Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report

We report the fourth described case of severe toxic rhabdomyolysis occurring in an 81-year-old woman caused by the concomitant administration of palbociclib taken at the usual dosage (125 mg per day) and simvastatin. To the best of our knowledge, this is the first reported case successfully treated by plasma exchanges, with complete functional recovery within two months. The severity of this case justifies further consideration of pharmacokinetic interactions between palbociclib or other CDK-4-6 inhibitors and statins, which potentially increase the risk of an adverse event

Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology

Anti-amyloid-β immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-β-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-β 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 µm) were more abnormal than those far from plaques (i.e. beyond 50 µm) (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-β 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-β 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-β immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's diseas

Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

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

Long-term outcomes of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive series of 12 patients.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease. OBJECTIVE: To describe the disease course of CLIPPERS. DESIGN: A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS. SETTING: Academic research. PATIENTS: Twelve patients with CLIPPERS. MAIN OUTCOME MEASURES: The therapeutic management of CLIPPERS was evaluated. RESULTS: Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy. CONCLUSIONS: CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.journal article2012 Julimporte

Intérêt des anticorps anti Olig 1 et anti Olig 2 dans le diagnostic des gliomes supra tentoriels de l'adulte (étude immunohistochimique de 140 cas)

Les tumeurs oligodendrogliales, constituent un groupe particulier au sein des gliomes, car elles sont chimiosensibles et de bon pronostic. Leur diagnostic anatomopathologique est indispensable mais difficile, en l'absence de marqueur immunohistochimique des oligodendrocytes tumoraux. Les facteurs de transcription Olig 1 et Olig 2, exprimés par les progéniteurs oligodendrocytaires à tous les stades de développement, pourraient servir de marqueurs des oligodendrogliomes. En immunohistochimie à l'aide d'anticorps anti Olig 1 et anti Olig 2, nous avons observé sur une série de 96 gliomes, que ces marqueurs n'étaient pas spécifiques des oligodendrogliomes, mais étaient plus fréquemment et plus intensément exprimés dans les tumeurs à composante oligodendrogliale. Ces résultats ne sont pas statistiquement significatifs et nécessiteront des travaux complémentaires sur une plus grande sérieTOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Maladie de Creutzfeldt-Jakob sporadique (corrélations entre la neuropathologie, la clinique et le génotype de 17 cas)

Il est reconnu que le polymorphisme du codon 129 Méthionine/Valine joue un rôle important dans la variabilité des présentations phénotypiques des Maladies de Creutzfeldt-Jakob sporadiques (MCJs). L'objectif de ce travail était d'étudier les corrélations entre la neuropathologie, la clinique et le génotype de 17 cas de MCJs. Le matériel prélevé dans 11 régions du cerveau a été analysé au microscope optique en coloration standard et en immunohistochimie (anti-protéine prion). Les signes neurologiques ont été recueillis dans les dossiers médicaux et auprès des cliniciens. Nos résultats montrent une corrélation par groupe génotypique entre les signes cliniques et les intensités des lésions dans les régions fonctionnelles correspondantes pour : l'aphasie, l'apraxie, la mémoire, le syndrome extra pyramidal, le syndrome frontal, le syndrome cérébelleux et les troubles visuels. Deux cas atypiques ont été mis en évidence : un patient MM2 et un patient MV1 avec des plaques de type kuru dans le cortex cérébral et cérébelleux...TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La translocation MECT1-MAML2 dans les carcinomes mucoepidermoïdes des glandes salivaires : implications diagnostique, pronostique et thérapeutique

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Toxoplasmic encephalitis IRIS in HIV-infected patients: a case series and review of the literature

