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Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l&rsquo, Universit&eacute, de Montr&eacute, al between 1 January 2005 and 27 July 2016. Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

The blood–brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT1) expressed by BBB endothelial cells (ECs). Activation of AT1restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent,in vitro, on the proinflammatory cytokines tumor necrosis factor-α and interferon-γ. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions.

Haemorrhagic complications can occur following aneurysm treatment with flow diverters (FD), but the underlying mechanism remains unknown. We describe a case where deformation of the device may have contributed to the complication. A patient with a giant, previously unruptured cavernous aneurysm that extended intracranially to cause oedema of the internal capsule was treated with flow diversion. Treatment was followed by multiple episodes of peri-aneurysmal haemorrhages within eight days. A deformation of the device which occurred where it curved to cross the aneurysm neck created residual flows which, in the presence of a stent stenosis immediately beyond the neck, may have contributed to the observed ruptures. Following multiple haemorrhages the patient subsequently died. Autopsy demonstrated early red thrombus partially bridging the struts of the flow diverter, and intra-aneurysmal thrombus of various ages. Microscopic pathology showed an aneurysm wall consisting of collagen infiltrated with neutrophils, but the wall was absent near the cerebral peduncle, adjacent to the brain haemorrhage. Radiographs of the extracted specimen confirmed deformation of the FD construct, located at the transition zone of the stent, leading to increased pore size and porosity. The site of the deformation correlated with the angiographic presence of a continued blood inflow jet into the aneurysm. Stent deformation at the transition zone may promote persistent blood entry into the aneurysm, and in turn potentially contribute to haemorrhagic complications.

BACKGROUND AND PURPOSE: The relationship between aneurysm dimensions, flow, thrombosis, and rupture remains poorly understood. We attempted to clarify this relationship by exploring various swine aneurysm models. MATERIALS AND METHODS: Bilateral carotid aneurysms were constructed according to 3 protocols in 24 animals: small aneurysms with wide necks (group 1; n = 6 animals); small aneurysms with small necks (group 2; n = 4 animals), and giant aneurysms with large necks (group 3; n = 14 animals). Group 3 included 3 subgroups, related to testing the model in various experimental conditions: The neck was clipped in 3 animals; venous pouches lacked an endothelial lining in 4 animals; and 7 were control animals. Animals were followed until rupture, or for 1–4 weeks. Angiography was performed postoperatively and before euthanasia. We studied lesion pathology, paying attention to thrombosis, recanalization, wall composition, and perianeurysmal hemorrhage. RESULTS: Groups differed significantly in aneurysm dimensions and aspect ratio (P = .002). Ruptures occurred more frequently in animals with untreated giant aneurysms (7/7) than in animals with small wide-neck (0/6) or small-neck (2/4) aneurysms (P = .002). Ruptures occurred only in animals with thrombosed aneurysms. Lesions lacking an endothelial lining and 5 of 6 clipped venous pouches thrombosed but did not rupture. One giant lesion ruptured despite complete clipping. The wall was deficient in α-actin and was infiltrated with inflammatory cells and erythrocytes in all thrombosed cases, ruptured or not. Ruptures were associated with recanalizing channels in 9 of 10 cases. CONCLUSIONS: Thrombosis, inflammation, and recanalization may precipitate aneurysmal ruptures in a swine model

The existence of a dopamine (DA) projection from nucleus raphe dorsalis (RD) to neostriatum was demonstrated in the rat by combined tyrosine hydroxylase (TH) immunohistochemistry and radioautography after retrograde axonal transport of [3H]noradrenaline ([3H]NA). Intrastriatal injections of [3H]NA were carried out in normal rats or after ipsilateral destruction of the nigrostriatal DA system by injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra. Some 1,000 TH-positive nerve cell bodies were counted within the confines of RD as defined by its content in serotonin (5-HT) neurons. These DA neurons occupied the upper third of the RD and they were part of its small cell population. In all cases, a small proportion of the TH-immunoreactive nerve cell bodies in RD were retrogradely radiolabeled. Radiolabeled but immunonegative cells were exceedingly rare. The double-labeled neurons were generally more numerous after elimination of the nigrostriatal DA innervation than in normal rats. They mostly lay within the ventral portion of the medial subdivision of RD and always predominated on the [3H]NA- injected side. Some were also present in nucleus linearis caudalis. It was concluded that [3H]NA had been taken up and retrogradely transported exclusively by catecholamine neurons; part of the DA cell group in RD projects to the neostriatum; and that most if not all non-5-HT neurons projecting from RD to neostriatum are likely to be dopaminergic.