CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Astrocytes express aberrant immunoglobulins as putative gatekeeper of astrocytes to neuronal progenitor conversion.

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.

Unruptured cerebral arteriovenous malformation in children: Outcome in treated and untreated patients.

BACKGROUND: The management of unruptured cerebral arteriovenous malformation (URCAVM) is highly controversial; however, data regarding URCAVM in children are scarce. MATERIAL AND METHODS: We retrospectively reviewed consecutive children followed for URCAVM in our department between 2001 and 2021. RESULTS: Out of 36 patients, 12 were initially managed by observation, and 24 underwent first-line treatment: 8 by microsurgery, 10 by radiosurgery, 2 by embolization, and 4 by combined treatment. Mean follow-up of the whole group was 63months. Complete cure of the malformation was obtained in 14 patients (58%) in the treatment group: 8/8 in the microsurgery group, 5/10 in the radiosurgery group, 1/4 in the combined treatment group, and none in the embolization group. Two of the initially non-treated patients presented cerebral hemorrhage, with significant neurological consequences. In the treatment group, 5 patients presented new neurological deficits, only 1 of which, however, was functionally significant. Headache improved in 11 cases, mostly in the treatment group. Overall, 6 patients in the treatment group became asymptomatic, versus none in the observation group. CONCLUSIONS: The treatment of URCAVM is a reasonable option in many pediatric cases, considering the cumulative risk of cerebral hemorrhage during the child's lifetime, as well as the symptoms specific to URCAVM. Microsurgery, when feasible, offers the best functional results and control of the AVM; however, the risk-benefit ratio should be weighed on a case-by-case basis. More studies will be needed to inform treatment decisions in pediatric URCAVM.

Auricles Anomalies in Patients With a TCF12 Gene Mutation.

Craniostenosis is a morphological anomaly affecting about 0.5 of 1000 births and one third of the cases are of genetic origin. Among the syndromes responsible for craniostenosis, there is the Saethre-Chotzen syndrome due to a mutation of the TWIST 1 gene located on chromosome 7. This polymalformative syndrome classically includes a particular morphology of the auricles. The penetrance is variable and results in a phenotypic variability at the origin of "Saethre-Chotzen like" clinical pictures for which the TWIST 1 gene mutation is sometimes not found. Recently, the TCF 12 gene has been implicated in some of these cases. Among the multiple facial malformations, we have carefully examined the particular morphology of the auricle of these patients. The authors found several abnormalities in patients with a TCF 12 gene mutation, namely a thickened and hammered upper pole of the helix, a narrow concha without crux cymbae and a thickened lobe. These morphological features may guide the diagnosis and allow an earlier search for a TCF 12 gene mutation.

Efficacy of lanreotide 120 mg primary therapy on tumour shrinkage and ophthalmologic symptoms in acromegaly after 1 month.

INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.

Growth Hormone Replacement Therapy Seems to Be Safe in Children with Low-Grade Midline Glioma: A Series of 124 Cases with Review of the Literature.

There is little scientific evidence regarding the safety of GHRT in LGG, where GH deficiency is common. PURPOSE: to compare the recurrence rate in children with midline LGG, depending on whether or not they have received GHRT, in order to assess its impact on the risk of tumor recurrence. METHODS: This bicentric retrospective study included 124 patients under the age of 18 who were diagnosed with a midline low-grade glial tumor between 1998 and 2016. We also reviewed literature on this subject. The main outcome measure was tumor relapse, demonstrated by brain MRI. RESULTS: There were 17 patients in the GH-supplemented group (14%) and 107 patients in the non-supplemented group (86%). Relapse occurred in 65 patients (45.5%); 7 patients died (4.9%); no deaths occurred in patients receiving GHRT. Two patients developed a second tumor (1.4%), none of which had received GHRT. Relapse concerned 36.4% of patients without GHRT and 52.9% of patients with GHRT. The difference was not statistically significant between the two groups (p = 0.3). CONCLUSION: GHRT does not lead to a statistically significant increase in risk of relapse for pediatric midline low-grade pediatric glioma in our cohort. Although these results appear reassuring, future natural history or prospective studies should be done to ascertain these findings. Nevertheless, these reassuring data regarding GHRT are in agreement with the data in the current literature.

