The FRESH Study: Treatment of Intracranial Aneurysms with the New FRED X Flow Diverter with Antithrombotic Surface Treatment Technology-First Multicenter Experience in 161 Patients.

BACKGROUND AND PURPOSE: Flow diverters with antithrombotic coatings are increasingly used to improve the safety of flow diverter treatments of intracranial aneurysms. This study aimed to investigate the safety and short-term efficacy of the new FRED X flow diverter. MATERIALS AND METHODS: Medical charts and procedural and imaging data of a consecutive series of patients with intracranial aneurysms who were treated with the FRED X at 9 international neurovascular centers were retrospectively analyzed. RESULTS: One hundred sixty-one patients (77.6% women; mean age, 55 years) with 184 aneurysms (11.2% acutely ruptured) were included in this study. Most aneurysms were located in the anterior circulation (77.0%), most frequently at the ICA (72.7%). The FRED X was successfully implanted in all procedures. Additional coiling was performed in 29.8%. In-stent balloon angioplasty was necessary in 2.5%. The rate of major adverse events was 3.1%. Thrombotic events occurred in 7 patients (4.3%) with 4 intra- and 4 postprocedural in-stent thromboses, respectively (1 patient had both peri- and postprocedural thrombosis). Of these thrombotic events, only 2 (1.2%) led to major adverse events (ischemic strokes). Postinterventional neurologic morbidity and mortality were observed in 1.9% and 1.2%, respectively. The rate of complete aneurysm occlusion after a mean follow-up of 7.0 months was 66.0%. CONCLUSIONS: The new FRED X is a safe and feasible device for aneurysm treatment. In this retrospective multicenter study, the rate of thrombotic complications was low, and the short-term occlusion rates are satisfactory.

Surpass flow diverter in the treatment of intracranial aneurysms: a prospective multicenter study.

BACKGROUND AND PURPOSE: Incomplete occlusion and recanalization of large and wide-neck brain aneurysms treated by endovascular therapy remains a challenge. We present preliminary clinical and angiographic results of an experimentally optimized Surpass flow diverter for treatment of intracranial aneurysms in a prospective, multicenter, nonrandomized, single-arm study. MATERIALS AND METHODS: At 24 centers, 165 patients with 190 intracranial aneurysms of the anterior and posterior circulations were enrolled. The primary efficacy end point was the percentage of intracranial aneurysms with 100% occlusion on 6-month DSA. The primary safety end point was neurologic death and any stroke through a minimum follow-up of 6 months. RESULTS: Successful flow-diverter delivery was achieved in 161 patients with 186 aneurysms (98%); the mean number of devices used per aneurysm was 1.05. Clinical follow-up (median, 6 months) of 150 patients (93.2%), showed that the primary safety end point occurred in 18 subjects. Permanent neurologic morbidity and mortality were 6% and 2.7%, respectively. Morbidity occurred in 4% and 7.4% of patients treated for aneurysms of the anterior and posterior circulation, respectively. Neurologic death during follow-up was observed in 1.6% and 7.4% of patients with treated intracranial aneurysms of the anterior and posterior circulation, respectively. Ischemic stroke at ≤30 days, SAH at ≤7 days, and intraparenchymal hemorrhage at ≤7 days were encountered in 3.7%, 2.5%, and 2.5% of subjects, respectively. No disabling ischemic strokes at >30 days or SAH at >7 days occurred. New or worsening cranial nerve deficit was observed in 2.7%. Follow-up angiography available in 158 (86.8%) intracranial aneurysms showed 100% occlusion in 75%. CONCLUSIONS: Clinical outcomes of the Surpass flow diverter in the treatment of intracranial aneurysms show a safety profile that is comparable with that of stent-assisted coil embolization. Angiographic results showed a high rate of intracranial aneurysm occlusion.

CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity.

