Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets.

Anti-cancer therapies often exhibit only short-term effects. Tumors typically develop drug resistance causing relapses that might be tackled with drug combinations. Identification of the right combination is challenging and would benefit from high-content, high-throughput combinatorial screens directly on patient biopsies. However, such screens require a large amount of material, normally not available from patients. To address these challenges, we present a scalable microfluidic workflow, called Combi-Seq, to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout for drug effects. We devise a deterministic combinatorial DNA barcoding approach to encode treatment conditions, enabling the gene expression-based readout of drug effects in a highly multiplexed fashion. We apply Combi-Seq to screen the effect of 420 drug combinations on the transcriptome of K562 cells using only ~250 single cell droplets per condition, to successfully predict synergistic and antagonistic drug pairs, as well as their pathway activities.

Surgical management of anterior clinoidal meningiomas: consensus statement on behalf of the EANS skull base section.

BACKGROUND: The optimal management of clinoidal meningiomas (CMs) continues to be debated. METHODS: We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of these tumors. The data from the literature along with contemporary practice patterns were discussed within the task force to generate consensual recommendations. RESULTS AND CONCLUSION: This article represents the consensus opinion of the task force regarding pre-operative evaluations, patient's counselling, surgical classification, and optimal surgical strategy. Although this analysis yielded only Class B evidence and expert opinions, it should guide practitioners in the management of patients with clinoidal meningiomas and might form the basis for future clinical trials.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

History, development and use of classification of thoracolumbar spine fractures.

The main goal of this comprehensive paper is to clarify the way of thoracolumbar spine The main goal of this summary paper is to describe the way of thoracolumbar spine injury classification development and to provide a detailed description of two of the most commonly used classifications - the Thoracolumbar Injury Classification and Severity Scale (TLICS) and the AOSpine Classification for Traumatic Fracture of the Thoracolumbar Spine, including their comparison and clarification of the merits introduced by the second one. The paper also formulates a recommendation of a simple algorithm enabling even less experienced clinicians to distinguish between an injury indicated for conservative treatment and one that requires surgery.

BRD4 bimodal binding at promoters and drug-induced displacement at Pol II pause sites associates with I-BET sensitivity.

BACKGROUND: Deregulated transcription is a major driver of diseases such as cancer. Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are chromatin readers essential for maintaining proper gene transcription by specifically binding acetylated lysine residues. Targeted displacement of BET proteins from chromatin, using BET inhibitors (I-BETs), is a promising therapy, especially for acute myeloid leukemia (AML), and evaluation of resistance mechanisms is necessary to optimize the clinical efficacy of these drugs. RESULTS: To uncover mechanisms of intrinsic I-BET resistance, we quantified chromatin binding and displacement for BRD2, BRD3 and BRD4 after dose response treatment with I-BET151, in sensitive and resistant in vitro models of leukemia, and mapped BET proteins/I-BET interactions genome wide using antibody- and compound-affinity capture methods followed by deep sequencing. The genome-wide map of BET proteins sensitivity to I-BET revealed a bimodal pattern of binding flanking transcription start sites (TSSs), in which drug-mediated displacement from chromatin primarily affects BRD4 downstream of the TSS and prolongs the pausing of RNA Pol II. Correlation of BRD4 binding and drug-mediated displacement at RNA Pol II pause sites with gene expression revealed a differential behavior of sensitive and resistant tumor cells to I-BET and identified a BRD4 signature at promoters of sensitive coding and non-coding genes. CONCLUSIONS: We provide evidence that I-BET-induced shift of Pol II pausing at promoters via displacement of BRD4 is a determinant of intrinsic I-BET sensitivity. This finding may guide pharmacological treatment to enhance the clinical utility of such targeted therapies in AML and potentially other BET proteins-driven diseases.

Epidural hematoma - benign or potentially malignant disease?

