Seven trials met the inclusion and exclusion criteria. Each trial was analyzed during different follow-up periods to determine whether the mean reduction in the visual analog scale score associated with SCS treatment reached the minimal clinically important difference and/or the minimal significant difference associated with adequate pain management. The number and the rate of complications during different follow-up periods were also evaluated for each trial. Results:The review demonstrated that SCS treatment provides in part long-term pain relief in otherwise intractable chronic pain of ischemic origin with a relatively low complication rate. Discussion:SCS is a minimally invasive and reversible pain intervention. On the basis of the current literature, SCS may be an alternative treatment strategy in refractory angina pectoris and peripheral vascular disease patients, presenting a low surgical risk profile. However, further clinical trials with larger sample sizes and extended follow-up are required to confirm this finding.

Treatment of Cerebral Arteriovenous Malformations with Radiosurgery or Hypofractionated Stereotactic Radiotherapy in a Consecutive Pooled Linear Accelerator Series

OBJECTIVE To review outcomes after linear accelerator stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (hfSRT) of arteriovenous malformations (AVMs) from a consecutive and pooled series of 2 Novalis centers and to analyze the influence of AVM size, Spetzler-Martin (SM) grade, pretreatment, and hemorrhagic versus nonhemorrhagic presentation. A subgroup analysis of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients also was performed. METHODS Prospectively collected treatment and outcome data were supplemented by retrospectively collected follow-up data for 93.8% of all patients. A total of 129 patients with AVM had SRS or hfSRT between 2000 and 2014 with the same linear accelerator system in 2 centers. Data analysis included initial presentation, SM grade, occlusion rates assessed by magnetic resonance and/or digital subtraction angiography, neurologic and therapeutic complications, and pretreatments. Statistical analysis was performed for patient demographic data and for factors potentially influencing outcome. RESULTS Initial presentation was hemorrhage in 43.8% or seizures/neurologic deficits in 46.2%. The series included 6 SM grade I (5%), 26 SM II (21.5%), 55 SM III (45.5%), 28 SM IV (23%), and 6 SM V cases (5%). Pre-embolization was used in 36 patients (29.8%), 8 patients had previous surgery (6.6%), and 6 patients were irradiated before elsewhere (5%); 5 patients (4.2%) received multimodal pretreatment. Mean follow-up was 43 months. The occlusion rate for the total series was 71.1%, for SM I/II cases 80.6%, and 67.4% for the SM ≥ subgroup. The occlusion rate was 75.0% for the small volume (<4 cc) and 55.6% for the large volume (>10 cc) subgroup. There was no statistical difference between the occlusion rate of patients with or without pretreatment if taken all modalities together (72.7% and 69.7%, respectively). There was only a trend of a belated occlusion of pre-embolized AVMs. The occlusion rate for hemorrhagic AVM was with 77.4% better than for nonhemorrhagic (66.2%) or ARUBA-eligible AVMs (64.8%) but without reaching statistical significance. Neurologic deterioration was seen in 13.2% of the patients. There were 2 re-bleedings within 17-18 months (1.7%), 1 of them without a new neurologic deficit and total occlusion after re-SRS. One patient with pre-existing epilepsy died a sudden unexpected death (mortality rate: 0.8%). CONCLUSIONS Overall SRS and hfSRT are valuable therapy options, especially in symptomatic patients with AVM, with a low rate of morbidity and mortality and an acceptable overall complete occlusion rate of >70% and >80% for SM I/II AVMs.

