Characteristics of Anaplastic Oligodendrogliomas Short-Term Survivors: A POLA Network Study.

BACKGROUND: Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics. METHODS: We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network. RESULTS: Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival. CONCLUSION: The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population.

Intracranial aneurysms in pediatric population: a two-center audit.

OBJECTIVE: Intracranial aneurysms (IA) in children are rare, accounting for less than 5% of all IA. Due to their scarcity, the epidemiology is poorly understood and differs from adults in term of clinical presentation, size, location, and origin. Consequently, the treatment strategies are specific and cannot be only based on data from adult series. The aim of our study was to report the characteristics, management, and outcomes of children treated for IA in two university hospitals located in Normandy (France) over the last 17 years and to perform a literature review of this rare pathology. METHODS: This retrospective study included 18 consecutive children (< 18 years old) admitted with cerebral aneurysm treated in two neurosurgery departments in Normandy, from 2001 to 2018. Computerized tomography and cerebral angiography established the diagnosis. Both endovascular and surgical procedures were discussed in all cases. Data focused on clinical condition at admission, characteristics of the IA, choice of the treatment modalities, and complications. The outcome at follow-up is based on Glasgow outcomes scale (GOS) at 1 year. RESULTS: During the study period, 18 children (mean age: 12.6 years; sex ratio male/female: 2.3) were admitted with 21 IA. Aneurysms had a mean size of 13.6 mm with 4 giant aneurysms and were mostly located in the anterior circulation (16/21). Clinical presentations at onset were sudden symptoms related to a subarachnoid hemorrhage in 13 patients, headaches in 4 patients with giant aneurysm, and asymptomatic in one patient. Among the 13 patients with ruptured IA, 6 presented in poor preoperative condition (Hunt and Hess Grade ≥ 4). Treatment modalities consisted in embolization in 9 patients and surgery in 9 patients including 2 by-pass surgeries in fusiform aneurysms. Complications were similar in the two groups, but two cases of recanalization were observed in the endovascular group. At 1 year of follow-up, 14 children were in good condition (GOS Score > 4) and one died. Three children presented associated IA treated by the same technique as initial aneurysm. CONCLUSIONS: Pediatric aneurysm is a different pathology compared with adults, occurring more frequently in male population with a higher proportion of giant aneurysms and aneurysms located in the internal carotid bifurcation. The use of endovascular techniques has progressed in the last years, but surgery was proposed for half of our population.

[Low-grade dural extranodal marginal zone lymphoma]. / Lymphome de la zone marginale localisé à la dure-mère.

Primary low-grade dural marginal zone lymphoma is an indolent low grade lymphoma occurring especially among middle-aged immunocompetent women, and is not associated to an infectious process, contrary to gastric or intestinal marginal zone lymphomas. Dural location is rare since only 105 cases have been reported so far. We report herein on two additional cases, a 72-year-old woman and a 36-year-old man whose lymphoma was revealed by partial seizures and headaches. Morphological analysis of surgical specimens displayed a tumoral proliferation made of small lymphocytes arranged in sheets or in nodules with CD20, CD79a and BCL2-immunopositivity, but CD5 and CD10 negativity. Molecular analysis using a panel of 34 genes involved in lymphomagenesis disclosed a deletion of SOCS1 and TNFAIP3 genes, implicated in the JAK/STAT and NFκB pathways respectively in the first patient that could explain unfavourable prognosis despite complementary radiotherapy. No anomaly was identified in the second patient who is alive with no recurrence or progression seven years after the diagnosis. Currently, there are no standardized treatment schedules, but the vast majority of patients are treated by surgery, then radiotherapy followed by adjuvant chemotherapy using methotrexate alone or in combination with rituximab. Literature review indicates that five-year survival has been estimated at 96.7%, suggesting a better prognosis compared to other locations.

Early platelet variation during concomitant chemo-radiotherapy predicts adjuvant temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma patients.

