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Butz H.,Semmelweis University | Liko I.,Gedeon Richter Plc. | Czirjak S.,National Institute of Neurosurgery | Igaz P.,Semmelweis University | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: The tumorigenic mechanisms involved in pituitary adenomas, especially of nonfunctional pituitary adenomas (NFAs), remains unclear. Various cell cycle inhibitors have been found to be underexpressedinpituitarytumors; however, Wee1 kinase, a nuclear protein that delays mitosis and was recently recognized as a tumor suppressor gene, has not been previously investigated in pituitary tumors. Objective: Our objective was to examine the expression of Wee1 in pituitary tumors and to identify microRNAs (miRs) that can regulate its expression. Design: Expression of Wee1 was examined by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Identification of miRs targeting the Wee1 3́-untranslated region was performed bymiRarray followed by expression analysis of identified miRs using qRT-PCR. Dual-luciferase assay and transient transfection of miRs into Hela cells followed by immunoblot analysis of Wee1 protein and cell proliferation analysis were carried out. Patients: A total of 57 pituitary tissue samples including 27 NFAs, 15 GH-producing adenomas with or without prolactin overproduction, and 15 normal pituitary glands were analyzed. Results: Wee1 protein expression was decreased in NFAs and GH-producing tumors with or without prolactin production, but no change in mRNA expression was observed with qRT-PCR. A specific subset of five miRNAs revealed by in silico target prediction was significantly overexpressed in NFA samples; three miRs (miR-128a, miR-155, and miR-516a-3p) targeted the 3′-untranslated region of the Wee1 transcript, and exogenous overexpression of these miRs inhibited Wee1 protein expression and HeLa cell proliferation. Conclusions: To our knowledge, this is the first report suggesting that regulation of Wee1 kinase by miRs may be linked to pituitary tumorigenesis. Copyright © 2010 by The Endocrine Society.


PubMed | University of Belgrade, National Institute of Neurosurgery, Hungarian Academy of Sciences, Semmelweis University and Queen Mary, University of London
Type: | Journal: Pathology oncology research : POR | Year: 2016

Dysregulation of G1/S checkpoint of cell cycle has been reported in pituitary adenomas. In addition, our previous finding showing that deregulation of Wee1 kinase by microRNAs together with other studies demonstrating alteration of G2/M transition in nonfunctioning pituitary adenomas (NFPAs) suggest that G2/M transition may also be important in pituitary tumorigenesis. To systematically study the expression of members of the G2/M transition in NFPAs and to investigate potential microRNA (miRNA) involvement. Totally, 80 NFPA and 14 normal pituitary (NP) tissues were examined. Expression of 46 genes encoding members of the G2/M transition was profiled on 34 NFPA and 10 NP samples on TaqMan Low Density Array. Expression of CDC25A and two miRNAs targeting CDC25A were validated by individual quantitative real time PCR using TaqMan assays. Protein expression of CDC25A, CDC25C, CDK1 and phospho-CDK1 (Tyr-15) was investigated on tissue microarray and immunohistochemistry. Several genes expression alteration were observed in NFPA compared to normal tissues by transcription profiling. On protein level CDC25A and both the total and the phospho-CDK1 were overexpressed in adenoma tissues. CDC25A correlated with nuclear localized CDK1 (nCDK1) and with tumor size and nCDK1 with Ki-67 index. Comparing primary vs. recurrent adenomas we found that Ki-67 proliferation index was higher and phospho-CDK1 (inactive form) was downregulated in recurrent tumors compared to primary adenomas. Investigating the potential causes behind CDC25A overexpression we could not find copy number variation at the coding region nor expression alteration of CDC25A regulating transcription factors however CDC25A targeting miRNAs were downregulated in NFPA and negatively correlated with CDC25A expression. Our results suggest that among alterations of G2/M transition of the cell cycle, overexpression of the CDK1 and CDC25A may have a role in the pathogenesis of the NFPA and that CDC25A is potentially regulated by miRNAs.


