Aymeric Amelot

Thrombin bound to a fibrin clot confers angiogenic and haemostatic properties on endothelial progenitor cells

Recent data suggest that endothelial progenitor cells (EPCs) are involved in recanalizing venous thrombi. We examined the impact of a fibrin network, and particularly of adsorbed thrombin, on EPCs derived from cord blood CD34+ cells. Fibrin networks generated in microplates by adding CaCl2 to platelet‐depleted plasma retained adsorbed thrombin at the average concentration of 4.2 nM per well. EPCs expressed high levels of endothelial cell protein C receptor and thrombomodulin, allowing the generation of activated protein C on the fibrin matrix in the presence of exogenous human protein C. The fibrin matrix induced significant EPC proliferation and, when placed in the lower chamber of a Boyden device, strongly enhanced EPC migration. These effects were partly inhibited by hirudin by 41% and 66%, respectively), which suggests that fibrin‐adsorbed thrombin interacts with EPCs via the thrombin receptor PAR‐1. Finally, spontaneous lysis of the fibrin network, studied by measuring D‐dimer release into the supernatant, was inhibited by EPCs but not by control mononuclear cells. Such an effect was associated with a 10‐fold increase in plasminogen activator inhibitor‐1 (PAI‐1) secretion by EPCs cultivated in fibrin matrix. Overall, our data show that EPCs, in addition to their angiogenic potential, have both anticoagulant and antifibrinolytic properties. Thrombin may modulate these properties and contribute to thrombus recanalization by EPCs.

Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin

Platelet factor-4 (PF4/CXCL4) is an orphan chemokine released in large quantities in the vicinity of growing blood clots. Coagulation of plasma supplemented with a matching amount of PF4 results in a translucent jelly-like clot. Saturating amounts of PF4 reduce the porosity of the fibrin network 4.4-fold and decrease the values of the elastic and loss moduli by 31- and 59-fold, respectively. PF4 alters neither the cleavage of fibrinogen by thrombin nor the cross-linking of protofibrils by activated factor XIII but binds to fibrin and dramatically transforms the structure of the ensuing network. Scanning electron microscopy showed that PF4 gives rise to a previously unreported pattern of polymerization where fibrin assembles to form a sealed network. The subunits constituting PF4 form a tetrahedron having at its corners a RPRH motif that mimics (in reverse orientation) the Gly-His-Arg-Pro-amide peptides that co-crystallize with fibrin. Molecular modeling showed that PF4 could be docked to fibrin with remarkable complementarities and absence of steric clashes, allowing the assembly of irregular polymers. Consistent with this hypothesis, as little as 50 μm the QVRPRHIT peptide derived from PF4 affects the polymerization of fibrin.

Polymorphonuclear leukocyte and monocyte activation induced by plasma from patients with heparin-induced thrombocytopenia in whole blood

Heparin-induced thrombocytopenia (HIT), a severe complication of heparin therapy, results from platelet activation by heparin-dependent antibodies. Previously, we have shown that plasma from patients with HIT (HIT plasma) induces leukocyteplatelet aggregation in blood. In this report, we examined leukocyte activation by HIT plasma and the contribution of heparin and platelets to this activation, in whole blood. Degranulation of leukocytes from HIT patients was evaluated as a leukocyte activation marker. We showed that polymorphonuclear leukocytes (PMN) and monocytes were the leukocyte subpopulations involved in platelet-leukocyte aggregation induced by HIT plasma in healthy donor blood. PMN and monocyte activation, reflected by increased surface expression of the CD11b adhesion molecule, was induced by HIT plasma in a heparin-dependent manner. The CD11b increase induced by HIT plasma was observed on PMN only when they were associated with platelets. Moreover, the increased CD11b expression on monocytes and PMN correlated strongly with the degree of platelet adhesion to these cells. Degranulation of leukocytes from HIT patients and control subjects (non-HIT heparin-treated patients and healthy subjects) was evaluated in vivo by measuring the plasma myeloperoxidase concentration. HIT plasma contained higher myeloperoxidase concentrations than control plasma, suggesting leukocyte degranulation during HIT. In conclusion, this study provides the first evidence that PMN activation is induced by HIT plasma. HIT plasma induced PMN and monocyte activation in a heparin-dependent manner. In whole blood, platelet association with monocytes and PMN, and the activation of these leukocytes by HIT plasma were interrelated. Finally, leukocyte degranulation could be involved in HIT physiopathology.

