Delayed Hypersensitivity Reaction: An Increasingly Recognized Complication of Metal-on-Metal Total Disc Replacement

We report the case of a 32-year-old woman who presented with pain recurrence 20 months after she underwent a C5C6 metal-on-metal total replacement. Plan radiographs demonstrated a modification of the shape of the vertebral bodies making the prosthesis more protruding. Then, infection has been ruled out and patch testing revealed a strongly positive reaction for chromium and cobalt. The prosthesis has been removed and a fusion achieved using a cage filled with bone graft. She has been immediately and fully relieved from her pain. We report the radiological signs that enabled early diagnosis and treatment allowing favorable outcome

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

International audienceBackground: 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

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

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

Heimdall, an alternative protein issued from a ncRNA related to kappa light chain variable region of immunoglobulins from astrocytes: a new player in neural proteome

Abstract The dogma “One gene, one protein” is clearly obsolete since cells use alternative splicing and generate multiple transcripts which are translated into protein isoforms, but also use alternative translation initiation sites (TISs) and termination sites on a given transcript. Alternative open reading frames for individual transcripts give proteins originate from the 5′- and 3′-UTR mRNA regions, frameshifts of mRNA ORFs or from non-coding RNAs. Longtime considered as non-coding, recent in-silico translation prediction methods enriched the protein databases allowing the identification of new target structures that have not been identified previously. To gain insight into the role of these newly identified alternative proteins in the regulation of cellular functions, it is crucial to assess their dynamic modulation within a framework of altered physiological modifications such as experimental spinal cord injury (SCI). Here, we carried out a longitudinal proteomic study on rat SCI from 12 h to 10 days. Based on the alternative protein predictions, it was possible to identify a plethora of newly predicted protein hits. Among these proteins, some presented a special interest due to high homology with variable chain regions of immunoglobulins. We focus our interest on the one related to Kappa variable light chains which is similarly highly produced by B cells in the Bence jones disease, but here expressed in astrocytes. This protein, name Heimdall is an Intrinsically disordered protein which is secreted under inflammatory conditions. Immunoprecipitation experiments showed that the Heimdall interactome contained proteins related to astrocyte fate keepers such as “NOTCH1, EPHA3, IPO13” as well as membrane receptor protein including “CHRNA9; TGFBR, EPHB6, and TRAM”. However, when Heimdall protein was neutralized utilizing a specific antibody or its gene knocked out by CRISPR-Cas9, sprouting elongations were observed in the corresponding astrocytes. Interestingly, depolarization assays and intracellular calcium measurements in Heimdall KO, established a depolarization effect on astrocyte membranes KO cells were more likely that the one found in neuroprogenitors. Proteomic analyses performed under injury conditions or under lipopolysaccharides (LPS) stimulation, revealed the expression of neuronal factors, stem cell proteins, proliferation, and neurogenesis of astrocyte convertor factors such as EPHA4, NOTCH2, SLIT3, SEMA3F, suggesting a role of Heimdall could regulate astrocytic fate. Taken together, Heimdall could be a novel member of the gatekeeping astrocyte-to-neuroprogenitor conversion factors

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

Abstract 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

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

International audienceA 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