CD99, a transmembrane protein encoded by MIC2 gene is involved in multiple cellular events including cell adhesion and migration, apoptosis, cell differentiation and regulation of protein trafficking either in physiological or pathological conditions. In osteosarcoma, CD99 is expressed at low levels and functions as a tumour suppressor. The full-length protein (CD99wt) and the short-form harbouring a deletion in the intracytoplasmic domain (CD99sh) have been associated with distinct functional outcomes with respect to tumour malignancy. In this study, we especially evaluated modulation of cell-cell contacts, reorganisation of the actin cytoskeleton and modulation of signalling pathways by comparing osteosarcoma cells characterised by different metastasis capabilities and CD99 expression, to identify molecular mechanisms responsible for metastasis. Our data indicate that forced expression of CD99wt induces recruitment of N-cadherin and ß-catenin to adherens junctions. In addition, transfection of CD99wt inhibits the expression of several molecules crucial to the remodelling of the actin cytoskeleton, such as ACTR2, ARPC1A, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) as well as ezrin, an ezrin/radixin/moesin family member that has been clearly associated with tumour progression and metastatic spread in osteosarcoma. Functional studies point to ROCK2 as a crucial intracellular mediator regulating osteosarcoma migration. By maintaining c-Src in an inactive conformation, CD99wt inhibits ROCK2 signalling and this leads to ezrin decrease at cell membrane while N-cadherin and ß-catenin translocate to the plasma membrane and function as main molecular bridges for actin cytoskeleton. Taken together, we propose that the re-expression of CD99wt, which is generally present in osteoblasts but lost in osteosarcoma, through inhibition of c-Src and ROCK2 activity, manages to increase contact strength and reactivate stop-migration signals that counteract the otherwise dominant promigratory action of ezrin in osteosarcoma cells.

Treatment of cavernous sinus aneurysms with flow diversion: results in 44 patients.

BACKGROUND AND PURPOSE: Aneurysms of the cavernous segment of the ICA are difficult to treat with standard endovascular techniques, and ICA sacrifice achieves a high rate of occlusion but carries an elevated level of surgical complications and risk of de novo aneurysm formation. We report rates of occlusion and treatment-related data in 44 patients with cavernous sinus aneurysms treated with flow diversion. MATERIALS AND METHODS: Patients with cavernous segment aneurysms treated with flow diversion were selected from a prospectively maintained data base of patients from 2009 to the present. Demographic information, treatment indications, number/type of flow diverters placed, outcome, complications (technical or clinical), and clinical/imaging follow-up data were analyzed. RESULTS: We identified 44 patients (37 females, 7 males) who had a flow diverter placed for treatment of a cavernous ICA aneurysm (mean age, 57.2; mean aneurysm size, 20.9 mm). The mean number of devices placed per patient was 2.2. At final angiographic follow-up (mean, 10.9 months), 71% had complete occlusion, and of those with incomplete occlusion, 40% had minimal remnants (<3 mm). In symptomatic patients, complete resolution or significant improvement in symptoms was noted in 90% at follow-up. Technical complications (which included, among others, vessel perforation in 4 patients, groin hematoma in 2, and asymptomatic carotid occlusion in 1) occurred in approximately 36% of patients but did not result in any clinical sequelae immediately or at follow-up. CONCLUSIONS: Our series of flow-diversion treatments achieved markedly greater rates of complete occlusion than coiling, with a safety profile that compares favorably with that of carotid sacrifice.

Prevalence of cerebral aneurysms in patients treated for left cardiac myxoma: a prospective study.

AIM: To estimate the prevalence of cerebral aneurysms in patients previously treated for left cardiac myxoma (LCM). MATERIALS AND METHODS: This prospective institutional review board-approved study included patients treated for LCM. All patients treated at our institution (IRCCS Policlinico San Donato, Italy) were telephoned and those enrolled underwent unenhanced brain magnetic resonance imaging (MRI) using sagittal T1-weighted turbo spin-echo (TSE); axial T2-weighted TSE; axial fluid-attenuated inversion-recovery; axial echo-planar diffusion-weighted; and three-dimensional time-of-flight angiographic sequences. RESULTS: Seventy-six patients were telephoned, and data regarding their clinical history since tumor resection were obtained for 49 patients (64%). Four of the 49 (8%) patients were deceased, one due to a cerebral hemorrhage from a ruptured cerebral aneurysm 8 years after tumor resection. One patient had a pacemaker preventing MRI. Of the remaining 44 patients, 31 refused MRI and 13 were enrolled (10 females; mean age 64 years). Three of the 13 (23%; two females; 59-78 years) were diagnosed with a cerebral aneurysm, from 2 mm to 4-5 mm in diameter, involving the right middle cerebral artery (n = 2) or the right internal carotid artery (n = 1). Including the deceased patient, the resulting prevalence was 4/14 (29%). CONCLUSION: From this preliminary study, one-third of patients treated for LCM may present with a cerebral aneurysm. Longitudinal large studies are needed to further clarify this matter.

Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial.

OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke.

Angiographic follow-up of traumatic carotid cavernous fistulas treated with endovascular stent graft placement.

BACKGROUND AND PURPOSE: Endovascular treatment (EVT) of carotid cavernous fistulas (CCFs) is based on various techniques, mainly those using detachable balloons. Coronary covered stent grafts have been sporadically used in the intracranial arteries and only 2 traumatic CCFs have been reported in the literature; moreover, there is poor information about the long-term follow-up. We present 8 cases of CCFs treated by the placement of a covered stent, 5 of which have a 1-year clinical and angiographic follow-up. METHODS: Eight patients with posttraumatic CCF were treated by positioning a covered stent in the intracranial internal carotid artery (ICA) to occlude the fistula. They received periodic clinical and angiographic follow-up to evaluate the patency and the stability of clinical results. RESULTS: In all cases, the symptoms related to the CCF regressed after treatment and did not recur in the follow-up. Two patients presented residual filling of the CCF at the end of the procedure. The angiographic follow-up revealed in 6 patients of 7 a good patency of the ICA; in 1 patient, there was an ICA asymptomatic occlusion. One patient required transvenous coil occlusion of the cavernous sinus. CONCLUSION: When standard treatments fail, covered stent grafts can be used as a valid alternative in the treatment of CCFs, but more data are needed, especially in the long-term follow-up.

Expression profile of epidermal differentiation complex genes in normal and anal cancer cells.

Anal cancer originates from a peculiar histological region and provides a useful model for investigating alterations in proliferation and/or differentiation of neoplastic keratinocytes. Epidermal differentiation complex (EDC) genes, which form one of the major gene clusters in the human genome, are involved in the terminal differentiation of epithelial cells and in many instances have been implicated in epithelial tumours. We constructed a DNA macroarray capable of characterising the expression profiles of the entire EDC gene complex in normal mucosa and anal cancer biopsies of seven unrelated patients. Brain tissue and cultured keratinocytes were used as controls. All anal cancer samples showed expression profiles in which none of the EDC genes was silent, as evaluated by phosphor-imager analysis. Variance analysis showed significantly lower expression of SPRR2 with respect to SPRR1 or SPRR3, and significantly higher expression of S100A8 than of other S100A subfamily members. At hierarchical clustering analysis, the four basaloid anal cancer cases conglomerated in the top five positions. The macroarray method used by us provides the first demonstration of the expression profile of the EDC gene family in anal cancer, and is capable of producing significant information on the subgrouping of epithelial tumours such as anal cancer.

Expression analysis and mutational screening of the epithelium-specific ets gene-1 (ESE-1) in patients with squamous anal cancer.

To investigate whether ESE-1 gene abnormalities are involved in alterations of epithelial cell differentiation in squamous anal cancer ESE-1 expression and structure were screened in six patients by reverse transcriptase-polymerase chain reaction (RT-PCR) and automated sequence analysis. The complete cDNA of isoform ESE-1b was always expressed and correctly spliced, with single nucleotide polymorphism being observed in two cases. Presence of ESE-1b point mutations was excluded. Expression of SPRR2A and ENDOA/CK8, two epithelium-specific ESE-1 target genes, were revealed by RT-PCR in all cases. This first report of expression of ESE-1, and of SPRR2A and ENDOA/CK8 (both related to terminal differentiation in different types of epithelia lining) in anal cancer excludes the hypothesis that these genes influenced carcinogenesis in our patients. Despite selecting of patients without clinical evidence of HPV infection, PCR consistently revealed HPV-16 DNA, highlighting the importance of HPV infection in anal cancer.

Successful treatment of bronchial dehiscence with endobronchial stent in lung transplantation.

Bronchial dehiscence in lung transplantation is still a significant and threatening cause of morbidity, even if several progresses have been made in this field. In the present report we discuss a case of incomplete dehiscence of the right bronchial anastomosis in a patient who underwent sequential double lung transplantation for bronchiectasis. This complication has been successfully treated with endobronchial stent positioning, with the aim to allow the healing of the anastomosis around a rigid endobronchial support and to prevent the airway stenosis. The usefulness of 3D spiral CT reconstruction of bronchial tree is also underlined, for its capacity to detect the dehiscence and to monitor the healing of this complication.