IDH-Mutation Is a Weak Predictor of Long-Term Survival in Glioblastoma Patients

Background A very small proportion of patients diagnosed with glioblastoma (GBM) survive more than 3 years. Isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations define a small subgroup of GBM patients with favourable prognosis. However, it remains controversial whether long-term survivors (LTS) are found among those IDH1/2 mutated patients. Methods We retrospectively analyzed 207 GBM patients followed at Lariboisière Hospital (Paris) between 2005 and 2010. Clinical parameters were obtained from medical records. Mutations of IDH1/2 were analyzed in these patients, by immunohistochemistry for the R132H mutation of IDH1 and by high-resolution melting-curve analysis, followed by Sanger sequencing for IDH1 and IDH2 exon 4 mutations. Mutation rates in LTS and non-LTS groups were compared by Chi square Pearson test. Results Seventeen patients with survival >3 years were identified (8.2% of the total series). The median overall survival in long-term survivors was 4.6 years. Subgroup analysis found that the median age at diagnosis was significantly higher for non long-term survivors (non-LTS) compared to LTS (60 versus 51 years, p <0.03). The difference in the rate of IDH mutation between non-LTS and LTS was statistically not significant (1.16% versus 5.9%, p = 0.144). Among LTS, 10 out of 16 tumors presented a methylation of MGMT promoter. Conclusions This study confirms that long-term survival in GBM patients is if at all only weakly correlated to IDH-mutation.

Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Background Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Overall Survival in Spine Myeloma Metastases: Difficulties in Predicting with Prognostic Scores.

Study Design. Fifty-one patients with spinal multiple myeloma (MM) metastases were operated and followed between January 2004 and July 2014. Objective. The aim of this study was to consider the efficiency of surgical prognosis scores in the management of spinal metastases myelomas. Summary of Background Data. The spine is the most common site of bone metastases in MM. Surgery in spine metastases MM is a matter of debate and its impact on the increase of a patients survival time is not clear. Several surgical survival scores have been developed to determine the best treatment in these patients. Methods. We studied 51 patients operated for spinal MM metastases between January 2004 and July 2014. We determined the Tokuhashi and Tomita survival scores and compared them with documented patient survivals. The two scores were also compared with the International Staging System (ISS). Results. Median survival (MS) was 108 months [standard deviation (SD) 62] for ISS I, 132.2 (SD 40) for ISS II, and 45.5 months (SD 16.3) for ISS III (P = 0.09). According to Tokuhashi survival score, 21 patients (41.2%) will survive <6 months, 6 (11.8%) 6 to 12 months, and 24 (47%) >12 months. According to Tomita et al., 50 patients (98%) will survive >49.9 months and 1 patient (2%) <15 months. Regardless of the ISS grade prognosis, Tokuhashi survival score, and to a lesser extent Tomita score, underestimated the actual survival very significantly [P < 0.0001, Log Rank (Mantel-Cox)]. Conclusion. We suggest that spine surgical prognosis scores are not accurate and are not able to predict the survival of patients with spine myeloma metastases. Spine surgeons have to be guided not by the initial ISS stage but rather by spinal instability and neurological status. Level of Evidence: N/A

Sporadically second localization of cerebellar hemangioblastoma in sella turcica mimicking a meningioma with no associated von Hippel-Lindau disease.

Abstract A 72-year-old man presented with a gradual bilateral decrease in visual acuity. Imaging showed lesion in the sella turcica diagnosed as meningioma but proving secondarily to be a hemangioblastoma. His neurosurgical history included a resection of a cerebellar hemangioblastoma 30 years ago. To our knowledge, such a hemangioblastoma second localization from the infratentorial to supratentorial has not been reported in the literature for patients not presenting with von Hippel–Lindau disease.

In Reply: Surgical Decision Making From Image-Based Biophysical Modeling of Glioblastoma: Not Ready for Primetime

BACKGROUND: Biophysical modeling of glioma is gaining more interest for clinical practice. The most popular model describes aggressivity of tumor cells by two parameters: net proliferation rate (&rgr;) and propensity to migrate (D). The ratio &rgr;/D, which can be estimated from a single preoperative magnetic resonance imaging (MRI), characterizes tumor invasiveness profile (high &rgr;/D: nodular; low &rgr;/D: diffuse). A recent study reported, from a large series of glioblastoma multiforme (GBM) patients, that gross total resection (GTR) would improve survival only in patients with nodular tumors. OBJECTIVE: To replicate these results, that is to verify that benefit of GTR would be only observed for nodular tumors. METHODS: Between 2005 and 2012, we considered 234 GBM patients with pre‐ and postoperative MRI. Stereotactic biopsy (BST) was performed in 109 patients. Extent of resection was assessed on postoperative MRI and classified as GTR or partial resection (PR). Invasiveness &rgr;/D was estimated from the preoperative tumor volumes on T1‐Gadolinium‐enhanced and fluid‐attenuated inversion recovery sequences. RESULTS: We demonstrate that patients with diffuse GBM (low &rgr;/D), as well as more nodular (mid and high &rgr;/D) GBM, presented significant survival benefit from GTR over PR/BST (P < .001). CONCLUSION: Whatever the degree of tumor invasiveness, as estimated from MRI‐driven biophysical modeling, GTR improves survival of GBM patients, compared to PR or BST. This conflicting result should motivate further studies.

