Marc Zanello

Long-term results of carmustine wafer implantation for newly diagnosed glioblastomas: a controlled propensity-matched analysis of a French multicenter cohort

BACKGROUNDnThe standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care.nnnMETHODSnIncluded were adult patients with (n = 354, implantation group) and without (n = 433, standard group) carmustine wafer implantation during first surgical resection followed by chemoradiation standard protocol. Multivariate and case-matched analyses (controlled propensity-matched cohort, 262 pairs of patients) were conducted.nnnRESULTSnThe median progression-free survival was 12.0 months (95% CI: 10.7-12.6) in the implantation group and 10.0 months (9.0-10.0) in the standard group and the median overall survival was 20.4 months (19.0-22.7) and 18.0 months (17.0-19.0), respectively. Carmustine wafer implantation was independently associated with longer progression-free survival in patients with subtotal/total surgical resection in the whole series (adjusted hazard ratio [HR], 0.76 [95% CI: 0.63-0.92], P = .005) and after propensity matching (HR, 0.74 [95% CI: 0.60-0.92], P = .008), whereas no significant difference was found for overall survival (HR, 0.95 [0.80-1.13], P = .574; HR, 1.06 [0.87-1.29], P = .561, respectively). Surgical resection at progression whether alone or combined with carmustine wafer implantation was independently associated with longer overall survival in the whole series (HR, 0.58 [0.44-0.76], P < .0001; HR, 0.54 [0.41-0.70], P < .0001, respectively) and after propensity matching (HR, 0.56 [95% CI: 0.40-0.78], P < .0001; HR, 0.46 [95% CI: 0.33-0.64], P < .0001, respectively). The higher postoperative infection rate in the implantation group did not affect survival.nnnCONCLUSIONSnCarmustine wafer implantation during surgical resection followed by the standard chemoradiation protocol for newly diagnosed glioblastoma in adults resulted in a significant progression-free survival benefit.

Spectral and lifetime domain measurements of rat brain tumors.

During glioblastoma surgery, delineation of the brain tumor margins is difficult because the infiltrated and normal tissues have the same visual appearance. We use a fiber-optical fluorescence probe for spectroscopic and time domain measurements to assist surgeon in differentiating the healthy and the infiltrated tissues. First study was performed on rats that were previously injected with tumorous cells. Measurements of endogenous tissue fluorescence were performed on fresh and fixed rat tumor brain slices. Spectral characteristics, fluorescence redox ratios and fluorescence lifetime measurements were analyzed. The study aimed at defining an optical index that can act as an indicator for discriminating healthy from tumorous tissue.

Incidental diffuse low-grade gliomas: from early detection to preventive neuro-oncological surgery

Although a large amount of data supports early surgical resection for symptomatic diffuse low-grade glioma, the therapeutic strategy is still a matter of debate regarding incidentally discovered diffuse low-grade glioma. Indeed, early and “preventive” surgery has recently been proposed in asymptomatic patients with silent diffuse low-grade glioma with better outcomes. The present review discusses the importance of an early diagnosis and of a preventive surgical treatment to improve the outcomes of incidental diffuse low-grade glioma and suggests the possible relevance of a tailored screening policy.