INTRODUCTION: Epidural hematoma (EDH) is generally considered to be a condition with a good prognosis. However, postoperative results of numerous studies have shown that mortality and morbidity remain relatively high. The aim of our article is to evaluate surgical outcomes in patients undergoing EDH evacuation over the last five years. METHODS: Data were analysed retrospectively. Pre-operative GCS was assessed. Location and incidence of associated head injuries were recorded. Two groups were established: 1. "immediate-care-requiring" and "followed-up" patients. Time interval CT - surgery was measured in the first group and the number of CT scans in the second group. Complications were divided into general and surgical. Outcome was evaluated on GOS. RESULTS: 67 patients underwent the surgery. At admittance, GCS was 13-15 in 55%, 9-12 in 8% and 3-8 in 37% of the patients. EDH was mostly located in the temporal region - in 52%. Associated head injuries occurred in 76%. Mean interval CT - operation lasted 2h 15min in the first group. Two pre-operative CT scans were done in 88% of the patients in the second group. General complications occurred in 34% and surgical in 15%. Mortality rate was 6%. 20% of the patients had a GOS of 1-3 and 80% of them had a GOS of 4-5. CONCLUSION: Our results have shown that morbidity and mortality after EDH evacuation are still relatively high. 14% of the patients remained disabled, and 6% died. The outcome depends mostly on preoperative clinical picture and timing of the surgery. Key words: epidural hematoma - evacuation - neurological outcome - timing of the surgery.

Subdural empyema case report of a rare disease with a high mortality.

Subdural empyema is a rare purulent intracranial infection. Outcome is dependent on the preoperative level of consciousness, therefore an early diagnosis and urgent neurosurgical intervention are necessary. Mortality of subdural empyema remains high, ranging from 6% to 15%. The case report presents a patient with subdural empyema which resulted from sinusitis. The integral and first part of therapy was an urgent neurosurgical drainage of subdural empyema, followed by functional endoscopic sinus surgery performed by ENT surgeon. Conservative treatment consisted of systemic antibiotics and antiedematous therapy. Later the patient developed post-infectious hydrocephalus, which was solved by implantation of a ventriculo-peritoneal shunt. Consequently, cranioplasty was performed. Despite acute onset of the disease and severe neurologic deficit prior to the first neurosurgical intervention, the clinical condition of the patient is favorable after multiple surgeries. The patient is able to live independently without any significant limitations in everyday activities. The presenting symptoms of subdural empyema are reflective of increased intracranial pressure, meningeal irritation, and cerebritis. Radiographic imaging (contrast CT, DWI-MRI, contrast MRI) is an essential diagnostic tool. The integral part of therapy is a neurosurgical evacuation of subdural empyema combined with intravenous antibiotic therapy. Subdural empyema is a rare, rapidly progressing disease which is underestimated by the physicians in many cases. Diagnosis is often delayed and therefore, despite recent progress in treatment, the mortality rate remains high. Key words: empyema - subdural - sinusitis - diagnostic imaging - surgical method.

Intramedullary ependymoma: long-term outcome after surgery.

BACKGROUND: Overall (OS) and progression-free survival (PFS) of patients undergoing spinal ependymoma resection has been frequently reported. Contrarily, OS and PFS of purely intramedullary ependymomas have not been clearly determined yet. METHODS: The data of 37 patients undergoing resection of an intramedullary ependymoma (IE) from January 2000 to December 2016 were analysed retrospectively. RESULTS: The mean age was 46 years. The male:female ratio was 24:13. The median duration of symptoms was 12 months. Sixty-two per cent of ependymomas were in the cervical, 24% in the thoracic, and 14% in the conus region in our series. The median volume was 1.3 ml. A syrinx was found in 49% and a cyst in 32%. GTR was achieved in 89%, STR in three (8%), and PR in one patient (3%). Median follow-up was 114 months. PFS was 87%, 82%, and 82% at 5, 10, and 15 years, respectively. OS was 97%, 88%, and 63% at 5, 10, and 15 years, respectively. There was a significant difference in PFS depending on the extent of resection and in OS depending on the pre-operative clinical status. There was no significant difference in OS and PFS regarding the other examined influencing factors. CONCLUSION: GTR resection was the most important factor influencing PFS. According to our results OS of IEs is much worse than that of spinal ependymomas. Our analysis confirms that patients with good pre-operative (McCormick grade 1 and 2) clinical status have significantly better OS than patients with McCormick grade 3 and higher.

Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia.

In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0.0068, Fisher's exact test) in 32/67 of T-ALL relapse samples. Alterations of TP53 were frequently homozygous events, which significantly correlated with higher rates of copy number alterations in other genes compared with wild-type TP53 (P=0.0004, Mann-Whitney's test). We subsequently focused on mutations with prognostic impact and identified genes governing DNA integrity (TP53, n=8; USP7, n=4; MSH6, n=4), having key roles in the RAS signaling pathway (KRAS, NRAS, n=8), as well as IL7R (n=4) and CNOT3 (n=4) to be exclusively mutated in fatal relapses. These markers recognize 24/49 patients with a second event. In 17 of these patients with mostly refractory relapse and dire need for efficient treatment, we identified candidate targets for personalized therapy with p53 reactivating compounds, MEK inhibitors or JAK/STAT-inhibitors that may be incorporated in future treatment strategies.

IDH1/2 Mutation and MGMT Promoter Methylation - the Relevant Survival Predictors in Czech Patients with Brain Gliomas.

Gliomas are a heterogeneous group of tumours varying in prognosis, treatment approach, and overall survival. Recently, novel markers have been identified which are linked to patient prognosis and therapeutic response. Especially the mutation of the enzyme isocitrate dehydrogenase 1 or 2 (IDH1/2) gene and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival. From 2012 to 2015, 94 Czech patients with primary brain tumours were enrolled into the study. The IDH1/2 mutation was detected by denaturing capillary electrophores.The methylation status of the MGMT gene and other 46 genes was revealed by MS-MLPA. In all 94 patients, the clinical data were correlated with molecular markers by Kaplan-Meier analyses and Cox regression model. The MGMT promoter methylation status was established and compared to clinical data. In our study eight different probes were used to elucidate the MGMT methylation status; hypermethylation was proclaimed if four and more probes were positive. This 3 : 5 ratio was tested and confirmed by Kaplan-Meier and Cox analyses. The study confirmed the importance of the IDH1/2 mutation and hypermethylation of the MGMT gene promoter being present in tumour tissue. Both markers are independent positive survival predictors; in the Cox model the IDH hazard ratio was 0.10 and in the case of MGMT methylation it reached 0.32. The methylation analysis of the panel of additional 46 genes did not reveal any other significant epigenetic markers; none of the candidate genes have been confirmed in the Cox regression analyses as an independent prognostic factor.

[Surgical approaches to pineal region - review article]. / Chirurgické prístupy do pineální krajiny - prehled.

INTRODUCTION: The pineal region is a deep-seated part of the brain surrounded by highly eloquent structures. Differential diagnosis of space-occupying lesions in this region encompasses pineal gland cysts, pineal gland tumours, metastases, germ cell tumours, meningiomas, gliomas, hemangioblastomas and neuroectodermal tumours. A treatment strategy is based mainly on tumour anatomical characteristics and histological type. Except germinatous tumours, a surgical excision is the treatment of choice. METHODS: Microsurgical approaches: The microsurgical supracerebellar-infratentorial approach is an essential approach to the pineal region. Despite certain risks, it allows a straightforward and completely extracerebral approach with a minimal cerebellar retraction. The other basic approach is the microsurgical occipital-transtentorial approach that is advantageous in patients with a supratentorial tumour extension or a steep tentorium. The interhemispheric-transcallosal approach and the transcortical-transventricular approach are possible options in selected cases.Endoscopic approaches: The neuroendoscopy provides a minimally invasive method to perform a tumour biopsy and to treat hydrocephalus in one session. Stereotactic biopsy: The stereotactic needle biopsy represents an alternative to the endoscopic biopsy in patients without hydrocephalus and in patients with dorsally located lesions inaccessible from the third ventricle. CONCLUSION: Modern neurosurgery offers a rich variety of surgical approaches to the pineal region. The complexity of space-occupying lesions in this region requires an individualised treatment, a prudent preoperative planning and a meticulous surgical technique.

Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.

[Endoscopic endonasal treatment of cerebrospinal fluid leak caused by clival fracture--a case report]. / Endoskopické endonazální osetrení nasální likvorey pri zlomenine klivu--kazuistika.

INTRODUCTION: Clivus is a central structure of the skull base located in the vicinity of the brainstem and vital brain vessels. Clival fractures are usually caused by a high-energy trauma. Cerebrospinal fluid leak is one of the most common complications. CASE REPORT: A middle-aged male sustained a mild head trauma, followed by a nasal cerebrospinal fluid leak. CT scan revealed the massive pneumocephalus and the fracture of the clivus in the posterior wall of the sphenoidal sinus. We performed an endoscopic endonasal surgery to seal the defect. DISCUSSION: Pneumatization of a sphenoidal sinus shows high variability. In the presented case, extreme pneumatization of the sinuses was combined with the gracile clivus, which was the predisposing factor for fracture. Traumatic cerebrospinal fluid leak carries the risk of intracranial hypotension and meningitis. Microscopic transseptal management is the classical surgical approach, while endoscopy provides the modern miniinvasive option. CONCLUSION: Endoscopic endonasal treatment of traumatic cerebrospinal fluid leak is the treatment of choice for the clival fractures.

[Correction of kyphotic deformity of the cervical spine in ankylosing spondylitis using pedicle subtraction osteotomy of the seventh cervical vertebra]. / Korekce kyfotické deformity krcní pátere pri ankylozující spondyloartritide pedikl subtrakcní osteotomií sedmého krcního obratle.

PURPOSE OF THE STUDY: The aim of the study is to present the technique of pedicle subtraction osteotomy (PSO) of the seventh cervical vertebra (C7) for correction of rigid kyphotic deformity of the cervicothoracic junction (C/Th) in patients with severe ankylosing spondylitis (AS).. MATERIAL AND METHODS: The PSO technique for correction of rigid deformity of the C/Th spine was used in five patients with the aim to restore their ability of horizontal vision. The follow-up in all patients lasted two years at least. Clinical assessment of treatment results was based on the patients' neurological status and their satisfaction with the correction achieved. Improvement in a vertical 2) line of sight was evaluated using the angle measured between the forehead-chin line and the vertical (FCv angle) in a lateral view photograph of the standing patient. The achieved correction of kyphotic deformity was assessed by comparing the pre-operative Cobb's angle between the second cervical and the fourth thoracic vertebra with the post-operative one. RESULTS: The average operative time was 4 hours (range, 3.5 to 5 h). The average blood loss was 1600 ml (range, 800 to 2100 ml). On the average, the FCv angle was reduced by 45.2° and Cobb's angle was corrected) by 54.6°. All patients were satisfied with the degree of correction achieved and reported alleviation of neck pain. none of the patients showed any significant loss of correction or neurological deterioration at two-year follow-up. DISCUSSION: The theoretical and technical principles of corrective osteotomy at the C7 level performed for rigid kyphotic deformity of the spine at the C/Th junction are presented in our group of patients. Our results give support to the superiority of instrumented PSO used currently over the previous techniques. In accordance with the relevant literature data, attention is drawn to a relatively higher risk of this procedure in comparison with corrective surgery performed at the other spinal levels. CONCLUSIONS: Corrective osteotomy of a rigid kyphotic deformity at the C/Th spine level in AS patients involves a complex reconstructive surgical procedure. The PSO technique reduces the risk of injury to the visceral structures ventral to the spine, and provides optimal conditions for bone healing at the site of vertebral body resection. If the patient heals well, a successful PSO procedure will markedly improve the quality of his/her life.

