Improvement of a dendritic cell-based tumour vaccine by an influenza virus.

BACKGROUND: Induction of cytotoxic T cells by dendritic cells (DCs) is a promising approach to tumour-immunotherapy. A standardized effective preparation of DCs remains a challenge for clinical application. MATERIAL AND METHODS: We assessed whether influenza A partial NS1 deletion (NS1-124) - or complete NS1 deletion (delNS1) vaccine viruses can be employed to enhance monocyte-derived dendritic cell (MODC)-based T-cell stimulation directed against malignant cells in vitro. RESULTS: Infection of cultures containing human MODCs and CD3(+) T cells with NS1 deletion viruses led to an increased induction of type I interferons and IL-6 compared with infection with wild-type virus. This correlated with the fact that infection of MODCs with NS1 deletion viruses but not with wild type virus led to stimulation of a cytotoxic T-cell (CTL) response against the Panc-1 cells, which were used as cell lysate to prime the MODCs. Moreover, stimulation of MODCs with Panc-1 tumour cell lysate obtained via lysis with the complete deletion virus delNS1, but not with the partial NS1 deletion virus also enhanced the CTL response against the tumour cells. Induction of function CTL response in those assays correlated with an increased proliferation of CD8(+) T cells. CONCLUSIONS: The pro-inflammatory capacity of influenza NS1 deletion vaccine viruses could serve as an adjuvant-like agent to improve preparations of MODC-based anti-cancer vaccines. The complete NS1 deletion virus appears to be more potent as adjuvant when used for production of tumour lysates.

Vein of galen aneurysmal malformations.

Different types of malformations share a dilated vein of Galen, but only one of them is a true vein of Galen aneurysmal malformation (VGAM). The optimal window of opportunity for treatment is between 4 and 5 years of months [corrected], because this allows the child to grow and mature. Heart failure and hydrocephalus respond favorably to embolization. Cerebrospinal fluid ventricular shunting, if needed, should be performed after the embolization. The transvenous approach carries significantly elevated morbidity and mortality and is rarely indicated. Anatomic cure of the VGAM is not the main goal of treatment; the ultimate goal is control of the malformation to allow the brain to mature and develop normally.

A genetically engineered influenza A virus with ras-dependent oncolytic properties.

The NS1 protein of influenza virus is a virulence factor that counteracts the PKR-mediated antiviral response by the host. As a consequence, influenza NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS1 open reading frame) fails to replicate in normal cells but produces infectious particles in PKR-deficient cells. Because it is known that oncogenic ras induces an inhibitor of PKR, we addressed the question of whether the delNS1 virus selectively replicates in cells expressing oncogenic ras. We show that upon transfection and expression of oncogenic N-ras, cells become permissive for productive delNS1 virus replication, suggesting that the delNS1 virus has specific oncolytic properties. Viral growth in the oncogenic ras-transfected cells is associated with a reduction of PKR activation during infection. Moreover, treatment of s.c. established N-ras-expressing melanomas in severe combined immunodeficiency mice with the delNS1 virus revealed that this virus has tumor-ablative potentials. The delNS1 virus does not replicate in nonmalignant cell lines such as melanocytes, keratinocytes, or endothelial cells. The apathogenic nature of the delNS1 virus combined with the selective replication properties of this virus in oncogenic ras-expressing cells renders this virus an attractive candidate for the therapy of tumors with an activated ras-signaling pathway.

Modification of cerebral vascular anatomy induced by Leo stent placement depending on the site of stenting: A series of 102 cases.

BACKGROUND AND PURPOSE: Recent studies demonstrated the capacity of stents to modify cerebral vascular anatomy. This study evaluates arterial anatomy deformation after Leo stent placement according to the stenting site and the impact on the immediate postoperative and six-month degree of aneurysmal occlusion. MATERIALS AND METHODS: A total of 102 stents were placed against the neck of aneurysms situated in the anterior cerebral circulation. Aneurysms were classified into two groups: The first was called the distal group (n = 62) and comprised aneurysms situated in the middle cerebral and anterior communicating arteries and the second was called the proximal group (n = 40) and comprised aneurysms in other sites. The stented arterial segment was classified as deformed or non-deformed by blinded review and superimposition of anonymised films before and after stenting. The degree of occlusion was determined immediately postoperatively and at six months. RESULTS: Significantly, anatomical deformity was observed in the distal group compared to the proximal group (85% vs 28%). No significant difference was observed between the two groups in terms of postoperative degree of occlusion. At six months, a significant difference was observed between the two groups: three recurrences in the distal group vs 10 recurrences in the proximal group. Two (3%) recurrences were observed in the deformed group vs 11 (31%) recurrences in the non-deformed group. CONCLUSIONS: Arterial deformity induced by stenting is even more marked for distal aneurysms. The recurrence rate is smaller when the stent placement results in an arterial anatomical change. The percentage of recurrence is lower when anatomy was amended by stent implantation.