Endovascular treatment with GDCs: results in 100 patients.

BACKGROUND: In this paper we review the clinical and morphological results of intracranial aneurysms treated with Guglielmi Detachable Coils. METHODS: We report our experience in 100 patients with intracranial aneurysms treated with GDC. Since February 1993 we have treated 70 females and 30 males, with a mean age of 57 years old, for a total of 118 intracranial aneurysms. Sixty-five patients had a recent history of ruptured aneurysm, 10 suffered from a previous subarachnoid hemorrhage and 25 patients had never bled. In the choice of treatment for subarachnoid aneurysm, in accordance with our neurosurgeons, we have not applied a protocol, rather we have followed guidelines in relation to: age, neurological clinical conditions, systemic disease and location of aneurysm. Morphological aspect of immediate aneurysm occlusion was: 60% more or less complete occlusion, 30% loose packing with 10% failures. RESULTS AND CONCLUSIONS: The clinical outcome at follow-up (1 month-3 years) was: 72 patients without neurological deficits, 19 patients improved pre-existing neurological deficits, 3 patients worsened for procedural complications; 6 patients died (1 patient unrelated).

[Surgical versus endovascular treatment in cerebral aneurysm. The opinion of a neuroradiologist]. / Trattamento chirurgico o endovascolare dell'aneurisma cerebrale. Il parere del neuroradiologo.

Surgery is currently the treatment of choice for acutely ruptured aneurysms, representing an efficient option both in the short and long term. We believe that the endovascular option may be of help in high surgical-risk cases.

[Relapsing epistaxis: embolization as treatment of choice]. / Epistassi recidivanti: l'embolizzazione come trattamento di elezione.

Epistaxis is a very common disease. Fortunately it occurs most commonly in the anterior septal network of blood vessel and is therefore readily controlled with simple local measures. Severe posterior epistaxis is less frequent but is still a common and much more serious clinical problem and usually requires hospitalization. The classic treatment of these epistaxis is combined anterior-posterior nasal packing. Occasionally, however, this treatment does not control bleeding. The most popular alternative for these patient is arterial ligation. Initially only carotid ligation was performed. Later further advances in surgical technique and instrumentation, permitted internal maxillary and etmoid artery ligation to be carried out. However often arterial ligation cannot be easily performed in some ent departments and furthermore, surgical failure rate is not exceptionally high if one consider the numerous hypsilateral-contralateral arterial anastomoses present in the etmoid-nasal region. Fifteen patients with recurring nasal bleeding were treated with embolization between 1991 and 1993. Ten of them suffered of essential epistaxis while the other five had chronic local and/or systemic diseases (hereditary haemorrhagic teleangectasia and angiomas). Analysis of the results show a good control of bleeding in the first group of patients (90% after one embolization) and a satisfactory control in patients with haemorrhagic teleangectasia. In conclusion, owing to its efficacy, speed and safety therapeutic embolization with PVA particles may be considered treatment of choice in recurrent persistent epistaxis.

Presence and characteristics of circulating megakaryocyte progenitor cells in human fetal blood.

The in vitro growth of early (burst-forming unit-megakaryocyte [BFU-meg]) and late (colony-forming unit-megakaryocyte [CFU-meg]) megakaryocyte progenitors was investigated in midtrimester human fetal blood and compared with adult bone marrow. Most of the experiments were performed in a serum-free fibrin-clot assay, using purified hematopoietic progenitor (CD34+) cells. High BFU-meg and CFU-meg levels were found in human fetal blood, with a clear prevalence of BFU-meg (BFU-meg:CFU-meg ratio, 2.5:1), at variance with adult bone marrow, in which mature CFU-meg predominate (BFU-meg:CFU-meg ratio, 0.6:1). Fetal and adult megakaryocyte progenitors had a similar phenotypic profile for the expression of CD34, HLA-DR, and glycoprotein-complex IIB-IIIA. However, fetal BFU-meg were larger in size (number of megakaryocytic elements per colony) than adult BFU-meg, but were usually composed by only one or two foci of development. On the other hand, fetal and adult CFU-meg were similar in both morphology and size. Fetal megakaryocyte progenitors appeared earlier in culture and had an increased proliferative activity as demonstrated by the higher number of megakaryocyte progenitors in S phase with respect to adult CFU-meg and BFU-meg. Finally, fetal megakaryocyte progenitors displayed a higher sensitivity to stimulatory cytokines, in particular recombinant interleukin-3, than adult megakaryocyte progenitors, whereas they were inhibited by purified transforming growth factor-beta 1 in a similar fashion to adult megakaryocyte progenitors.