PURPOSE: Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma. METHODS: A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia ≤ 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set. RESULTS: Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 ≥ 35% (∆W6 ≥ 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ∆W6 ≥ 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5-107.5)) corresponding to sensitivity of 77% (66-87%), specificity of 73% (62-84%), a positive predictive value of 42% (29-54%), and a negative predictive value of 92% (86-99%). CONCLUSION: Platelet decrease at W6 ≥ 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance.

Spinal meningioma and factors predictive of post-operative deterioration.

PURPOSE: Spinal meningiomas are slow-growing intradural-extramedullary tumors. They are usually associated with good outcomes. However, there are few descriptions of factors predictive of impaired evolution. Our objective was to identify predictive factors of post-operative deterioration as well as outcomes at follow-up. METHODS: Between 2009 and 2016, 87 patients had surgery for spinal meningioma in our referral center. Clinical presentation, management and outcomes were reported during the post-operative period and at 3-month follow-up. Evaluation was based on post-operative neurological deterioration defined as an increase of at least one point in the McCormick score compared to the status at admission. RESULTS: During the study period, post-operative deterioration occurred in 17 patients (19.5%). Risk factors associated with this deterioration were the absence of pre-operative neurological signs (Relative Risk; RR = 2.38, p = 0.04), an anterior location of the meningioma and a grade 2 meningioma on WHO classification score (RR = 6, p ≤ 0.01). At 3-month follow-up, in patients who initially presented with a motor deficit, partial recovery was found in 75%, stability in 20% and a deterioration of their clinical status in 5%. After a mean follow-up of 92.4 ± 51.9 months, the recurrence rate was 8%. CONCLUSIONS: Spinal meningiomas are usually benign tumors whose treatment is based on complete surgical resection. Progress in surgical techniques has resulted in lower morbidity rates and improvement in post-operative recovery. In this study, we observed several factors associated with clinical deterioration. Before surgery, patients should be fully informed of these predictive factors of post-operative deterioration and their association with surgical morbidity.

Prognostic factors for survival in adult patients with recurrent glioblastoma: a decision-tree-based model.

We assessed prognostic factors in relation to OS from progression in recurrent glioblastomas. Retrospective multicentric study enrolling 407 (training set) and 370 (external validation set) adult patients with a recurrent supratentorial glioblastoma treated by surgical resection and standard combined chemoradiotherapy as first-line treatment. Four complementary multivariate prognostic models were evaluated: Cox proportional hazards regression modeling, single-tree recursive partitioning, random survival forest, conditional random forest. Median overall survival from progression was 7.6 months (mean, 10.1; range, 0-86) and 8.0 months (mean, 8.5; range, 0-56) in the training and validation sets, respectively (p = 0.900). Using the Cox model in the training set, independent predictors of poorer overall survival from progression included increasing age at histopathological diagnosis (aHR, 1.47; 95% CI [1.03-2.08]; p = 0.032), RTOG-RPA V-VI classes (aHR, 1.38; 95% CI [1.11-1.73]; p = 0.004), decreasing KPS at progression (aHR, 3.46; 95% CI [2.10-5.72]; p < 0.001), while independent predictors of longer overall survival from progression included surgical resection (aHR, 0.57; 95% CI [0.44-0.73]; p < 0.001) and chemotherapy (aHR, 0.41; 95% CI [0.31-0.55]; p < 0.001). Single-tree recursive partitioning identified KPS at progression, surgical resection at progression, chemotherapy at progression, and RTOG-RPA class at histopathological diagnosis, as main survival predictors in the training set, yielding four risk categories highly predictive of overall survival from progression both in training (p < 0.0001) and validation (p < 0.0001) sets. Both random forest approaches identified KPS at progression as the most important survival predictor. Age, KPS at progression, RTOG-RPA classes, surgical resection at progression and chemotherapy at progression are prognostic for survival in recurrent glioblastomas and should inform the treatment decisions.

Recurrent glioblastomas in the elderly after maximal first-line treatment: does preserved overall condition warrant a maximal second-line treatment?

