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This study tested the sensitivity and specificity of VE1 antibody raised against BRAFV600E protein, on 189 melanoma samples, compared with molecular testing. In addition, the therapeutic response to BRAF inhibitors was analysed in 27 patients, according to staining intensity (scored from weak to strong) and pattern (homogeneous or heterogeneous). BRAFV600E status during melanoma progression was evaluated in a cohort of 54 patients with at least paired-samples. High sensitivity (98.6%) and specificity (97.7%) of VE1 were confirmed. During melanoma progression different samples showed concordant phenotypes. Heterogeneous VE1 staining was observed in 28.5% of cases, and progression-free survival was higher in patients with tumour samples displaying such staining. These findings suggest that only VE1-negative tumours would be genotyped to detect other BRAFV600 mutations, and that either primary melanoma or metastasis can be tested using immunohistochemistry, according to the material available. [ABSTRACT FROM AUTHOR]

Diffuse adult high-grade gliomas ( HGGs) with necrosis encompass anaplastic oligodendrogliomas ( AOs) with necrosis (grade III), glioblastomas ( GBM, grade IV) and glioblastomas with an oligodendroglial component ( GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into 'anaplastic oligoastrocytoma ( AOA) with necrosis grade IV/GBMO,' restricted to tumors showing intermingled astrocytic and oligodendroglial component, and ' GBM/GBMO' based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/ GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) ( P < 10−4). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H- GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO. [ABSTRACT FROM AUTHOR]

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

The article presents case studies of patients who developed paediatric glial and glioneuronal tumours due to BRAF V600E and H3F3A K27M mutations. The first patient had a large tumour in the pons and cerebellar hemisphere, the second patient had a large pineal tumour while the third patient had a glioma located in the brainstem.

Background Mammary analog secretory carcinoma ( MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular ( ETV6- NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified ( NOS), cystadenocarcinoma, and acinic cell carcinoma (Aci CC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. Methods A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma ( LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (Ade CCs), 5 polymorphous low-grade adenocarcinomas ( PLGAs), and 10 pleomorphic adenomas ( PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. Results Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in Aci CCs and never in Ade CCs. Positivity for GCDFP-15 was observed in most of the tumor types except in Ade CCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. Conclusion Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement. [ABSTRACT FROM AUTHOR]

Primary sinonasal intestinal-type adenocarcinomas (ITAC) are defined on the basis of their morphological similarities to colorectal adenocarcinomas (CRA). Thus, differential diagnosis with sinonasal metastasis of CRA could be a real challenge. Neuroendocrine differentiation has been variably described in several types of adenocarcinomas and notably in ITACs and CRAs. In a series of 25 ITACs and 25 lymph node metastasis of CRAs (nmCRA), we analysed neuroendocrine differentiation by immunohistochemistry with antichromogranin A and synaptophysin antibodies. Neuroendocrine differentiation (chromogranin A and/or synaptophysin positivity) was significantly different (p=0.0002) in ITACs (72%) and in nmCRAs (20%). In conclusion, presence of neuroendocrine cells seems more in favour of a sinonasal intestinal-type adenocarcinoma, than metastatic CRA. This immunohistochemical study could be useful in difficult cases and should be an interesting complement in a clinical discussion. [ABSTRACT FROM AUTHOR]

Anti-amyloid-beta immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-beta active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques (i.e. beyond 50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-beta immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-beta immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability. [ABSTRACT FROM AUTHOR]

Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies. [ABSTRACT FROM AUTHOR]

The article discusses a study that examines whether the molecular target of maraviroc is expressed on pathogenic T cells infiltrating progressive multifocal leukoencephalopathy (PML) immune reconstitution inflammatory syndrome (IRIS) lesions. The study suggests that maraviroc is beneficial in preventing or treating PMLIRIS. It reveals that the CCR5/CCL5 axis is implicated in T cell activation.

This article presents three cases of rosette-forming glioneuronal tumors (RGNT) that were diagnosed through DNA-methylation profiling. These cases did not exhibit the classical FGFR1 alteration commonly associated with this type of tumor. The article provides detailed descriptions of each case, including patient history, symptoms, MRI findings, histological analysis, and molecular analysis. The study expands the understanding of RGNT by identifying genetic abnormalities other than FGFR1 mutation, which has implications for potential therapeutic interventions. [Extracted from the article]

1:CAS:528:DC%2BC1cXpsV2hu7k%3D. 10.1007/s00401-018-1865-4 6 Navarro RE, Golub D, Hill T, McQuinn MW, William C, Zagzag D. Pediatric midline H3K27M-mutant tumor with disseminated leptomeningeal disease and glioneuronal features: case report and literature review. Gliomas with concomitant mutations of H3K27M and I BRAF/FGFR1 i are supposed to be associated with a better prognosis than other DMG, H3K27-altered according to some publications [[7]]. Arguing for this hypothesis, a previously published monothalamic tumor classified as ganglioglioma, H3K27M- and I BRAF i V600E-mutant presented secondary leptomeningeal dissemination 7 years after the initial diagnosis [[10]]. [Extracted from the article]