[Lung separation after reintubation with airway exchange catheter in multiple trauma patient with massive haemoptysis]. / Succès de réintubation avec une sonde à double lumière grâce à un mandrin, lors d'une hémoptysie massive post-traumatique.

A 24-year-old man fell from the third floor. He developed an unilateral pulmonary parenchymal injury and a significant haemoptysis following blunt thoracic trauma. Because of its abundance, it was not possible to obtain adequat oxygenation. To protect controlateral lung from inhalation and to achieve adequat oxygenation, we used double lumen endotracheal tube, lung separation and one lung ventilation. To solve potential airway management difficulties (haemorrhage, trauma, cervical immobilization), we used airway exchange catheter (Cook) to place the double lumen endotracheal tube. Haemoptysis has been controlled by embolization of the right bronchial artery.

Risk factors of hematomyelia recurrence and clinical outcome in children with intradural spinal cord arteriovenous malformations.

BACKGROUND AND PURPOSE: Few published data are available concerning the risk of re-bleeding of spinal cord AVM after an hematomyelia and concerning the long-term clinical outcome. Our aim was to assess the risk of recurrence and long-term clinical outcome after hematomyelia in children with spinal cord AVMs. MATERIALS AND METHODS: This single-center retrospective study reviewed the clinical and radiologic data of 28 children younger than 18 years of age with arteriovenous malformation who had experienced at least 1 episode of hematomyelia between 1988 and 2012. Long-term clinical outcome was assessed by the American Spinal Injury Association Impairment Scale, and radiologic review included MR imaging and angioarchitecture on angiography (blinded to clinical information) before treatment and at recurrence. RESULTS: Sixteen children (57%) experienced 1 episode of hematomyelia, while 12 children (43%) experienced recurrence. Girls and boys were equally affected (sex ratio, 1:1), and mean clinical follow-up was 5.7 ± 4.4 years. The risk of recurrence was higher for AVMs of the cervical and upper thoracic spine, 12 (100%) versus 11 (69%) (P = .01). A high American Spinal Injury Association scale score at last follow-up was reported for 11 children (39%), and the risk of recurrence tended to be associated with poorer functional prognosis (7 [64%] versus 5 [29%], P = .07). At the time of recurrence, perimedullary venous drainage was the main factor associated with recurrence (P = .002). Occlusion rate ≥50% was associated with a decreased risk of recurrence (P = .047). CONCLUSIONS: In the present series, cervical and upper thoracic spinal cord AVMs and microarchitecture were predictive of the risk of hematomyelia recurrence. Perimedullary venous drainage was one of the main parameters associated with recurrence. Functional prognosis was better in patients with a single episode of hematomyelia.

Cerebral venous thrombosis after embolization of pediatric AVM with jugular bulb stenosis or occlusion: management and prevention.

PURPOSE: Thrombosis of cerebral arteriovenous malformation after embolization is rare, but can involve the normal venous network with extensive venous thrombosis. We report angioarchitecture findings, our management and prevention strategy for this complication in pediatric AVMs. METHODS: In this 5.5-year retrospective series, we reviewed records of 13 patients under 15 years who were anticoagulated after embolization. In our initial experience 4 children who didn't receive any prophylactic anticoagulation presented with extensive venous thrombosis after embolization (group 1). Following this, nine children with similar angioarchitecture and embolization modalities were treated with prophylactic anticoagulation immediately after embolization (group 2). We analyzed the type of AVM, angioarchitecture, dose of prophylactic anticoagulant, efficacy/complications of treatment and late outcome. RESULTS: All patients in group 1 had severe jugular bulb stenosis/occlusion associated with cerebral venous dilatation. In group 2 with similar angioarchitecture, only three patients (33%) developed extensive thrombosis. In both groups, thrombosis occurred within two days of treatment in six children and two weeks in one child. The diagnosis was suspected on intracranial hypertension in five patients and occulomotor disorder in one. One was asymptomatic. All children were treated with therapeutic doses of LMWH (anti-Xa: 0.5-1). No hemorrhagic complications occurred. Good venous remodeling was observed in all but one patient. CONCLUSION: Anticoagulation in extensive venous thrombosis after AVM embolization in children appears to be safe and effective. In cases with angioarchitectural features of dilatation of the cerebral venous network and occlusion/severe stenosis of the jugular bulbs, full dose anticoagulation may be required to prevent thrombosis.

IL-24 sensitizes tumor cells to TLR3-mediated apoptosis.

Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL-24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3.

[Medical care of brain malformative vascular diseases discovered during the pre- or neonatal period]. / Prise en charge des malformations vasculaires cérébrales découvertes en période ante- ou néonatale.