Nelson P.K.,NYU Langone Medical Center | Lylyk P.,Eneri Instituto Medico | Szikora I.,National Institute of Neurosurgery | Wetzel S.G.,University of Basel | And 2 more authors.
American Journal of Neuroradiology | Year: 2011

BACKGROUND AND PURPOSE: Endoluminal reconstruction with flow diverting devices represents a novel constructive technique for the treatment of cerebral aneurysms. We present the results of the first prospective multicenter trial of a flow-diverting construct for the treatment of intracranial aneurysms. MATERIALS AND METHODS: Patients with unruptured aneurysms that were wide-necked (>4 mm), had unfavorable dome/neck ratios (<1.5), or had failed previous therapy were enrolled in the PITA trial between January and May 2007 at 4 (3 European and 1 South American) centers. Aneurysms were treated with the PED with or without adjunctive coil embolization. All patients underwent clinical evaluation at 30 and 180 days and conventional angiography 180 days after treatment. Angiographic results were adjudicated by an experienced neuroradiologist at a nonparticipating site. RESULTS: Thirty-one patients with 31 intracranial aneurysms (6 men; 42-76 years of age; average age, 54.6 years) were treated during the study period. Twenty-eight aneurysms arose from the ICA (5 cavernous, 15 parophthalmic, 4 superior hypophyseal, and 4 posterior communicating segments), 1 from the MCA, 1 from the vertebral artery, and 1 from the vertebrobasilar junction. Mean aneurysm size was 11.5 mm, and mean neck size was 5.8 mm. Twelve (38.7%) aneurysms had failed (or recurred after) a previous endovascular treatment. PED placement was technically successful in 30 of 31 patients (96.8%). Most aneurysms were treated with either 1 (n = 18) or 2 (n = 11) PEDs. Fifteen aneurysms (48.4%) were treated with a PED alone, while 16 were treated with both PED and embolization coils. Two patients experienced major periprocedural stroke. Follow-up angiography demonstrated complete aneurysm occlusion in 28 (93.3%) of the 30 patients who underwent angiographic follow-up. No significant in-construct stenosis (≥50%) was identified at follow-up angiography. CONCLUSIONS: Intracranial aneurysm treatment with the PED is technically feasible and can be achieved with a safety profile analogous to that reported for stent-supported coil embolization. PED treatment elicited a very high rate (93%) of complete angiographic occlusion at 6 months in a population of the most challenging anatomic subtypes of cerebral aneurysms. Copyright © 2011 by the American Society of Neuroradiology.


Vitanovics D.,National Institute of Neurosurgery | Balint K.,National Institute of Neurosurgery | Hanzely Z.,National Institute of Neurosurgery | Banczerowski P.,National Institute of Neurosurgery | Afra D.,National Institute of Neurosurgery
Pathology and Oncology Research | Year: 2010

Purpose: to retrospectively determine the long-term outcome of adult intracranial ependymoma patients treated with surgery, reoperation, and postoperative radiation therapy. Material and Methods: 61 patients were treated at our institution between 1980 and 2004. Forty patients had World Health Organization (WHO) Grade II ependymoma, and 21 patients had Grade III ependymoma. The median age was 34 years. The majority of patients were female (59%), and 35 had gross total resections (60%). Eighteen patients were reoperated, 15 only once but 2 twice and one six times. Survival times following reoperation was mostly short but some of them reached more than 5 or 10 years. Postoperative radiation therapy was delivered to 31 patients postoperative (55.4%) and to 5 after reoperation, a median total dose of 54 Gy. Results: The median follow-up of surviving patients was 10.6 years. The 5-year and 10-year diseasefree survival rates for all patients were 50% and 32.9% respectively. The 5-year and 10-year overall survival rates for all patients were 57.1% and 39.4%, respectively. A statistically significant effect on prognosis was observed with WHO tumour grade as well as with MIB-1 labelling index. Subtotal resection predicted a worse overall survival, but this failed to reach statistical significance. No statistically significant effect on prognosis was observed with tumour location and radiation therapy. Conclusion: In our experience the use of radiotherapy in adult, intracranial WHO Grade II ependymoma patients had no significant effect on prognosis. Radical surgery and eventual reoperation seems to be more favorable. © 2009 Arányi Lajos Foundation.