Simple Summary: Supported by the "easy-to-use" and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts—including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH—62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ "classifier" and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores <0.84 (74.3%). (3) CNV investigations also evidenced alterations used for diagnosis and prognostication. (4) A diagnosis was finally established for 44 tumors (71%). Our results support the use of DNA methylation for challenging pediatric tumors. We demonstrated how additional methylation-based analyses complement the classifier score to support conventional histopathological diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To assess the feasibility of synthesis of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma. Design: Prospective nonrandomized trial. Patients: Twelve patients with suspicion of high-grade glioma. Results: The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16(0.75) for the 11 patients with glioblastoma. Conclusion: The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma. [ABSTRACT FROM AUTHOR]

High-grade neuroepithelial tumor with I MN1 i alteration (HGNET- I MN1 i ) is a rare, recently described central nervous system (CNS) entity with a distinct methylation profile, which was formerly part of CNS-primary neuroepithelial tumors (PNET). HGNET- I MN1 i affects children (77% of reported cases [[1]-[5]]) and are characterized by a recurrent fusion implicating the I MN1 i (meningioma 1) gene [[1]]. Children with HGNET- I MN1 i present a favourable outcome with 88.0% survival (median follow-up of 65.5 months), although 48.0% presented with tumor progression. Analysis of correlation between malignant criteria defined in astroblastoma applied to HGNET- MN1 with overall survival and progression-free survival. [Extracted from the article]

Diffuse gliomas are classified according to the 2016 WHO Classification of Tumors of the Central Nervous System, which now defines entities by both histology and molecular features. Somatostatin receptor subtype 2A (SSTR2A) expression has been reported in various solid tumors as associated with favorable outcomes. Its expression has been reported in gliomas with uncertain results regarding its prognostic value. The objective of this study was to assess the prognostic impact of SSTR2A protein expression in a large cohort of grade III and IV gliomas classified according to the updated 2016 WHO classification. We further validated our result with an independent cohort of low grade glioma using dataset generated by The Cancer Genome Atlas (TCGA) Research Network. We analyzed clinical and molecular data from 575 patients. SSTR2A protein expression was evaluated using immunohistochemistry on tissue microarrays. High expression of SSTR2A protein associated with the anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted subgroup (p < 0.001). Among these tumors, SSTR2A protein expression was significantly associated with a lower proliferative index, the absence of microvascular proliferation and the absence of necrosis (p < 0.001). Furthermore SSTR2A protein expression associated with better overall survival (p = 0.007) and progression-free survival (p = 0.01) in both univariate and multivariate analysis when adjusted by the age, the presence of necrosis and the mitotic index. Similar results were obtained regarding SSTR2 mRNA expression in the TCGA low grade glioma, subtype IDH-mutant and 1p/19q-codeleted, dataset. SSTR2A might represent an attractive biomarker and therapeutic target in anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted specific subgroup. Understanding the implicated molecular pathways may represent a step forward to improve therapeutic approaches. [ABSTRACT FROM AUTHOR]

To conclude, we report, for the first time, two embryonal tumors with I PLAG1 i fusions sharing clinico-radiological, histopathological, immunohistochemical, and epigenetic similarities to CNS embryonal tumors with PLAG-family amplification. Central Nervous System (CNS) embryonal tumors with PLAG-family amplification have been isolated by a distinct DNA-methylation profile [[1]]. References 1 Keck M-K, Sill M, Wittmann A, Joshi P, Stichel D, Beck P. Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. [Extracted from the article]

• Known disease associated with THOC2 mutations is Intellectual developmental disorder, X-linked 12. • Recently, fetal arthrogryposis multiplex congenita was associated to a specific splice site mutation in THOC2 gene. • The muscular phenotype of this new disease shows the presence of cytoplasmic bodies. • We expand the clinical phenotype of THOC2 gene related defects and suggest its involvement in a myopathy with cytoplasmic bodies. Until recently, the disease known to be associated with THOC2 mutations was Intellectual developmental disorder, X-linked 12 (MIM300957). However, recently, fetal arthrogryposis multiplex congenita has been associated with a specific splice site mutation in the THOC2 gene. We report a family with the same splice site mutation in the THOC2 gene involved in fetal arthrogryposis as well. We provide the first description of the muscular phenotype of this disease which reveals the presence of cytoplasmic bodies. Our findings expand the clinical phenotype of THOC2 gene related defects. [ABSTRACT FROM AUTHOR]