Craniovertebral Junction Transoral Approach: Predictive Factors of Complications

BACKGROUND The transoral approach provides the most direct exposure to extradural lesions of the ventral craniovertebral junction. The morbidity and mortality from this approach greatly limits its use because they are still feared and debated. Using univariable and multivariable logistic regression analyses, this study aims to identify the factors associated with short-term complications in patients undergoing the transoral approach. METHODS A consecutive cohort analysis of prospectively collected data in several neurosurgery spine departments evaluated 143 consecutive patients who had undergone craniovertebral junction transoral approach surgery. The mean age at the time of surgery was 45.1 ± 19.1 years. The study analyzed the comorbidities, the operative procedure, and postoperative morbidity and mortality. RESULTS Seventeen patients (11.9%) had a postoperative complication in the first month. In our univariable analysis: age, smoking, tumor etiology, preoperative posterior fixation, posterior bone graft, preoperative external lumbar shunt, and the transoral approach pathway were significantly associated with postoperative mortality and morbidity. In our multivariable analyses, preoperative external lumbar shunt was significantly associated with complication risks (odds ratio [OR] 6.7; 95% confidence interval [CI] 2.1-21.7, P < 0.001), whereas preoperative posterior fixation (OR 0.28; 95% CI 0.08-1.1, P < 0.04) and posterior bone graft (OR 0.14; 95% CI 0.03-0.6, P < 0.008) were significantly associated with lower complication risks. CONCLUSIONS To reduce complications, it is essential to be aware of and to manage these preoperative risk factors. In such manner, we insinuate that postoperative complications depend on the surgeons familiarity with the transoral approach.

Multiple meningiomas in patients with Turner syndrome

Dear Editor, We report two cases of multiple meningiomas in patients with Turner syndrome. Turner (Ullrich-Turner) syndrome is the most common diagnosed sex chromosome abnormality in females, affecting 1 in 2,000 live-born girls, and is characterized by complete or partial X chromosome monosomy [16]. A recent cohort study demonstrated an increased incidence of meningiomas in patients with Turner syndrome [14]. As girls diagnosed with Turner syndrome receive hormone replacement therapy and meningiomas are well-known hormone-related tumors, a possible role of hormones has been proposed to explain this association. These two cases add additional information on the relationships among Turner syndrome, hormone therapy andmeningioma, stressing the possible roles of genetic and/or hormonal factors. In the first case, a 56-year-old female with a history of Turner syndrome was diagnosed with multiple meningiomas after a vaso-vagal episode: in the left pterional area (22.4 cm), in the right cerebellopontine angle (CPA) (2.95 cm) and at the floor of the middle cerebral fossa (0.8 cm). She had been under substitutive estrogen-progesterone hormonal therapy for 42 years. Three years later, the control MRI revealed a significant increase in size of the left pterional meningioma (21 %) associated with perilesional edema without associated symptoms. Subtotal resection of the left pterional meningioma was performed, while maintaining surveillance for the left CPA tumor in the absence of mass effect on the brainstem and the desire to preserved ipsilateral serviceable hearing. The final pathological diagnosis was grade I meningothelial meningioma, with a high expression of progesterone receptors. After a 9-year follow-up, the patient remained asymptomatic. MRI follow-up showed a slight increase of the APC meningioma (8.86 cm) and stability of the left temporal meningioma (1.83 cm) (Fig. 1, upper panel). In the second case, a 54-year-old patient with Turner syndrome was seen in our department for progressive right transmission deafness and tinnitus. The diagnosis magnetic resonance imaging (MRI) performed revealed multiple meningiomas: one right pterional, one left pterional and one parasagittal rolandic. As the patient was under estrogen therapy, hormonal substitution was stopped. On imaging follow-up the left pterional meningioma progressively increased in size with evidence of perilesional edema without clinical expression. This lesion was totally removed 4 years later because it had grown almost 40% in volume, and no residual tumor was found on imaging. Microscopically, this was a WHO Grade I meningioma with a high expression of progesterone receptors. The two others meningiomas where stable on 7-year MRI follow-up (Fig. 1, lower panel). To date, 13 cases of meningiomas in patients with Turner syndrome have been published in the literature, including our cases. Of those, three were multiple meningiomas (23 %) [4, 8, 13]. Sporadic multiple meningiomas account for 9 % of all meningiomas [7]. Multiple meningiomas were initially reported to be related to the NF2 gene mutation with a clonal spread across the meninges [15], but might also correspond to mosaic NF2 cases [3, 6, 11]. Apart from patients with Turner syndrome, loss of chromosome X has already been found in A. Amelot (*) :G. Lemaistre : P. Cornu :M. Kalamarides : M. Peyre Department of Neurosurgery, Batiment Babinski, Groupe Hospitalier Pitie-Salpetriere, APHP, 47-83 boulevard de l’Hopital, 75013 Paris, France e-mail: aymmed@hotmail.fr