Three types of brain arteriovenous vascular malformations can be found during the neonatal period, according to their anatomical location. Vein of Galen malformations are the most common. The others are pial arteriovenous malformations or dural arteriovenous malformations, which include dural sinus malformations. They can be asymptomatic, but most often they are associated with different symptoms, related to their angioarchitecture or their effect on the brain. High-flow arteriovenous malformations can thus be responsible for heart failure. Local or regional venous hyperpressure exposes the patient to subacute or chronic brain lesions, or to hydrovenous disorders such as hydrocephalus. Some types of venous reflux can expose patients to brain hemorrhage. The treatment chosen for these vascular malformations and their consequences is transarterial or transvenous embolization, depending on the angioarchitecture and type of lesion. The schedule for the treatment will be determined according to the malformation type and its local or general effects on the brain. The aim of this article is to present the recommendations of the French National Referral Center for neurovascular malformations in children, in order to help clinicians and radiologists treat these patients during pre- or neonatal period.

External carotid artery branches involvement in reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by segmental vasoconstriction and dilatation of intracranial arteries, usually revealed by headaches, which spontaneously resolve in few weeks. We report a patient with RCVS, revealed by thunderclap headaches, involving both internal and external carotid artery (ECA). She received fluoxetin for depression and took a great amount of cannabis in the last months. While angio-MR, transcranial Doppler and CSF analysis were normal, cerebral angiography disclosed stenoses and dilatations of the middle cerebral artery. It also showed an involvement of maxillary arteries. Fluoxetin and cannabis were stopped. After few days, she had no more headaches. At 8th week, angiography was normalized confirming the RCVS. ECA angiogram may help reaching a diagnosis in patients with suspected RCVS when intracerebral abnormalities are minor or absent.

Cytomegalovirus hyperimmunoglobulin: mechanisms in allo-immune response in vitro.

BACKGROUND: Cytomegalovirus hyperimmunoglobulin (CMVIg) containing drugs are routinely administered in cardiac transplantation for prophylaxis against CMV disease. Yet little is known about their influence on transplant relevant immune functions. The aim of this study was to evaluate the effect of CMVIg on cellular immunity in in vitro experiments and to define their role in tolerance inducing mechanisms. MATERIALS AND METHODS/RESULTS: CMVIg reduces proliferation in mixed lymphocyte reactions and anti-CD3 blastogenesis assays and is related to decreased production of immune modulating cytokines interleukin (IL)-2, interferonr (IFNgamma), IL-10. This antiproliferative effect is associated with a cell-cycle arrest in the G0/G1 phase and induction of apoptosis in CD8+ and natural killer cells. Co-incubation with CMVIg causes down-regulation of cell bound immunoglobulin and FcgammaRIII surface expression on natural killer cells and leads to attenuation of antibody dependent cellular cytotoxicity effector functions. CONCLUSIONS: We conclude that CMVIg induces immunological features on leukocytes in vitro that are known to be related to tolerance induction. Our observations extend the current concept of CMVIg as passive CMV prophylaxis to a therapeutic drug compound capable of reducing allogeneic immune response.

Supratentorial cerebral arteriovenous fistulas (AVFs) in children: review of 41 cases with 63 non choroidal single-hole AVFs.

PURPOSE: In this article we explore the various aspects of the supratentorial Single-Hole AVFs (ST AVFs) in children, focusing on their clinical features, angio-architecture, treatment indications and the role and results of endovascular management. MATERIALS AND METHODS: Among 1565 cases of brain AVMs seen at our neurovascular center, 620 cases were seen in the pediatric age group (

Cerebrofacial venous metameric syndrome (CVMS) 3: Sturge-Weber syndrome with bilateral lymphatic/venous malformations of the mandible.

We present a case of Sturge-Weber syndrome with a bilateral lymphatic/venous malformation of the mandible. Modern biology suggests an explanation for such a case. The classification of cerebrofacial venous metameric syndromes (CVMS) enables us to recognise this lesion as involving the most caudal of the cranial metamere (CVMS 3).

5-year Angiographic and Clinical Follow-up of Coil-embolised Intradural Saccular Aneurysms. A Single Center Experience.