Carotid endarterectomy and carotid artery stenting: changing paradigm during 10 years in a high-volume centre.

BACKGROUND: We analysed the results of internal carotid artery (ICA) stenosis treatment at our institution over the last 10 years according to treatment modalities (carotid endarterectomy [CEA] vs carotid artery stenting [CAS]). Furthermore, we compared our results of treatment prior to the EVA-3S study being implemented into our practice (2003-2007) and after that (2008-2012). METHOD: During the years 2003-2012, a total of 1,471 procedures were performed for ICA stenosis. CEA was done in 815 cases and CAS in 656 cases. The primary outcome was disabling stroke (mRS > 2) or myocardial infarction (MI) within 30 days after treatment. Secondary outcomes were frequency of transient ischaemic attacks (TIAs), minor strokes (stroke without impaired activities of daily living [ADL]) and any other significant complication. Comparisons of the results before and after 2008 were performed. RESULTS: Major mortality and morbidity were divided according to treatment groups; reached 1.0 % in the CEA group and 3.0 % in the CAS group, p = 0.004. Minor stroke was recorded at 1.8 % and 2.7 % in the CEA and CAS, p = 0.245. TIAs in 1.0 % (CEA) and 4.7 % (CAS), p < 0.001. Any complication in 11.9 % (CEA) and 13.3 % (CAS), p = 0.401. In the overall results (i.e. CEA and CAS together), we found in 2008-2012 a decrease of incidence of TIAs (from 30/840 to 9/631, p = 0.011) and any complications (from 120/840 to 64/631, p = 0.017). CONCLUSIONS: CEA performed in a high-volume centre is a safe procedure in properly indicated patients. In all subgroup analyses, CEA fared better than or at least of equal benefit as CAS. Since 2008, the frequency of TIAs and other complications decreased significantly. This study supports an idea of CEA being the first choice of treatment and CAS being reserved for strictly selected cases, such as re-stenosis after a previous carotid procedure, carotid dissection, ICA stenosis after radiotherapy, previous major neck surgery, contralateral cranial nerve palsy or tandem stenosis.

Surgery of brainstem cavernous malformations.

BACKGROUND: Cavernomas are vascular hamartomas made up of thin-walled, grossly dilated blood vessels lined with endothelium. Between 4 and 35 % (mean 15 %) of cerebral cavernomas are located in the brainstem making resection of these lesions one of the most challenging tasks in neurosurgery. METHODS: Patients with cavernomas within the brainstem or deep supratentorial structures were chosen from our prospectively collected database of operated patients with brain cavernomas. The timespan of treatment was between January 1998 and June 2012. Primary outcome was defined as percentage of patients with favourable outcome (Glasgow Outcome Scale (GOS) 4 or 5) at 1 year. Secondary outcome was defined as operation-related morbidity and mortality (drop at least 1 point on GOS at 1 year). RESULTS: A total of 37 patients underwent surgery. The mean age was 34.7 ± 11.7 years. The male to female ratio was 19:16. Thirty-two patients had a solitary lesion and 12 patients harboured multiple lesions. The Glasgow outcome score 4 or 5 was achieved after 34 operations (89.5 %). The mean follow-up was 39 months. We experienced two early post-operative deaths (5.3 %) and decrease in the Glasgow outcome scale postoperatively in 4 patients (10.5 %). CONCLUSIONS: • Favourable outcome was achieved in 89.5 % of cases. • Although M&M appears to be relatively high, surgery is method of choice for surgically accessible lesion which has bled for the first time due to reported high rebleed rate and high probability of poor outcome after cavernoma rebleed. • Radiosurgery should be reserved for those lesions which are deemed unresectable and where surgical intervention is considered favourable to observation alone.

[The significance of biological intracranial meningioma behaviour for their long-term management]. / Význam biologického chování nitrolebních meningiomu pro jejich dlouhodobý management.