A growing literature supports maximal safe resection followed by standard combined chemoradiotherapy (i.e. maximal first-line therapy) for selected elderly glioblastoma patients. To assess the prognostic factors from recurrence in elderly glioblastoma patients treated by maximal safe resection followed by standard combined chemoradiotherapy as first-line therapy. Multicentric retrospective analysis comparing the prognosis and optimal oncological management of recurrent glioblastomas between 660 adult patients aged of < 70 years (standard group) and 117 patients aged of ≥70 years (elderly group) harboring a supratentorial glioblastoma treated by maximal first-line therapy. From recurrence, both groups did not significantly differ regarding Karnofsky performance status (KPS) (p = 0.482). Oncological treatments from recurrence significantly differed: patients of the elderly group received less frequently oncological treatment from recurrence (p < 0.001), including surgical resection (p < 0.001), Bevacizumab therapy (p < 0.001), and second line chemotherapy other than Temozolomide (p < 0.001). In multivariate analysis, Age ≥70 years was not an independent predictor of overall survival from recurrence (p = 0.602), RTOG-RPA classes 5-6 (p = 0.050) and KPS at recurrence <70 (p < 0.001), available in all cases, were independent significant predictors of shorter overall survival from recurrence. Initial removal of ≥ 90% of enhancing tumor (p = 0.004), initial completion of the standard combined chemoradiotherapy (p = 0.007), oncological treatment from recurrence (p < 0.001), and particularly surgical resection (p < 0.001), Temozolomide (p = 0.046), and Bevacizumab therapy (p = 0.041) were all significant independent predictors of longer overall survival from recurrence. Elderly patients had substandard care from recurrence whereas age did not impact overall survival from recurrence contrary to KPS at recurrence <70. Treatment options from recurrence should include repeat surgery, second line chemotherapy and anti-angiogenic agents.

Prognostic value of circulating short-length DNA fragments in unresected glioblastoma patients.

BACKGROUND: Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients. METHODS: Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration [slDNA] variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and [slDNA]; and the impact of slDNA detection at pre-RT on survival. RESULTS: Thirty-six patients were analyzed: 11 patients (30.6 %) experienced [slDNA] decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of [slDNA] during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months [11.4 - NA] vs 10.1 months [7.8 - 12.6] and 6.8 months [4.5 - NA], p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. [slDNA] was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size. CONCLUSION: [slDNA] decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required. TRIAL REGISTRATION: ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Microsurgical Clipping of Middle Cerebral Artery Aneurysms: Complications and Risk Factors for Complications.

OBJECTIVE: Middle cerebral artery aneurysms (MCAAs) have been considered good candidates for microsurgery. Our objective was to evaluate the risk of complications and the risk factors for complications with microsurgical treatment of MCAAs to better define the indications for microsurgery. METHODS: We conducted a retrospective cohort study from 3 tertiary neurosurgical units from January 2013 to May 2020. We evaluated the frequency of complications and searched for the risk factors for complications after microsurgery. Complications were defined as a composite criterion with the presence of one of the following: procedural-related death, symptomatic cerebral ischemia, impossible exclusion, incomplete exclusion, or rebleeding of the treated aneurysm and symptomatic surgical site hematoma. RESULTS: A total of 292 MCAAs were treated, with 29 complications (9.9%), including symptomatic cerebral ischemia (4.8%), aneurysm rebleeding (0.3%), surgical site hematoma (1.0%), impossible exclusion (0.3%), and incomplete exclusion (4.1%). Severe complications, defined as death or a modified Rankin scale score of ≥4 at 3 months, were infrequent, occurring in 7 of the 292 patients (2.4%). On multivariate analysis, the risk factors were a ruptured aneurysm, a larger maximum aneurysm size, a larger neck size, and arterial branches passing <1 mm from the aneurysm neck or dome. CONCLUSIONS: Microsurgical management of MCAAs can be performed with very low morbidity rates. In some cases, at least for factors that do not result in significant difficulty for endovascular therapy, such as the presence of an en passage artery or ruptured aneurysm, endovascular therapy can be considered to be as safe and effective as clipping.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Results: Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. Conclusion: the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma.