Morphological and surgical results in sagittal synostosis: early craniectomy versus later cranioplasty.

BACKGROUND AND PURPOSE: Morphological correction is one of the main aims of surgery for sagittal synostosis (SSO). Different surgical techniques have been developed; however, few studies have compared the different surgical protocols. The morphological outcome is poorly documented, because a consensual evaluation tool is lacking. MATERIAL AND METHODS: We performed a prospective study of children operated for SSO in our institution. Children were operated whenever possible at 4 months for craniectomy; by default, children underwent cranioplasty at or after 9 months. The morphological outcome of all children was evaluated using traditional craniometry with head circumference (HC) and the cephalic index (CI), and with the Rotterdam scaphocephaly morphology score (RSMS), a total of semi-quantitative assessments of morphological hallmarks. RESULTS: Craniectomy was significantly associated with a shorter operation time and hospital stay, and a better impact on HC and CI measurements, compared with cranioplasty. The RSMS was markedly improved after surgery in both groups; however, we found no significant difference in improvement between the two groups. Although the transfusion rate and the prevalence of developmental delay were lower in the craniectomy group, and reoperations for calvarial lacunae or complex craniosynostosis occurred only this group, these differences were not significant. CONCLUSIONS: Our results support early surgery with craniectomy whenever possible; however, cranioplasty at a later age is a very acceptable by-default indication. In addition to classical craniometry, morphological evaluation using the RSMS or a similar quantitative scale appears highly desirable for future studies.

Fusiform dilatation of internal carotid artery after pterional but not subfrontal craniotomy in 6 patients.

PURPOSE: Our study aimed to evaluate potential risk factors for the development of FDICA after suprasellar tumor resection. MATERIALS AND METHOD: After reviewing all cases of pediatric patients who benefited from a suprasellar lesion resection in our two medical institutions, we found 6 patients with a FDICA. Surgical approach strategy (pterional or subfrontal approaches) was noted. Postoperative cranial MRI was performed in each patient 3 months after surgery and every year. When a FDICA occurred, MRI was performed 6 months after the diagnosis and 1 year later to detect any progression. RESULTS: There were 6 males with a mean age at treatment of 11 years (6 to 15). Pterional approach was performed in these 6 patients. At the 2 institutions, we have done at least 50 pterional craniotomies for suprasellar lesion resection. No FDICA was reported after subfrontal approach in 27 consecutive pediatric patients operated on from a craniopharyngioma. The delay between the surgery and the diagnosis of the FDICA was 9 months (3 to 17 months). No symptoms related to the FDICA were recorded. The mean maximal diameter of the aneurysm was 14 mm (10 to 21). ICA bifurcation was involved in 2 cases. Asymptomatic FDICA progression was noted in 2 cases but no treatment was proposed. CONCLUSION: The pathogenesis of FDICA is unclear, and might involve arterial wall necrosis caused by postoperative arachnoid fibrosis which might be worsened by the pterional approach.

Minimally invasive resection of large dumbbell tumors of the lumbar spine: Advantages and pitfalls.

OBJECTIVES: The surgical management of dumbbell tumors of the lumbar spine remains controversial, because of their large volume and complex location, involving both the spinal canal and the retro peritoneum. While sporadically reported, our study aims to confirm the value of minimally invasive posterior access for the complete resection of large lumbar dumbbell tumors. PATIENTS AND METHODS: In this prospective study, we included all consecutive patients who underwent the resection of a voluminous dumbbell tumor at the lumbar spine through a minimally invasive approach, between March 2015 and August 2017. There were 4 men and 4 women, with a mean age at diagnosis of 40.6 years (range 29-58 years). The resection was performed through a trans muscular tubular retractor by the same surgical team. Operative parameters and initial postoperative course were systematically reported. Clinical and radiological monitoring was scheduled at 3 months, 1 year and 2 years. RESULTS: The mean operative time was 144 min (range 58-300 minutes) and the mean estimated blood loss was 250 ml (range 100-500 ml). Gross total resection was achieved in all patients. No major complication was reported. The mean length of hospital stay was 3.1 days (range 2 to 6 days). Histological analysis confirmed the diagnosis of grade 1 schwannoma in all patients. The mean follow up period was 14.9 months (range 6 to 26 months), and 5 patients completed at least 1-year follow-up. At 6 months the Macnab was excellent in 6 patients, good in one patient and fair in one patient because of residual neuropathic pain requiring the maintenance of a long-term treatment. No tumor recurrence was noted to date. CONCLUSION: Lumbar dumbbell tumors can be safely and completely resected using a single-stage minimally invasive procedure, in a trained team.