K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway

Here we describe the presence of the mutation p.K27M of H3F3A (H3.3K27M) in two tumours of young patients with classical histopathology of ganglioglioma (grade I WHO 2007), although H3.3K27M represents a hallmark of midline High Grade Glioma (HGG). Ganglioglioma grade I is a rare, circumscribed, glioneuronal tumour of the central nervous system (CNS) that occurs most often in young patients, most frequently in the temporal lobe and presents with seizures [1]. The neuronal component consists of ganglion cells, abnormally grouped and occasionally binucleated. The glial component consists of piloid or fibrillary astrocytic elements, or of pseudo-oligodendroglial elements. Mitoses are occasional and necrosis is absent. Eosinophilic granular bodies (EGB) and perivascular lymphocytes are associated [1]. The glial component variably expresses GFAP and OLIG2 and the neuronal component variably expresses synaptophysin, chromogranin A and MAP2. The progenitor marker CD34 often shows an extravascular stellar immunostaining [1]. Ki67 labelling index is usually less than 3% and p53 immunostaining is negative. The majority of gangliogliomas are benign grade I tumours, however 6% present as grade III anaplastic ganglioglioma or undergo malignant transformation. Markers to predict anaplastic transformation of grade I tumours are poorly defined [1]. The most frequent genetic alterations in ganglioglioma are BRAF p.V600E mutation (40–60%), gain of chromosomes 7 (23%) and 5 (18%) [1–4]. Recurrent mutations in the genes H3F3A and HIST1H3B (encoding histones H3.3 and H3.1 respectively) were described in paediatric and adult HGG and carry a dismal prognosis [5–7]. These mutations show a distinct anatomical segregation: K27M mutation of H3F3A is observed in thalamus, pons and spinal cord, K27M mutation of HIST1H3B is specifically observed in diffuse intrinsic pontine gliomas and G34R/V mutation of H3F3A is observed in the cerebral hemispheres [5–7]. At position 27, lysine is replaced by methionine (K27M) resulting in decreased K27 trimethylation (H3K27me3) [5]. H3.3K27M immunolabelling shows 100% sensitivity and specificity compared to sequencing [5]. Recently, five H3.3K27M paediatric tumours with histopathology other than HGG were reported: three tumours of unclassified histopathology and harbouring BRAF V600E mutation [8], one ganglioglioma harbouring BRAF V600E mutation which underwent a delayed malignant transformation [9], a spinal pilocytic astrocytoma which underwent a delayed malignant transformation after 10 years [10]. Here we extend the histopathological spectrum of H3.3K27M tumours and present two extratemporal grade I gangliogliomas with secondary malignant transformation. One paediatric midline ganglioglioma had combined H3.3K27M and BRAF V600E mutations and its long-term malignant relapse was BRAF wild type. The second case represented a cerebellar tumour with a rapid malignant transformation. The first case was a 12-year-old girl diagnosed with a partially resected right thalamic tumour. Histopathology was of a ganglioglioma grade I. The tumour was reticulin free and composed of astrocytic piloid elements, pseudo-oligodendroglial elements and ganglionic cells associated with EGBs, lymphocytes and CD34 extravascular stellar immunostaining (Figure 1A–C). Binucleated chromogranin A positive cells and mononucleated synaptophysin expressing cells were detected (Figure 1D). The neurofilament immunolabelling confirmed the circumscribed nature of the tumour. The Ki67 labelling index was 2% (Figure 1E). The residual tumour was stable for 7 years until the patient presented with intracranial hypertension. MRI showed an in situ relapse (Figure 1G). The surgical resection was subtotal. Histopathology demonstrated an anaplastic ganglioglioma. The lesion contained lowgrade areas (Figure 1H) and anaplastic areas with high cellularity, marked atypia, mitotic activity exceeding 5 mitoses per 10 high power field (HPF), microvascular proliferation, pseudopalisading necrosis, high p53 expression and Ki67 index reaching 20% (Figure 1I).

Clinical, Imaging, Histopathological and Molecular Characterization of Anaplastic Ganglioglioma

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.

Spectral and fluorescence lifetime endoscopic system using a double-clad photonic crystal fiber

We present a customized small-core double-clad photonic crystal fiber for spectral and fluorescence lifetime measurements of human samples. In this Letter, the new fiber has been characterized on different fluorophores and samples of human brain tumor; a comparison to a bi-fiber homemade system and a commercial fiber probe was made.

Delaying standard combined chemoradiotherapy after surgical resection does not impact survival in newly diagnosed glioblastoma patients.

BACKGROUNDnTo assess the influence of the time interval between surgical resection and standard combined chemoradiotherapy on survival in newly diagnosed and homogeneously treated (surgical resection plus standard combined chemoradiotherapy) glioblastoma patients; while controlling confounding factors (extent of resection, carmustine wafer implantation, functional status, neurological deficit, and postoperative complications).nnnMETHODSnFrom 2005 to 2011, 692 adult patients (434 men; mean of 57.5 ± 10.8 years) with a newly diagnosed glioblastoma were enrolled in this retrospective multicentric study. All patients were treated by surgical resection (65.5% total/subtotal resection, 34.5% partial resection; 36.7% carmustine wafer implantation) followed by standard combined chemoradiotherapy (radiotherapy at a median dose of 60 Gy, with daily concomitant and adjuvant temozolomide). Time interval to standard combined chemoradiotherapy was analyzed as a continuous variable and as a dichotomized variable using median and quartiles thresholds. Multivariate analyses using Cox modeling were conducted.nnnRESULTSnThe median progression-free survival was 10.3 months (95% CI, 10.0-11.0). The median overall survival was 19.7 months (95% CI, 18.5-21.0). The median time to initiation of combined chemoradiotherapy was 1.5 months (25% quartile, 1.0; 75% quartile, 2.2; range, 0.1-9.0). On univariate and multivariate analyses, OS and PFS were not significantly influenced by time intervals to adjuvant treatments. On multivariate analysis, female gender, total/subtotal resection and RTOG-RPA classes 3 and 4 were significant independent predictors of improved OS.nnnCONCLUSIONSnDelaying standard combined chemoradiotherapy following surgical resection of newly diagnosed glioblastoma in adult patients does not impact survival.