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a "tortuous" vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvß3 were confirmed by in vivo 99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

Usefulness of multislice computerized tomographic angiography in the postoperative evaluation of patients with clipped aneurysms.

BACKGROUND: The aim of our study was to evaluate the diagnostic efficacy of multislice computed tomographic angiography (MSCTA) regarding exclusion quality after aneurysm clipping. METHODS: Sixty patients (74 aneurysms) underwent microsurgical exclusion using titanium clips. The presence of aneurysm remnants on MSCTA was compared by a neuroradiologist to 2D digital subtraction angiography (DSA), which was considered as a reference examination. The contribution of 3D DSA was assessed in a subpopulation of 29 patients (35 aneurysms). RESULTS: With 2D DSA, six aneurysm remnants (8%) were diagnosed, and only five (7%) by MSCTA. The specificity and sensitivity were 98.5 and 83%, respectively. MSCTA failed to demonstrate one large remnant (>2 mm) because of clip artifacts (six clips). With 3D DSA six supplementary remnants were diagnosed. Two were large remnants blinded by vessel overlaps and clip artifacts. Four were small "dog-eared" remnants (< or =2 mm). No additional treatment was required for small remnants. CONCLUSION: In the postoperative period, MSCTA was considered a useful tool to evaluate the large remnants as well as a non-invasive ulterior examination for suspected bifurcation. Nevertheless, 3D DSA is still required for an accurate evaluation of aneurysms treated by more than three clips.

Ruptured Intracranial Aneurysm in a Neonate: Case Report and Review of the Literature.

BACKGROUND: Intracranial aneurysms (IAs) are exceptional in neonates accounting for less than 2% of all IAs occurring during the first decade of life. Little is known about this pathology in this specific population. Because of its scarcity and this specific age at onset, the treatment of IA in neonates is challenging. We describe a rare case of aneurysmal subarachnoid hemorrhage in a neonate and review the current literature. CASE DESCRIPTION: A 21-day-old boy was admitted for hypotonia, vomiting, and seizures. Computed tomography scan revealed a subarachnoid hemorrhage in the sylvian fissure, a frontoparietal subdural hematoma, a left middle cerebral artery (MCA) aneurysm with a diameter of 11 mm, and an infarct of the MCA frontal region. He was successfully treated with endovascular coiling, neuroprotection, and antiepileptic drugs. Immediate postoperative magnetic resonance imaging showed a good aneurysm occlusion without any further ischemia. The outcome was favorable with extubation at day 10. At follow-up, the child experienced normal psychomotor development with no motor deficit. CONCLUSIONS: Ruptured IAs in neonates are rare. Subarachnoid hemorrhage is the most common presentation. Intracranial aneurysms are frequently larger than 10 mm and located on the MCA. The treatment could be surgical or endovascular depending on the characteristics of the aneurysm. There is no recommendation concerning the prevention or treatment of vasospasm in neonates.

Cell-free DNA and circulating TERT promoter mutation for disease monitoring in newly-diagnosed glioblastoma.

The clinical implications of plasmatic cell-free and tumor DNA (cfDNA and ctDNA) are challenging in glioblastoma. This prospective study included 52 consecutive newly diagnosed glioblastoma (n = 49) or gliosarcoma (n = 3) patients treated with concomitant temozolomide and radiotherapy (RT-TMZ), followed by a TMZ maintenance phase. Plasma samples were collected at baseline, before RT-TMZ (pre-RT-TMZ) and at the end of adjuvant TMZ, or at the time of progression in cases of progressive disease (PD). The cfDNA concentration was measured with a fluorometric method, and ctDNA was detected using targeted droplet digital PCR. The main objectives were to analyze the associations between cfDNA and ctDNA measurements during the course of treatment with PD and survival. There was a significant decrease in median cfDNA concentration from baseline to pre-RT-TMZ-19.4 versus 9.7 ng/mL (p < 0.0001)-in the entire cohort. In patients with PD, a significant increase in cfDNA concentration from pre-RT-TMZ to time of PD was observed, from 9.7 versus 13.1 ng/mL (p = 0.037), respectively, while no difference was observed for nonprogressive patients. Neither the cfDNA concentration at baseline nor its kinetics correlated with survival. ctDNA was detected in 2 patients (3.8%) and only in gliosarcoma subtypes.Trial registration ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1 .