SUMMARY: The purpose of the paper is the follow-up of embolised intradural saccular Arterial Aneurysms (AA), excluding giant, dissecting, inflammatory, fusiform or AA associated to BVAM. Since its introduction in 1991, the Guglielmi Detachable Coil has offered protection against aneurysmal rebleeding in the critical few days and months after SAH regardless of the grade. A number of questions remain: is complete angiographic obliteration necessary at first embolisation? What duration of clinical / angiographic follow-up (FU) is required to ensure the risk of haemorrhage has been eliminated? What is the long-term protection against rebleeding? One hundred and two patients with 160 intradural saccular AA embolised before april 1997 were selected for this study. They had at least 5-yrs clinical FU, of which 22 patients had a mid- term (3 years) and 45 patients had a 5-year or more angiographic FU (mean 67,7 months per patient). Twenty-eight embolised AAs with 100% occlusion at 1 year, remained unchanged on the 5-year angiograms. A further 14 patients with complete occlusion at 1 year showed persisting complete occlusion on angiogram at 3-years FU, which in our series means that complete occlusion after the first year post-embolisation implies that the aneurysm will remain completely occluded. All secondary spontaneous thromboses (27.6% of cases), occurred during the first year pos- embolisation. In six patients with subtotal or partial occlusion no change was seen for three consecutive years of FU; none showed later change at 5-year angiography. Below 80% occlusion our series does not provide enough information but we consider the situation instable. No mortality related to the procedure was observed in the unruptured AA group.No bleeding or re-bleeding has occurred since the beginning of our experience (1993) in saccular AA treated by GDC-Coil. Coil-embolisation of properly selected patients is effective in protecting against bleeding or re-bleeding at short and long-term with stable morphological results provided a strict follow-up control is established at short term.

Growing dural sinus malformation with associated developmental venous anomaly, multiple cavernomas and facial venous malformation in an infant. An associated disease or a disease spectrum?

SUMMARY: This is an unusual case report of an infant, who initially presented with a facial haemangioma and was later diagnosed to have a dural sinus malformation (DSM) involving the torcula. The DSM increased in size lateralising to the right transverse sinus at three months of age. Postnatal enlargement of the dural sinus has not been described before suggesting a delay in the maturation of the dural sinus which normally would occur antenatally. There was a further association with a complex developmental venous anomaly (DVA) draining the right cerebral hemisphere into the deep cerebral vein and multiple cavernous malformations. The DVA was not clearly demonstrated at age one month but was more obvious at age three months. This would be the first reported case of DSM associated with a DVA. Increasing venous hypertension probably contributed to the poor opacification of the DVA on follow-up angiography at age six months and to the haemorrhagic changes within the cavernomas on magnetic resonance imaging (MRI). The therapeutic goal was to correct venous hypertension by partially embolising the dural shunts to remodel the cerebral vasculature and preserve the patent sinus. The treatment strategy and possible link between the complex disease entities presented in this infant are discussed. Despite these attemps, the lesion continued to grow compressing the posterior fossa structures. The infant died at nine months of age.

Posterior cranial fossa single-hole arteriovenous fistulae in children: 14 consecutive cases.

We report 14 consecutive children with 23 posterior cranial fossa arteriovenous fistula (AVF); six had multifocal lesions, involving the supratentorial brain in three and the spinal cord in one. There were two boys and four girls with a family history compatible with hereditary haemorrhagic telangiectasia. The diagnosis was made in infancy in eight cases and in a further six before the age of 12 years; mean age at diagnosis was 3.5 years. The male-to-female ratio was 1.8:1. Presenting features were macrocrania in four cases, haemorrhage or headache in three and nonhaemorrhagic neurological deficits or and cardiac overload in two. Dominant supply to the symptomatic fistula arose from the posterior inferior cerebellar artery in five cases, anterior inferior cerebellar artery in two and the upper basilar artery system in seven. All children were primarily treated by transarterial embolisation. We treated thirteen children (93%) by transarterial embolisation alone; one older child with a history of haemorrhage also underwent radiosurgery. We obtained 100% exclusion of the fistula(e) in six children, 95-80% in five, 80-50% in one and <50% in one. Of the incompletely treated cases, three had conservative management, and two with 80% and one with 60% reduction of their lesion are scheduled for elective treatment; two partially treated case died. There was no morbidity due to the endovascular procedures. Follow-up since referral is 6 months-10 years (mean 4.5 years). Ten children are neurologically normal, two have persistent (pre-existing) neurological deficits and two are dead.

Encephalocraniocutaneous lipomatosis syndrome in a child: association with multiple high flow cerebral arteriovenous fistulae. Case report and review.

SUMMARY: We describe the case of a three-year-old Danish boy born at term by Cesarean due to cardiac insufficiency in the last trimestre of intra-uterine life for which he is being treated with cardiac drugs. At birth, he was noted to have bilateral ocular malformations on the upper eyelids, and diffuse scalp lipoma and alopecia. Due to the retarded growth (score - 3D) he had a MRI and angiography which demonstrated a high flow fistula on the basilar tip artery and another one on the MCA branch treated by endovascluar approach. Intracranial arachnoid cysts, dysplastic cortex, ventricular enlargement and lipoma were noted too, establishing the diagnosis of Encephalocraniocutaneous Lipomatosis Syndrome, a rare disease, especially in bilateral presentation. To our knowledge this is the first observation of ECCL associated with intracranial pial arteriovenous fistulas.