Nonpulmonary thoracic biopsy.

The aim of the present paper is to distinguish between thoracic pulmonary needle biopsy--which can be carried out under fluoroscopic guidance--and thoracic extrapulmonary needle biopsy, which requires a more accurate type of guidance, such as CT. Among the 500 thoracic punctures performed during the last 5 years, we considered only 90 biopsies of mediastinal (N = 58) or thoracic wall (N = 32) masses. We have thus excluded all parenchymal lesions of the lungs. For extrapulmonary thoracic masses, CT was the method of choice for biopsy guidance which provided diagnostic evidence of small-diameter mediastinal lesions that permitted analysis of the relationship to vascular structures and performance of extrapleural needle insertion, using larger-gauge needles to ensure accurate needle placement within the lesion. In both mediastinal and thoracic wall lesions an overall accuracy rate of 84% was obtained. In no case was thoracic drainage required for treatment of the moderate degree of pneumothorax that occurred in 1% of our patient population.

Differential activity of saporin 6 on normal and leukemic hemopoietic cells.

The antiproliferative effect of saporin 6 (SO6), a ribosome-inactivating protein (RIP) purified from the seeds of Saponaria officinalis has been tested on three leukemic cell lines (K562, U937, and HL60), human normal bone marrow, and peripheral blood hemopoietic progenitor cells from normal subjects. In leukemic cell lines, SO6 appeared much more effective against erythrocytic than against monocytic and promyelocytic leukemic cells, as shown by protein synthesis assays carried out after up to 72 h of culture. Among the normal hemopoietic progenitor cells, erythroid burst-forming units were the most affected, with results similar to those observed in the erythroid leukemic cell line, both in treated and in pretreated cultures, with strong damage after 24 h of exposure to SO6. On the other hand, granulocyte-macrophage colony-forming units (CFU-GM) from bone marrow were significantly more affected than the myeloid leukemic cell lines after permanent treatment with the inhibitor, the damage being significantly lower after an exposure of 24 h. CFU-GM from peripheral blood and megakaryocyte CFU showed an intermediate sensitivity after 24 h of exposure to SO6, similar to that of the other normal precursors after permanent treatment with the drug.

[Magnetic resonance of the thoracic aorta]. / Risonanza magnetica dell'aorta toracica.

Various pathological conditions of the thoracic aorta were studied by MR Imaging in 31 patients: 23 were aneurysms (branching and non-branching), 2 arterio-venous fistulae, 2 aortic prostheses, 2 Marfan's syndromes, 1 coronary sinus aneurysm, and 1 isthmic stenosis. MRI studies were always performed on patients who had been examined by other imaging procedures. A comparative study was carried out on the results of MRI, angiography, computerized tomography, and ultrasounds. The possibility of propedeutic protocol was explored. Our experience, in accordance with the literature on the subject, indicates MRI as the procedure of choice in the study of aneurysms of the thoracic aorta. The advantages offered by MRI--the high natural contrast between circulating blood and the supporting structures, the possibility of obtaining multiplanar images as well as data on intraluminal, parietal, and extraparietal conditions--make it a highly competitive procedure if compared to either CT or angiography. While awaiting further evidence, the use of a propedeutic protocol in non-aneurysmatic diseases is still not advisable, due to insufficient patient population, and to the lack of a consistent literature on the subject.

The in vitro effect of epirubicin on human normal and leukemic hemopoietic cells.

Epirubicin, at concentrations ranging between 10(-7) and 10(-13) M, was assayed in semisolid cultures of human normal hemopoietic cells and in liquid cultures of 5 different human leukemic cell lines. The growth of all normal hemopoietic progenitor cells was inhibited by the higher drug concentrations; at the lowest concentration, only CFU-E and 7th-day CFU-GM were not inhibited. On the other hand, leukemic cells were sensible only to the higher concentration of epirubicin, which, nevertheless, was not fully inhibitory. Leukemic cell differentiation was not promoted by the drug, as evidenced by a panel of monoclonal antibodies, by cytochemistry and by functional tests. These results suggest a marked in vitro myelotoxicity of epirubicin, that does not appear to be compensated by a powerful control of leukemic cell proliferation.