International audienceBackground: Toxoplasmic encephalitis associated with immune reconstitution inflammatory syndrome (TE-IRIS) is rarely described. Methods: To identify TE-IRIS cases, we performed a retrospective study of all HIV-infected patients diagnosed with TE in our unit between January 2000 and June 2009, and a review of published cases. Results: Three patients out of our 65 TE cases, together with six from the literature, fulfilled unmasking TE-IRIS definition. None fulfilled paradoxical TE-IRIS definition. TE occurred within a median time of 48.5 days [IQ25-75 21-56] after starting antiretroviral therapy. Cases did not have distinctive clinical nor neuroimaging features from TE occurring without immune reconstitution. However: i) Cases occurred at a median CD4 lymphocytes count of 222/µL [IQ25-75 160-280], ii) TE occurred in five patients who were supposed to take an effective chemoprophylaxis, iii) Two patients had a brain biopsy showing an intense angiocentric inflammatory infiltrates with predominantly CD8 lymphocytes, iv) In one patient, the abnormal length of evolution under treatment might be due to the heightened immune response. Conclusion: Although rare, unmasking TE-IRIS exists and might occur despite effective prophylaxis and an unusually high CD4 lymphocytes count. IRIS does not modify TE diagnosis and treatment but might extend its clinical course

Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 Leu1793pro mutation.

International audienceMyosin Storage Myopathies (MSM) have emerged as a new group of inherited myopathies with heterogenous clinical severity and age of onset. We have identified in a woman and her daughter, a pLeu1793Pro mutation in MYH7. This mutation has already been reported to be associated with MSM presenting as neonatal hypotony. Our index case complained of proximal muscle weakness at age 30. Her daughter presented at birth with a cardiomyopathy without any skeletal muscle involvement. This report underlines the clinical variability of MSM even with a given mutation or in a same family

What is hiding behind S100 protein and SOX10 positive oncocytomas? Oncocytic pleomorphic adenoma and myoepithelioma with novel gene fusions in a subset of cases

Oncocytomas (OCs) in salivary glands are rare benign tumors composed of mitochondriarich epithelial cells (oncocytes), mostly localized in the parotid gland. The treatment of choice is simple excision. Extensive oncocytic metaplasia of pleomorphic adenoma (PA) and myoepithelioma (ME) can be diagnostically challenging and may camouflage the correct diagnosis. These tumors should be treated more carefully compared with OC, given the risk of frequent recurrences and the possibility of malignant transformation.We have investigated 89 oncocytic lesions from our files, including OC (n = 74) and metaplastic oncocytic variant of PA/ME (n = 15). All OCs were stained for 5100 protein and SOX10. The tumors with immunohistochemical expression of one or both markers were tested by next-generation sequencing (NGS). The NGS results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH).Ten cases originally diagnosed as OC, and 1 low-grade uncertain oncocytic tumor (11/74) revealed nuclear-cytoplasmic and/or nuclear positivity for S100 protein and/or SOX10, respectively. Fusion transcripts CHCHD7-PLAG1 and GEM-PLAG1 were found in 2 cases (1 fusion in each), and these were confirmed by RT-PCR and PLAG1 break-apart FISH probe, respectively. Another 5 cases were positive for PLAG1 rearrangement by FISH. In the control group of 15 oncocytic PA/ME, 4/15 tested tumors harbored gene fusions including NFT3-PLAG1, CHCHD7-PLAG1, FBX032-PLAG1, and Clorf116-PLAG1 (1 fusion in each case) as detected by NGS. Two fusions were confirmed by RTPCR, 1 case by FISH, and 1 case was not analyzable by FISH.We additionally tested 24 OCs negative for 5100 protein and SOX10 by immunohistochemistry (IHC) and by FISH for rearrangement of PLAG1 gene, but none of them were positive.SOX10 and/or 5100 protein immunopositivity in conjunction with rearrangement of the PLAG1 gene assisted in reclassification of a subset of oncocytomas as oncocytic variants of PA and ME. Therefore, we recommend to include S100 protein and SOX10 IHC when diagnosing tumors with predominantly oncocytoma-like differentiation. In addition, by NGS, 3 new gene fusions were detected in oncocytic ME, including NTF3-PLAG1, FBX032-PLAG1, and GEM-PLAG1, and a new fusion Clorf116-PLAG1 was detected in oncocytic PA. (C) 2020 Elsevier Inc. All rights reserved