INTRODUCTION: From the histological point of view, most meningiomas are benign tumours. Nevertheless, their recurrence is quite frequent, and identifying the risk factors for recurrent disease is of utmost importance. MATERIAL AND METHODS: Prospective study, patients operated on in the period 2/2008-9/2009. Inclusion criteria for enrolment into the study: age 18-70 years, good health status, and previously untreated solitary intracranial meningioma. Evaluation of clinical, surgical, MRI findings and vascular endothelial growth factor serum levels (prior to procedure, 3 months after, 12 months after, 24 months after procedure and at the time of the last follow-up in 11/2011) was performed. Immunohistochemical analysis of histological samples was carried out. Further treatment (wait and see, redo surgery, treatment with radiation using the Leksell Gamma Knife, external radiotherapy) was recorded in case of a positive follow-up MRI finding (recurrent disease, progression of residual tumour). RESULTS: A total of 50 consecutive patients (34 women and 16 men) were included into the study. Average age at the time of surgery was 59.2 years (range 27-75 years). Radical resection with no residual tumour left was achieved in 35 cases. Histological analysis showed grade I meningioma in 45 cases and grade II (atypical) meningioma in 5 cases. Correlation between E-cadherin expression and recurrent meningioma was proved by immunohistochemical examinations; in the remaining investigations, however, such a correlation was not found. No correlation was detected between the serum vascular endothelial growth factor level and the expression of vascular endothelial growth factor in immunohistochemical investigation. A correlation was found between the expression of vascular endothelial growth factor in immunohistochemical investigation and peritumoural oedema. The tumour recurred in 5 cases. CONCLUSIONS: On the basis of our results as well as literature findings we can conclude that all the patients after meningioma surgery need to be carefully followed for the rest of their life by repeated MRI invetigations.

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer.

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERα and ERß, transcription factors that display functional antagonism with each other, with ERß acting as oncosuppressor and interfering with the effects of ERα on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERα+ BC cells often lack ERß, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERß might influence BC cell behavior via miRNAs, we compared miRNome expression in ERß+ vs ERß- hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERß in BC cells, clearly distinguishes ERß+, node-negative, from ERß-, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERß+ in BC cell nuclei. In particular, ERß downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERα on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERß in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

Haemorrhage from a radiosurgically treated arteriovenous malformation after its angiographically proven obliteration: a case report.

Small lower-grade Spetzler-Martin arteriovenous malformations (AVMs) are mainly treated by microsurgical resection or stereotactic radiosurgery. The choice of treatment largely depends on the referring centre's preference and the patient's decision. We present here a patient with an AVM repeatedly treated at our Leksell Gamma Knife unit with radiographically confirmed obliteration of the AVM which subsequently began bleeding. This case demonstrates the possibility of late complications in radiosurgically treated AVMs even after their demonstrable obliteration. Meticulous histological examination was performed, proving patency of the AVM nidus. The risk of haemorrhagic complications of radiosurgically removed AVMs despite angiographic proof of their obliteration is, in our view, a cogent argument for preferring surgical resection if the AVM is accessible and for prolonged follow-up after radiosurgical treatment of an AVM.

[Solitary spinal osteochondroma. Case report]. / Solitární páterní osteochondrom diagnostikovaný u 75letého muze.

Spinal osteochondromas as solitary lesions are rare tumours of a maturing adolescent skeleton. The authors treated a 75-year-old man for low back pain and neurogenic claudication. Symptoms were attributed to a tumorous expansion originating from the spinous process and right lamina of L3 and expanding into the spinal canal and adjacent facet joints. The patient underwent marginal resection of the tumour together with transpedicular stabilization of the segment, and histological examination confirmed the diagnosis of osteochondroma. The patient remains without any complaint and there are no signs of local recurrence of the tumour 4 years after the surgery. The cases of osteochondroma in an aged spine published in the literature and pertinent aspects of this extremely rare condition are discussed. Key words: spinal tumors, osteochondroma.