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HYPOTHESIS: AR42, a histone deacetylase (HDAC) inhibitor, reduces viability of primary vestibular schwannoma (VS) cells and delays tumor progression and hearing loss (HL) in a xenograft model of VS. BACKGROUND: The impact of HDAC expression on AR42 response in primary VS cells is unknown, as well as the effects of AR42 on VS-associated HL and imbalance. METHODS: Primary human VS cells (n=7) were treated with AR42 (0–3.0μM), and viability assays were conducted. Immunohistochemistry and western blotting for phosphorylated-HDAC2 (pHDAC2) were performed on tumor chunks. Pharmacokinetic studies were conducted in Fischer rats using mass spectrometry. Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats and treated with vehicle (n=7) or AR42 (25mg/kg/day for 4 weeks; n=12). Tumor bioluminescence imaging, auditory brainstem response (ABR), and rotarod tests were conducted to 6 weeks. Final tumor weight and toxicities were measured. RESULTS: AR42 caused dose-dependent reductions in viability of VS cells. Tumors with higher pHDAC2:HDAC2 ratios had greater reductions in viability with AR42. On pharmacokinetic studies, AR42 reached peak levels in nerve ~24 hours after oral administration. Although AR42-treated rats demonstrated mean ABR threshold shifts ~10–20 dB lower than controls, this did not persist nor reach significance. When compared to controls, AR42 did not affect tumor bioluminescence, tumor weight, and rotarod measurements. CONCLUSIONS: Response of primary VS cells to AR42 may be influenced by pHDAC2 expression in tumor. Although AR42 may delay HL in our xenograft model, it did not halt tumor growth or vestibular dysfunction. Further investigations are warranted to evaluate the AR42 effectiveness in NF2-associated VS.

OBJECTIVE Indication for surgery in brainstem cavernous malformations (BSCMs) is based on many case series, few comparative studies, and no randomized controlled trials. The objective of this study was to seek consensus about surgical management aspects of BSCM. METHODS A total of 29 experts were invited to participate in a multistep Delphi consensus process on the surgical treatment of BSCM. RESULTS Twenty-two (76%) of 29 experts participated in the consensus. Qualitative analysis (content analysis) of an initial open-ended question survey resulted in 99 statements regarding surgical treatment of BSCM. By using a multistep survey with 100% participation in each round, consensus was reached on 52 (53%) of 99 statements. These were grouped into 4 categories: 1) definitions and reporting standards (7/14, 50%); 2) general and patient-related aspects (11/16, 69%); 3) anatomical-, timing of surgery–, and BSCM-related aspects (22/37, 59%); and 4) clinical situation–based decision-making (12/32, 38%). Among other things, a consensus was reached for surgical timing, handling of associated developmental venous anomalies, handling of postoperative BSCM remnants, assessment of specific anatomical BSCM localizations, and treatment decisions in typical clinical BSCM scenarios. CONCLUSIONS A summary of typical clinical scenarios and a catalog of various BSCM- and patient-related aspects that influence the surgical treatment decision have been defined, rated, and interpreted.

Background After internal carotid artery (ICA) injury during endoscopic skull base surgery, the majority of patients undergo ICA embolization or stenting to treat active extravasation or pseudoaneurysm development. However, management practices when embolization or stenting is not required have not been well described. The objective of this study was to determine how patients with ICA injury but no embolization, stenting, or ligation do long-term and ascertain the reconstruction methods utilized. Methods Twenty-nine cases of ICA injury were identified in an international multi-institutional retrospective review. Of these, we identified six cases that were not treated with embolization, stenting, or ICA sacrifice. Information was available for five cases. Results A muscle patch was used in the immediate repair of each case. A nasoseptal flap was used in one case. Prefabricated nasal tampons were used in all cases. Nasal packing was initially left in for a median of 7 days prior to removal. The initial muscle patch was reinforced with a second muscle graft in one case. One case demonstrated ICA bleeding at the time of packing removal and was repacked an additional week. Follow-up for each of these cases was at least 2 years. No cases of subsequent carotid rupture were found and none of these cases ultimately underwent endovascular stenting. Radiation or proton therapy has not been subsequently used in any of these patients. Conclusions This study details the reconstruction, lessons learned, and long-term follow-up for five cases of ICA injury not treated with embolization, stenting, or ligation.