Long-segment percutaneous screw fixation for thoraco-lumbar spine metastases: a single center's experience.

BACKGROUND: The management of spine metastases is an increasing concern for spine surgeons. Their treatment is mainly palliative with the goal to preserve or restore the patients' quality of life. Many minimally invasive techniques have been introduced with the aim to reduce the morbidity associated with more traditional open approaches. We aimed to evaluate the efficiency of long segment percutaneous pedicle screw stabilization for the treatment of instability associated with symptomatic thoracolumbar spine metastases. METHODS: In this prospective study, we included all patients who underwent the percutaneous placement of pedicle screws in our institution between January 2008 and June 2014, for the palliative treatment of a symptomatic thoracolumbar spine metastasis. All patients had a normal examination. Postoperative radiation therapy was planned within 2 weeks following the stabilization. A clinical and radiological follow-up were planned at 3 months, 6 months and 1 year. Pain was measured using VAS and functional status was assessed using the Frankel Grading system. CT scan was performed before discharge and at each office evaluation. RESULTS: Forty-four patients have been included. There were 26 men and 18 women, with a mean age of 57.3 years (range 36-79 years). The mean operative time was 85 minutes (range 47-124 min), and the estimated blood loss was inferior to 100 mL in all cases. The mean length of hospital stay was 5.2 days (range 3-18 days). All patients underwent postoperative radiation therapy within 2 weeks. Pain was significantly improved from the early postoperative period (P<0.001). Visual Analogic Scale scores decreased from 6.3 (2-10) to 3.0 (0-6) at discharge. No patient worsened his neurological condition postoperatively. One patient required a revision surgery at 3 months due to an important tumor progression at the treated level. Radiological follow-up demonstrated no case of misplacement, hardware breakage or loosening. CONCLUSIONS: As the treatment of spine metastases is largely palliative, minimally invasive techniques should be discussed first to limit the impact of surgery in critical patients. Long-segment percutaneous screw fixation followed by early radiation therapy, appears to be a safe and effective treatment option to ensure solid and durable stability, as well as a good local tumor control.

Evaluation of the relevance of surgery in a retrospective case series of patients who underwent the surgical treatment of a symptomatic spine metastasis from lung cancer.

BACKGROUND: The management of spine metastases is an increasing concern for spine surgeons. When considering surgery, it is crucial to ensure that its iatrogenic effects will not exceed its potential benefits, particularly in frail patients with short life expectancy. Among all prognostic factors, the primary site of cancer is the most important, lung cancer being the poorest. Although surgery has shown its effectiveness in the management of spine metastases, there is a lack of studies focusing on lung cancer alone. PURPOSE: To assess the effectiveness and safety of surgery in the management of symptomatic spine metastases from lung cancer. METHODS: We retrospectively reviewed all patients (n = 53) who underwent surgery for spine metastasis from lung cancer at the Lille University Hospital between January 2005 and December 2011. Patients for whom surgery was effective to restore or preserve ambulation, to relieve pain, and to ensure stability without severe complication were considered "surgical success". RESULTS: No patient was lost to follow-up and vital status data were available for all patients. The median survival was 2.1 months and was not influenced by the surgical success (p = 0.1766). We reported seven major complications in seven patients, including three epidural haematoma, two massive pulmonary embolisms and two deaths from cardiopulmonary failure. The surgical success rate was 49 % and on univariate analysis, the factors that have influenced the postoperative outcome were the KPS (p < 0.001), the Frankel grade (p = 0.0217) and the delay between the cancer diagnosis and the occurrence of spine metastases (p = 0.0216). CONCLUSION: A strict patient selection is required to limit the iatrogenic effect of surgery, which may alter the quality of life of these frail patients with limited life expectancy.