Butz H.,Semmelweis University | Liko I.,Gedeon Richter Plc | Czirjak S.,National Institute of Neurosurgery | Igaz P.,Semmelweis University | And 4 more authors.
Pituitary | Year: 2011

MicroRNAs (miRs) are small, 16-29 nucleotide long, non-coding RNA molecules which regulate the stability or translational efficiency of targeted mRNAs via RNA interference. MiRs participate in the control of cell proliferation, cell differentiation, signal transduction, cell death, and they play a role in carcinogenesis. The aims of our study were to analyse the expression profile of miRs in sporadic clinically non-functioning pituitary adenomas (NFPA) and in normal pituitary tissues, and to identify biological pathways altered in these pituitary tumors. MiR expression profiles of 12 pituitary tissue specimens (8 NFPA and 4 normal pituitary tissues) were determined using miR array based on quantitative real-time PCR with 678 different primers. Five overexpressed miRs and mRNA expression of Smads (Smad1-9), MEG and DLK1 genes were evaluated with individual Taqman assays in 10 NFPA and 10 normal pituitary tissues. Pathway analysis was performed by the DIANA-mirPath tool. Complex bioinformatical analysis by multiple algorithms and association studies between miRs, Smad3 and tumor size was performed. Of the 457 miRs expressed in both NFPA and normal tissues, 162 were significantly under- or overexpressed in NFPA compared to normal pituitary tissues Expression of Smad3, Smad6, Smad9, MEG and DLK1 was significantly lower in NFPA than in normal tissues. Pathway analysis together with in silico target prediction analysis indicated possible downregulation of the TGFβ signaling pathway in NFPA by a specific subset of miRs. Five miRs predicted to target Smad3 (miR-135a, miR-140-5p, miR-582-3p, miR-582-5p and miR-938) were overexpressed. Correlation was observed between the expression of seven overexpressed miRs and tumor size. Downregulation of the TGFβ signaling through Smad3 via miRs may have a possible role in the complex regulation of signaling pathways involved in the tumorigenesis process of NFPA. © 2010 Springer Science+Business Media, LLC.


Szikora I.,National Institute of Neurosurgery | Berentei Z.,National Institute of Neurosurgery | Kulcsar Z.,National Institute of Neurosurgery | Marosfoi M.,National Institute of Neurosurgery | And 4 more authors.
American Journal of Neuroradiology | Year: 2010

BACKGROUND AND PURPOSE: Aneurysm treatment by intrasaccular packing has been associated with a relatively high rate of recurrence. The use of mesh tubes has recently gained traction as an alternative therapy. This article summarizes the midterm results of using an endoluminal sleeve, the PED, in the treatment of aneurysms. MATERIALS AND METHODS: A total of 19 wide-neck aneurysms were treated in 18 patients: 10 by implantation of PEDs alone and 9 by a combination of PED and coils. Angiographic and clinical results were recorded immediately and at 6 months following treatment. RESULTS: Immediate angiographic occlusion was achieved in 4 and flow reduction, in another 15 aneurysms. Angiography at 6 months demonstrated complete occlusion in 17 and partial filling in 1 of 18 patients. There was no difference between coil-packed and unpacked aneurysms. Of 28 side branches covered by ≥1 device, the ophthalmic artery was absent immediately in 1 and at 6 months in another 2 cases. One patient experienced abrupt in-stent thrombosis resulting in a transient neurologic deficit, and 1 patient died due to rupture of a coexisting aneurysm. All giant aneurysms treated with PED alone were demonstrated by follow-up cross-sectional imaging to have involuted by 6 months. CONCLUSIONS: Treatment of large, wide-neck, or otherwise untreatable aneurysms with functional reconstruction of the parent artery may be achieved with relative safety using dedicated flow-modifying devices with or without adjunctive use of intrasaccular coil packing.


Banczerowski P.,National Institute of Neurosurgery | Banczerowski P.,Semmelweis University | Czigleczki G.,Semmelweis University | Papp Z.,National Institute of Neurosurgery | And 3 more authors.
Neurosurgical Review | Year: 2015

Minimally invasive procedures in spine surgery have undergone significant development in recent times. These procedures have the common aim of avoiding biomechanical complications associated with some traditional destructive methods and improving efficacy. These new techniques prevent damage to crucial posterior stabilizers and preserve the structural integrity and stability of the spine. The wide variety of reported minimally invasive methods for different pathologies necessitates a systematic classification. In the present review, authors first provide a classification system of minimally invasive techniques based on the location of the pathologic lesion to be treated, to help the surgeon in selecting the appropriate procedure. Minimally invasive techniques are then described in detail, including technical features, advantages, complications, and clinical outcomes, based on available literature. © 2014, Springer-Verlag Berlin Heidelberg.


