Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from cortical dementias

International audienceBackground: Considering that most of semantic dementia (SD) and frontotemporal dementia (FTD) patients show no postmortem Alzheimer's disease (AD) pathology, cerebrospinal fluid (CSF) biomarkers may be of value for distinguishing these patients from those with AD. Additionally, biomarkers may be useful for identifying patients with atypical phenotypic presentations of AD, such as posterior cortical atrophy (PCA) and primary progressive non-fluent or logopenic aphasia (PNFLA). Methods: We investigated CSF biomarkers (beta-amyloid 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau [P-tau]) in 164 patients with AD (n=60), PCA (n=15), behavioral variant FTD (n=27), SD (n=19), (PNFLA) (n=26) and functional cognitive disorders (FCD, n=17). We then examined the diagnostic value of these CSF biomarkers in distinguishing the patients from those with AD. Results: The P-Tau/Aβ42 ratio was found to be the best biomarker for discriminating AD from FTD and SD, with a sensitivity of 91.7% and 98.3%, respectively, and a specificity of 92.6% and 84.2%, respectively. As expected, biomarkers were less effective in differentiating AD from PNFLA and PCA, as significant proportions of PCA and PNFLA patients (60% and 61.5%, respectively) had concurrent alterations of both T-tau/Aβ42 and P-Tau/Aβ42 ratios. None of the FCD patients had a typical AD CSF profile or abnormal T-tau/Aβ42 or P-Tau/Aβ42 ratios. Conclusion: The P-Tau/Aβ42 ratio is a useful tool to discriminate AD from both FTD and SD, which are known to involve pathological processes distinct from AD. Biomarkers could be useful for identifying patients with an atypical AD phenotype that includes PNFLA and PCA

Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial

OBJECTIVE To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma. METHODS In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% (0 = 0.10; A = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success. RESULTS Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim. CONCLUSION The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia. CLINICALTRIALSGOV IDENTIFIER NCT02227576. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia

Radiotherapy for newly diagnosed primary central nervous system lymphoma: role and perspective

Whole brain radiotherapy (WBRT) has long been a key treatment of newly diagnosed primary central nervous system lymphoma (PCNSL). In the 1990s, the addition of high dose Methotrexate-based induction chemotherapy (HD MTX-based CT) has enabled a drastic improvement in PCNSL patients outcome. However, combined treatment has led to radiation-induced delayed neurotoxicity, especially in older patients. Alternative treatment strategies have been assessed to improve the efficacy and neurotoxicity ratio. Nowadays, in the elderly patients WBRT is widely omitted or deferred, and in younger patients WBRT is challenged by high dose chemotherapy with autologous stem cell transplant (HCT-ASCT) for consolidation treatment after HD MTX-based CT. In this setting, this review is addressed to clinicians with the aim to summarize the role of WBRT in the treatment of newly diagnosed PCNSL and its perspectives

Caractérisation moléculaire des glioblastomes (corrélation génotype/phénotype)

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Claudins in Renal Physiology and Pathology

International audienceClaudins are integral proteins expressed at the tight junctions of epithelial and endothelial cells. In the mammalian kidney, every tubular segment express a specific set of claudins that give to that segment unique properties regarding permeability and selectivity of the paracellular pathway. So far, 3 claudins (10b, 16 and 19) have been causally traced to rare human syndromes: variants of CLDN10b cause HELIX syndrome and variants of CLDN16 or CLDN19 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The review summarizes our current knowledge on the physiology of mammalian tight junctions and paracellular ion transport, as well as on the role of the 3 above-mentioned claudins in health and disease. Claudin 14, although not having been causally linked to any rare renal disease, is also considered, because available evidence suggests that it may interact with claudin 16. Some single-nucleotide polymorphisms of CLDN14 are associated with urinary calcium excretion and/or kidney stones. For each claudin considered, the pattern of expression, the function and the human syndrome caused by pathogenic variants are described

Perampanel in Drug-Resistant Epilepsy with Gliomas Seizure Response to Perampanel in Drug-resistant Epilepsy with Gliomas: Early Observations

International audienceDrug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognitive dysfunction associated with epilepsy and use of anticonvulsants. Treatment policy included reduction of dose or discontinuation of one or more concurrent AEDs, once a seizure-free response was observed. Twelve patients were included patients, median age 41 years, 9 men versus 3 women and 6 months median duration of follow-up. An objective seizure response (75%) was observed in 9 (75%) out of 12 patients: 50%-seizure response in 3, seizure-freedom in 6, which is plainly more than seen with other types of DRE. Side-effects occurred in six patients. Cognitive function as examined by CTCS improved in six out of eight associated withlowering of concurrent AEDs. The final median dose of PER was 8 mg (varying between 2 and 12 mg). These results of an objective seizure response in 9 (75%) out of 12 patients treated by PER in DRE may be interpreted as a surrogate-marker of tumor response secondary to AMPA blockade, advancing confirmation by MR imaging. These results warrant further study of PER on tumor activity in gliomas