Multimodal optical analysis of meningioma and comparison with histopathology.

Meningioma is the most frequent primary central nervous system tumor. The risk of recurrence and the prognosis are correlated with the extent of the resection that ideally encompasses the infiltrated dura mater and, if required, the infiltrated bone. No device can deliver real-time intraoperative histopathological information on the tumor environment to help the neurosurgeon to achieve a gross total removal. This study assessed the abilities of nonlinear microscopy to provide relevant and real-time data to help resection of meningiomas. Nine human meningioma samples (four World Health Organization Grade I, five Grade II) were analyzed using different optical modalities: spectral analysis and imaging, lifetime measurements, fluorescence lifetime imaging microscopy, fluorescence emitted under one- and two-photon excitation and the second-harmonic generation signal imaging using a multimodal setup. Nonlinear microscopy produced images close to histopathology as a gold standard. The second-harmonic generation signal delineated the collagen background and two-photon fluorescence underlined cell cytoplasm. The matching between fluorescence images and Hematoxylin and Eosin staining was possible in all cases. Grade I meningioma emitted less autofluorescence than Grade II meningioma and Grade II meningioma exhibited a distinct lifetime value. Autofluorescence was correlated with the proliferation rates and seemed to explain the observed differences between Grade I and II meningiomas. This preliminary multimodal study focused on human meningioma samples confirms the potential of tissue autofluorescence analysis and nonlinear microscopy in helping intraoperatively neurosurgeons to reach the actual boundaries of the tumor infiltration. Correspondence between H&E staining (top pictures) and the two-photon fluorescence imaging (bottom pictures).

Report of a successful human trepanation from the Dark Ages of neurosurgery in Europe

Dear Editor, Cranial trepanation is among the oldest surgical procedures performed. Remains of human skulls with evidence of successful trepanation have been found in many countries such as Peru [1], Syria [2] and China [3], dating from the Neolithic Age to modern times [4]. In 1876 [5], Paul Broca described three putative goals for such trepanations: (1) an intra-vitam trepanation as a surgical procedure to cure a specific disease; (2) a post-mortem trepanation as a ritual or magical ceremony and (3) a symbolic trepanation, performed on a healthy person, to form a shallow depression on the head [4]. During the Middle Ages in Europe, there was a general diminution in the frequency of surgical procedures performed. An anthropologic collection of 1,583 sets of human remains, originating from the ossuary in the basement of the High Court of Péronne, Somme, France, was examined. One skull, referenced as C8 (for Crâne 8), showed evidence of a trepanation (Fig. 1). Radiocarbon dating analysis demonstrated that the skull dated from between 990 and 1120 AD. The anthromorphic analysis suggested an adult but gave no clues as to the gender, given the limited material available. The dimensions of the skull were 13.3 cm in the anterioposterior axis, 14.8 cm in the transverse axis and 8.7 cm in the craniocaudal axis. Forensic analysis identified a bone perforation at the bregma (namely the anatomical point on the skull at which the coronal suture is intersected perpendicularly by the sagittal suture). The hole extended into the two parietal bones and presumably also on the frontal bone. The hole appeared to be circular or semicircular. The edge of the hole was regular in the outer table, while the edge of the hole was more irregular in the inner table. The hole shows a filling of the diploic alveolus, uncovered by the perforation. The measurements demonstrated a slight internal angle 10° from the strict perpendicular, with an external diameter of 24.0 mm at the outer table and with an internal diameter of 22.0 mm at the inner table. There was no notch or abrasion near the hole or anywhere else on the skull fragment. The skull showed no evidence of trauma, tumor or infection. This case is intriguing in a number of ways: (1) it was performed during the Dark Ages of surgery in Europe at a transitional period between the early and central medieval times; (2) it was performed on the bregma for a questionable indication. In Europe, trepanations are extremely rarely reported after the Neolithic era, partly because the dead were generally cremated during the later Bronze Age and partly because the frequency with which they were performed never reached the numbers observed during the Neolithic Age [6]. French cases date mostly from the Neolithic Era [7, 8]. If we consider the entire period of the Middle Ages, very few medieval surgical trepanations are reported from Europe [9]. The frequency of trepanations encompassing one or more skull sutures was quite high: (1) the first detailed analysis made by Stewart on an historical cohort of 112 trepanations from Peru, performed during the period of the Inca civilization, found a location involving the midline in 22 % and Johan Pallud and Philippe Charlier contributed equally. M. Zanello : J. Pallud Department of Neurosurgery, Sainte-Anne Hospital, Paris, France

Interactions between glioma and pregnancy: insight from a 52-case multicenter series.

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.