Deleterious impact of a generic temozolomide formulation compared with brand-name product on the kinetic of platelet concentration and survival in newly diagnosed glioblastoma.

Chemo-induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first-line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, hematological safety profile, and impact on survival following the initiation of either the brand-name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m2 per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed-effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand-name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo-induced thrombocytopenia was more frequent in the generic group: 19.6% [95% CI 8.7-30.5%] vs 3.1% [0-6.6%], P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ-induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 [1.21-2.8], P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand-name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results.

Simultaneous detection of EGFR amplification and EGFRvIII variant using digital PCR-based method in glioblastoma.

Epidermal growth factor receptor (EGFR) amplification and EGFR variant III (EGFRvIII, deletion of exons 2-7) are of clinical interest for glioblastoma. The aim was to develop a digital PCR (dPCR)-based method using locked nucleic acid (LNA)-based hydrolysis probes, allowing the simultaneous detection of the EGFR amplification and EGFRvIII variant. Sixty-two patients were included. An exploratory cohort (n = 19) was used to develop the dPCR assay using three selected amplicons within the EGFR gene, targeting intron 1 (EGFR1), junction of exon 3 and intron 3 (EGFR2) and intron 22 (EGFR3). The copy number of EGFR was estimated by the relative quantification of EGFR1, EGFR2 and EGFR3 amplicon droplets compared to the droplets of a reference gene. EGFRvIII was identified by comparing the copy number of the EGFR2 amplicon to either the EGFR1 or EGFR3 amplicon. dPCR results were compared to fluorescence in situ hybridization (FISH) and next-generation sequencing for amplification; and to RT-PCR-based method for EGFRvIII. The dPCR assay was then tested in a validation cohort (n = 43). A total of 8/19 EGFR-amplified and 5/19 EGFRvIII-positive tumors were identified in the exploratory cohort. Compared to FISH, the EGFR3 dPCR assay detected all EGFR-amplified tumors (8/8, 100%) and had the highest concordance with the copy number estimation by NGS. The concordance between RT-PCR and dPCR was also 100% for detecting EGFRvIII using an absolute difference of 10.8 for the copy number between EGFR2 and EGFR3 probes. In the validation cohort, the sensitivity and specificity of dPCR using EGFR3 probes were 100% for the EGFR amplification detection compared to FISH (19/19). EGFRvIII was detected by dPCR in 8 EGFR-amplified patients and confirmed by RT-PCR. Compared to FISH, the EGFR2/EGFR3 dPCR assay was estimated with a one-half cost value. These results highlight that dPCR allowed the simultaneous detection of EGFR amplification and EGFRvIII for glioblastoma.

Quality of life and brain damage after microsurgical clip occlusion or endovascular coil embolization for ruptured anterior communicating artery aneurysms: neuropsychological assessment.