Papp Z.,Semmelweis University | Papp Z.,National Institute of Neurosurgery | Czigleczki G.,National Institute of Neurosurgery | Banczerowski P.,Semmelweis University | Banczerowski P.,National Institute of Neurosurgery
Spine | Year: 2013

Study Design. Case report. Objective. To report an unusual case of a 4-week-old infant with multiple abscesses, which propagated to the cervical region and destroyed the C1-C2 vertebrae. Summary of Background Data. Cervical vertebral osteomyelitis involving the atlas and axis in childhood is distinctly unusual, which may lead to the rapid destruction of the vertebral body. Propagation of a retropharyngeal abscess is the major cause of cervical vertebral osteomyelitis. Only a limited number of infant case reports are published, and no case of osteomyelitis with the destruction of both the atlas and the dens axis has been reported previously. Methods. A 1-month-old infant with multiple craniospinal and thoracic abscesses was surgically treated. Therapy was completed with antibiotics and immobilization. Follow-up was carried out with magnetic resonance imaging, computed tomographic scans, and functional radiographical diagnostics. Results. The retropharyngeal and thoracic abscesses were surgically removed. The infant was placed in a custom-made fixation device for 8 weeks. Two months later, follow-up functional examination revealed no significant instability of the cervical spine. During a 3-year-long follow-up period, no signs of neurological impairment were observed, neck movements were limited but painless. It is assumed that the remnants of the bony elements of C1-C2 vertebrae and the massive interconnecting postinfl ammatory scar tissue make some degree of neck movements possible. Conclusion. C1-C2 osteomyelitis is a very rare entity even in children. There is limited experience with treatment, but immobilization of the neck, surgical debridement, drainage, and antibiotic treatment can be recommended. Close follow-up is required to check the reconstitution of affected bones and ligaments, any development of instability, and the necessity of surgical stabilization. Copyright © 2013 Lippincott Williams & Wilkins.


Banczerowski P.,National Institute of Neurosurgery | Veres R.,National Institute of Neurosurgery | Vajda J.,National Institute of Neurosurgery
Journal of Neurological Surgery, Part A: Central European Neurosurgery | Year: 2014

Background The conventional posterior approaches, which may involve multilevel laminectomies and facetectomies, may lead to spinal deformities, instability, or subluxation. Our objective was to develop a minimally invasive approach suitable for exploring neuromas with an intraforaminal component in the cervical spine, with the aim of preserving mechanically relevant bone structures and the facet joints as much as possible. Methods The authors used the hemi-semi-laminectomy combined with partial lateral facetectomy open-tunnel technique in nine adult patients with neuromas of the cervical spine extending into the foramen. Results The operating field under the operating microscope was sufficient for tumor removal according to the keyhole concept. The approach did not affect the extent of tumor resection or neurological outcome. Complete removal was achieved in all patients, as confirmed by magnetic resonance imaging (MRI). The affected nerve roots included C3 in three cases, C2 and C4 in two, and C5 and C6 in one case. Average follow-up was 12 months, with a range from 8 to 18 months. Histological results were as follows: six schwannomas and three neurofibromas. Computed tomographic scans demonstrated the extension of the keyhole approaches and the moderately affected bony structures and facet joints. Instability was detected in none of the patients on the flexion or extension lateral radiographs during the follow-up period. Conclusion This modified surgical approach fulfills the requirements of other minimally invasive techniques and lowers the risk of damage to the crucial posterior stabilizers of the spine; furthermore, disintegration of vertebral arches and facet joints is reduced. The approach is suitable for exploring and removing neuromas located in the spinal canal and in the neuroforamen. © 2014 Georg Thieme Verlag KG Stuttgart New York.


PubMed | National Institute of Neurosurgery
Type: Journal Article | Journal: Neurological research | Year: 2016

Three methods of intercepting the blood supply to the brain were tested by means of X-ray angiography and by monitoring the pressor response following cerebral ischaemia. The methods were: (1) occlusion of carotid and basilar artery; (2) occlusion of carotids and vertebral arteries in the cervical canal of the third vertebra; (3) occlusion of carotid and subclavian arteries. The X-ray angiographs showed that in most cases we could close the accessory sources of the cerebral circulation and drastically reduce the blood supply to the brain of the cat. With all three methods the cerebral ischaemia evoked strong blood pressor elevation, which was weaker however when the carotid and basilar artery were clamped, in comparison with the other two methods. This may be explained by the existence of small arteries supplying the lower brain stem and originating intracranially from the vertebral artery near to the junction of the vertebral and anterior spinal artery.

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