National audience; Un système de recherche d’information est un ensemble de ressources et d’outils permettantà des utilisateurs d’extraire des connaissances sur un ensemble de données. Dans detels systèmes, les utilisateurs peuvent mener leurs recherches de diverses manières en fonctionde leurs objectifs. Dans ce contexte, les processus suivis par les utilisateurs sont dits autodéfinis.La signification, la structure et les résultats varient en fonction des pratiques. L’objectifde ce travail consiste à représenter le comportement des utilisateurs dans la recherche d’informations.Nous avons ainsi appliqué des algorithmes de fouille de processus sur les tracesd’utilisation d’un moteur de recherche dans une bibliothèque numérique. Nous avons appliquésept algorithmes sur deux ensembles de données correspondant aux interactions réelles desutilisateurs avec une bibliothèque numérique mettant à disposition des documents. Nous en déduisonsensuite des recommandations pour concevoir une méthodologie de fouille de processusauto-définis.

Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed. Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry. Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus. Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model. Aivovaltimopullistuman repeämisestä johtuva lukinkalvonalinen verenvuoto (subaraknoidaalivuoto, SAV) on äkillinen ja raju kallonsisäinen verenvuoto joka tapahtuu noin tuhannelle henkilölle suomessa per vuosi. SAV aiheuttaa pysyvän neurologisen haitan tai kuoleman valtaosalle potilaista. Aivovaltimopullistumia voidaan hoitaa joko mikrokirurgisella leikkauksella tai tukkimalla pullistuma suonensisäisesti (endovaskulaarinen hoito). Suonesisäiset hoitomenetelmät ovat viime vuosikymmeninä kehittyneet merkittävästi, mutta edelleen osaa pullistumista ei voida tällä menetelmällä hoitaa ja ajoittain hoidon tulos ei ole pitkällä aikavälillä pysyvä. Suonensisäisten hoitomenetelmien jatkokehittämiseksi tarvitaan enemmän tietoa aivovaltimopullistuman seinämässä tapahtuvista biologisista mekanismeista ja realistisempiä kokeellisia malleja, mukaan lukien koe-eläinmalleja, joissa hoitomenetelmiä voidaan testata. Tässä väitöskirjassa on syvennytty tutkimaan kahta eri koe-eläinmallia, kani- ja rottamallia. Väitöskirjassa osoitetaan että mallit soveltuvat suonensisäisten hoitomenetelmien testaamiseen. Malleissa on kyetty realistisella tavalla mallintamaan todellisen aivovaltimopullistuman eri rappeutuneisuusasteita ja saatu merkittävää lisätietoa siitä miten pullistuman seinämän biologiset tapahtumat joko vahvistavat seinämää tai altistavat seinämän repeämiselle.