OBJECT: For anterior communicating artery (ACoA) aneurysms, endovascular coil embolization constitutes a safe alternative therapeutic procedure to microsurgical clip occlusion. The authors' aim in this study was to evaluate the quality of life (QOL), cognitive function, and brain structure damage after the treatment of ruptured ACoA aneurysms in a group of patients who underwent microsurgical clipping (36 patients) compared with a reference group who underwent endovascular coiling (14 patients). METHODS: At 14 months posttreatment all patients underwent evaluations by independent observers. These observers evaluated global efficacy, executive functions using a frontal assessment battery of tests (Trail making test, Stroop tasks, dual task of Baddeley, verbal fluency, and Wisconsin Card Sorting test), behavior dysexecutive syndrome (the Inventaire du Syndrome Dysexécutif Comportemental questionnaire [ISDC]), and QOL by using the Reintegration To Normal Living Index. Brain damage was analyzed using MR imaging. RESULTS: In the microsurgical clipping and endovascular coiling groups, the distribution on the modified Rankin Scale (p = 0.19) and mean QOL score (85.4 vs 83.4, respectively) were similar. Moreover, the proportion of executive dysfunctions (19.4 vs 28.6%, respectively) and the mean score on the ISDC questionnaire (8.9 vs 8.5, respectively) were not significant, but verbal memory was more altered in the microsurgical clipping group (p = 0.055). Magnetic resonance imaging revealed that the incidence of local encephalomalacia and the median number of lesions per patient increased significantly in the microsurgical clipping group (p = 0.003). CONCLUSIONS: In the 2 groups, no significant difference was observed regarding QOL, executive functions, and behavior. Despite the significant decrease in verbal memory after microsurgical clipping, the interdisciplinary approach remains a safe and useful strategy.

Intraventricular hemorrhage related to AVM rupture: Description, outcomes and impact of intraventricular fibrinolysis.

OBJECTIVES: Arteriovenous malformation (AVM) rupture could lead to intraventricular hemorrhage (IVH), a particularly severe form of intracranial bleeding. The epidemiology, presentation, management and outcomes of IVH related to AVM rupture have not been clearly addressed yet. The aim of the present study was to investigate the characteristics of IVH related to AVM rupture, with particular attention paid to functional outcomes and to the impact of intraventricular fibrinolysis (IVF). PATIENTS AND METHODS: Between 2011 and 2015, all patients suffering from IVH admitted in two tertiary neurosurgical centers were included in a prospective register. Patient with IVH related to AVM rupture were identified (n=29) and their data retrospectively collected. Particular attention was paid on patients who received IVF. We also compared them to 29 apparied aneurysmal IVH. RESULTS: IVH related to AVM rupture often occurred in young patients. In most cases, intracerebral hemorrhage was associated to IVH. 17% of the patients died, and functional outcome at 6 months was similar to those with aneurysmal IVH. Interestingly, 5 patients received IVF and none experienced any rebleeding. CONCLUSION: IVH related to AVM rupture is a severe form of hemorrhagic stroke, with a poor neurologic prognosis. IVF seems to be safe and may be considered in this particular form of IVH.

Predictive Factors of Headache Resolution After Chiari Type 1 Malformation Surgery.

BACKGROUND: Headache is the main and often isolated symptom of patients with Chiari type 1 malformation (CM1). Classically described as occipital and exacerbated by cough, headaches may be poorly characterized, making it difficult to establish CM1 as the underlying cause. Current guidelines for surgical posterior fossa decompression are undefined. The challenge is to distinguish headaches related to CM1 from headaches coincidentally coexisting with CM1. We aimed to determine predictive factors of headache resolution after surgery and applied to our cohort the Chiari Severity Index, a recently developed predictive prognostic score. METHODS: This retrospective study enrolled 49 patients with CM1 and preoperative headache. Standardized telephone interviews regarding headaches before and after surgery were conducted by the same neurologist; magnetic resonance imaging morphometric analyses were performed by an independent neuroradiologist. Headache resolution was defined as ≥50% reduction in frequency of headache days. RESULTS: Preoperative factors of headache resolution after multivariate analysis were attack duration <5 minutes (P = 0.001), triggering by Valsalva maneuvers (P = 0.003), severe intensity of attack (P = 0.05), occipital location (P = 0.05), and greater number of headache days per month (P = 0.04). These characteristics are part of International Headache Society diagnostic criteria for headache attributed to CM1. No radiologic predictive factor was demonstrated. Postoperative improvement was inversely correlated with Chiari Severity Index. CONCLUSIONS: This study confirms the relevance of International Headache Society criteria to identify headaches related to CM1. We propose their systematic use in a preoperative questionnaire.