Earlier and sustained response with incidental use of cardiovascular drugs among patients with low- to medium-grade meningiomas treated with radiosurgery (SRS) or stereotactic radiotherapy (SRT)

BACKGROUND AND PURPOSE Beneficial outcome for cancer treated with radiotherapy (RT) and β-blockers has been reported. We hypothesize a potential combined impact of stereotactic RT with incidental use of cardiovascular drugs also in meningiomas. MATERIALS AND METHODS In 64 patients with 70 intracranial meningiomas (male/female=17/53; median follow-up=2 years) from a prospective database with sustained RT/cardiovascular drug therapy tumor response (progression, stable disease, regression) was evaluated at predefined follow-up intervals of 3, 12 and 24 months based on MR-imaging. For this retrospective cohort analysis stepwise univariate and multivariate analyses for group comparison were performed. Between groups analysis and stepwise uni- and multivariate analysis was performed. RESULTS At one year follow-up there was a significant better tumor response for patients with antihypertensives use (p=0.008) and radiosurgery (SRS) (p=0.054), the difference between patients with and without antihypertensive medication remains significant in multivariate analysis. Two years after RT, only patients with β-blocker use had a significant better response to RT (p=0.032). Additionally, for the use of β-blockers a trend toward significance for early tumor response at 3 months compared to the control group was observed (p(one tailed)=0.059). CONCLUSIONS Our data suggest that concomitant antihypertensive medication (especially β-blockers) may lead to an earlier and sustained response in stereotactic irradiated low- to medium-grade intracranial meningiomas by affecting the β-adrenergic pathways.

Meningioma assessment: Kinetic parameters in dynamic contrast-enhanced MRI appear independent from microvascular anatomy and VEGF expression

BACKGROUND AND PURPOSE Kinetic parameters of T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are considered to be influenced by microvessel environment. This study was performed to explore the extent of this association for meningiomas. MATERIALS AND METHODS DCE-MRI kinetic parameters (contrast agent transfer constants Ktrans and kep, volume fractions vp and ve) were determined in pre-operative 3T MRI of meningioma patients for later biopsy sites (19 patients; 15 WHO Io, no previous radiation, and 4 WHO IIIo pre-radiated recurrent tumors). Sixty-three navigated biopsies were consecutively retrieved. Biopsies were immunohistochemically investigated with endothelial marker CD34 and VEGF antibodies, stratified in a total of 4383 analysis units and computationally assessed for VEGF expression and vascular parameters (vessel density, vessel quantity, vascular fraction within tissue [vascular area ratio], vessel wall thickness). Derivability of kinetic parameters from VEGF expression or microvascularization was determined by mixed linear regression analysis. Tissue kinetic and microvascular parameters were tested for their capacity to identify the radiation status in a subanalysis. RESULTS Kinetic parameters were neither significantly related to the corresponding microvascular parameters nor to tissue VEGF expression. There was no significant association between microvessel density and its presumed correlate vp (P=0.07). The subgroup analysis of high-grade radiated meningiomas showed a significantly reduced microvascular density (AUC 0.91; P<0.0001) and smaller total vascular fraction (AUC 0.73; P=0.01). CONCLUSIONS In meningioma, DCE-MRI kinetic parameters neither allow for a reliable prediction of tumor microvascularization, nor for a prediction of VEGF expression. Kinetic parameters seem to be determined from different independent factors.

Silencing of the nucleocytoplasmic shuttling protein karyopherin a2 promotes cell-cycle arrest and apoptosis in glioblastoma multiforme

We have previously shown that the nucleocytoplasmic carrier karyopherin a2 (KPNA2) is overexpressed in glioblastoma multiforme (GBM) whereas its expression is inversely associated with patient prognosis. However, the promoting role of KPNA2 in gliomagenesis is still poorly understood. This study aims to further elucidate this role of KPNA2 in in vitro GBM models. From four different tested GBM cell lines, the U87MG showed the highest proliferation, low adherence and outgrowth in 3D clusters as well as the highest expression of KPNA2, all features conferring greater malignant behaviour. Silencing of KPNA2 via siRNA interference in those cells significantly decreased their proliferative capacity (p = 0.001). We further observed both a significant cell cycle phase arrest (p = 0.040) and the promoting of cellular apoptosis (p = 0.016) as well as a strong trend (p = 0.062) for an inhibition of nuclear import of c-Myc. This study confirms that a higher expression of KPNA2 in GBM is associated with a more malignant phenotype also in in vitro models. While increased expression of KPNA2 promotes proliferation and survival of GBM tumour cells, silencing of KPNA2 conferred a less malignant behaviour. Our results strongly suggest that silencing of KPNA2 may play an important role in modulation of malignant features of GBM cells.

Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts

BackgroundWe compared the functional outcome and influential factors of two standard treatment modalities for central cerebral metastases: electrophysiological-controlled microsurgical resection (MSR) and stereotactic radiotherapy/stereotactic radiosurgery (SRT/SRS).MethodsWe performed a database search for central metastasis treatments during the period from January 2008 to September 2012 in two clinical registers: 1) register for intraoperative neuromonitoring (Department of Neurosurgery), and 2) prospective database for SRT/SRS (Department of Radiotherapy). Neurological status before and after treatment, Karnofsky performance index (KPI), histology, tumor localization and volume, and oncological status were standardized and pooled together for analysis. Muscle strength was graded on a scale of 0–5.ResultsWe identified 27 MSR and 41 SRT/SRS cases from 68 treatments. The MSR-treated patients had significant less muscle strength in the upper and lower extremities before and after the treatment as compared to the patients receiving SRT/SRS. Muscle strength of the extremities did not change for patients receiving SRT/SRS, while MSR patients had significant improvement in lower extremity muscle strength (p = 0.05) and a non-significant improvement in the upper extremities. MSR showed significant improvement in hemiparesis as compared to radiotherapy, but this was accompanied with a significant deterioration of extremity muscle strength after surgery, as compared to SRT/SRS (improvement p = 0.04, deterioration p = 0.10).ConclusionElectrophysiologically guided microsurgery of central metastases had a significantly better functional outcome regarding hemiparesis. However, there was also a trend for less secondary neurological deterioration after SRT/SRS.Trial registrationISRCTN81776764. Retrospectively Registered 27 July 2017.

Extended Long-Term Effects of Cervical Vagal Nerve Stimulation on Headache Intensity/Frequency and Affective/Cognitive Headache Perception in Drug Resistant Complex-Partial Seizure Patients

Invasive vagal nerve stimulation (iVNS) is an established treatment option for drug‐resistant focal seizures and has been assumed to diminish frequent co‐incidental daily headache/migraine. However, long‐term effects on cognitive/affective head pain perception, headache intensity/frequency are lacking. We therefore investigated potential iVNS‐induced effects in patients with drug‐resistant focal seizure and daily headache/migraine.

The Usefulness of Spinal Cord Stimulation for Chronic Pain Due to Combined Vasospastic Prinzmetal Angina and Diabetic Neuropathic Pain of the Lower Limbs.

OBJECTIVE To describe an unusual case of combined neuropathic and ischemia-induced chronic pain in a patient who was treated with one high thoracic paddle lead. BACKGROUND To the best of our knowledge, the use of spinal cord stimulation (SCS) utilizing a single lead as a treatment strategy for combined Prinzmetal angina, a cardiac ischemia-induced disturbance of nociceptive perception, and diabetic neuropathy of the lower limbs has rarely been described. CASE REPORT The underlying pain conditions and SCS technique used to treat both types of pain-Prinzmetal angina and lower-limb diabetic neuropathy-in a 73-year-old patient experiencing medical or interventional refractory complex pain syndrome are described. The SCS electrode was placed in the anatomical midline with a T2- to T3-level laminotomy and externalized for postoperative trial stimulation with systemic antibiotic administration. RESULTS After 8 months, stable pain control was achieved. No complications occurred. CONCLUSION We present a chronic pain syndrome due to combined Prinzmetal angina and diabetic neuropathy of the lower limbs with sustained pain relief utilizing a single SCS lead.