The rupture of a cerebral artery aneurysm causes a devastating subarachnoid hemorrhage (SAH), with a mortality of almost 50% during the first month. Each year, 8-11/100 000 people suffer from aneurysmal SAH in Western countries, but the number is twice as high in Finland and Japan. The disease is most common among those of working age, the mean age at rupture being 50-55 years. Unruptured cerebral aneurysms are found in 2-6% of the population, but knowledge about the true risk of rupture is limited. The vast majority of aneurysms should be considered rupture-prone, and treatment for these patients is warranted. Both unruptured and ruptured aneurysms can be treated by either microsurgical clipping or endovascular embolization. In a standard microsurgical procedure, the neck of the aneurysm is closed by a metal clip, sealing off the aneurysm from the circulation. Endovascular embolization is performed by packing the aneurysm from the inside of the vessel lumen with detachable platinum coils. Coiling is associated with slightly lower morbidity and mortality than microsurgery, but the long-term results of microsurgically treated aneurysms are better. Endovascular treatment methods are constantly being developed further in order to achieve better long-term results. New coils and novel embolic agents need to be tested in a variety of animal models before they can be used in humans. In this study, we developed an experimental rat aneurysm model and showed its suitability for testing endovascular devices. We optimized noninvasive MRI sequences at 4.7 Tesla for follow-up of coiled experimental aneurysms and for volumetric measurement of aneurysm neck remnants. We used this model to compare platinum coils with polyglycolic-polylactic acid (PGLA) -coated coils, and showed the benefits of the latter in this model. The experimental aneurysm model and the imaging methods also gave insight into the mechanisms involved in aneurysm formation, and the model can be used in the development of novel imaging techniques. This model is affordable, easily reproducible, reliable, and suitable for MRI follow-up. It is also suitable for endovascular treatment, and it evades spontaneous occlusion. Aivovaltimoaneurysman puhkeaminen aiheuttaa hengenvaarallisen lukinkalvonalaisen verenvuodon eli subaraknoidaalivuodon (SAVn). Suomessa SAVn insidenssi on yleisempi kuin muualla maailmassa, vuodon saa noin 1000 potilasta vuosittain. Heistä noin 50% menehtyy kuukauden sisällä vuodosta ja henkiinjääneistä puolet vammautuu vakavasti. Tauti kohdistuu pääasiallisesti työssäkäyvään väestöön, keski-ikä on 50-55 v. Vuotamaton aivovaltimoaneurysma löytyy 2-6% väestöstä. Menetelmää, jolla voisi ennakoida mitkä aneurysmat tulevat vuotamaan ja mitkä eivät, ei toistaiseksi ole. Valtaosaa vuotamattomista aneurysmista on pidettävä potentiaalisesti hengenvaarallisina, ja ne on pyrittävä sulkemaan joko mikrokirurgisella leikkauksella tai endovaskulaarisella (suonensisäisellä) embolisaatiolla. Leikkauksessa aneurysman tyvi suljetaan mikrokirurgisesti metallisella klipsillä. Endovaskulaarisessa embolisaatiossa aneurysma täytetään röntgenläpivalaisuavusteisesti eri mittaisilla platinalanka-"koileilla". Koilaaminen on vähemmän kajoava toimenpide kuin mikrokirurginen leikkaus ja täten varteenotettava vaihtoehto. Kaikki aneurysmat eivät kuitenkaan sovellu koilattaviksi nykytekniikoilla, joko leveän kaulan, suuren koon tai hankalan sijainnin takia. Endovaskulaarisen hoidon jälkeen seuranta on välttämätöntä, koska pitkäaikaistulokset ovat leikkaukseen verrattuna heikommat. Lisäkoilaus voidaan tehdä mikäli aneurysmaan tulee uudelleen verenvirtausta. Endovaskulaarisia hoitomenetelmiä on kehitettävä edelleen, jotta saavutettaisiin parempia pitkäaikaistuloksia. Uusia menetelmiä on testattava koe-eläinmalleilla ennen kuin niitä käytetään ihmisillä. Tässä tutkimuksessa olemme pystyttäneet ihmisen aivovaltimoaneurysmaa muistuttavan mikrokirurgisen aneurysmamallin rotassa, jolla pystymme tuottamaan vakiokokoisia aneurysmia, joita voidaan hoitaa endovaskulaarisesti. Seurantaa varten olemme optimoineet kuvanlaadun koe-eläinmagneettikuvantamislaitteessa, jotta pystymme seuraamaan hoitojen jälkeisiä tapahtuvia muutoksia aneurysmissa. Olemme käyttäneet rottamallia verrataksemme platinalankakoilia uudenlaiseen pinnoitettuun koiliin ja osoittaneet, että viimeksi mainitulla on hyödyllisiä ominaisuuksia. Rottamalli on aiempiin aneurysmamalleihin verrattuna halvempi. Lisäksi kokeelliset aneurysmat ovat vakiokokoisia, aukipysyviä ja magneettikuvausseurantaan soveltuvia.