Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement.
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ABSTRACT:
SUBMITTER: Reda G
PROVIDER: S-EPMC6518888 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement.
Reda Gianluigi G Cassin Ramona R Dovrtelova Gabriela G Matteo Cristina C Giannotta Juri J D'Incalci Maurizio M Cortelezzi Agostino A Zucchetti Massimo M
Haematologica 20190214 5
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Project description:ObjectiveWe evaluated the correlation between cerebrospinal fluid (CSF) cytokine levels and central nervous system (CNS) involvement in adult acute myeloid leukemia (AML).MethodsThe study sample consisted of 90 patients diagnosed with AML and 20 with unrelated CNS involvement. The AML group was divided into two sub-groups: those with (CNS+, n=30) and without CNS involvement (CNS-, n=60). We used a cytometric bead assay to measure CSF interleukin (IL)-2, IL-4, IL-6, and IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A. We used receiver operating characteristic curves to evaluate the ability of CSF cytokine levels to identify CNS involvement in adult AML.ResultsCSF IL-6 levels were significantly higher in CNS+adult AML patients and positively correlated with the lactate dehydrogenase levels (r=0.738, p<0.001) and white blood cell (WBC) count (r=0.455, p=0.012) in the blood, and the protein (r=0.686, p<0.001) as well as WBC count in the CSF (r=0.427, p=0.019). Using a CSF IL-6 cut-off value of 8.27 pg/ml yielded a diagnostic sensitivity and specificity was 80.00% and 88.46%, respectively (AUC, 0.8923; 95% CI, 0.8168-0.9678). After treating a subset of tested patients, their CSF IL-6 levels decreased. Consequently, the elevated CSF IL-6 levels remaining in CNS+ adult AML patients post-treatment were associated with disease progression.ConclusionCSF IL-6 is a promising marker for the diagnosis of adult AML with CNS involvement and a crucial dynamic indicator for therapeutic response.
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Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans. WHAT THIS STUDY ADDS: Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg(-1), sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h. AIMS: The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children. METHODS: A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg(-1). Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection. RESULTS: In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 microg l(-1). At 5.5 h the CSF concentration was 0.1 microg l(-1), and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 microg l(-1) (range 70-272 microg l(-1)). No serious or unexpected adverse effects were reported. CONCLUSIONS: Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.
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Project description:BackgroundDiagnosis of multiple sclerosis (MS) is established on criteria according to clinical and radiological manifestation. Cerebrospinal fluid (CSF) analysis is an important part of differential diagnosis of MS and other inflammatory processes in the central nervous system (CNS).MethodsIn total, 242 CSF samples were collected from patients undergoing differential MS diagnosis because of the presence of T2-hyperintensive lesions on brain MRI. The non-MS patients were subdivided into systemic inflammatory diseases with CNS involvement (SID) or cerebrovascular diseases (CVD) or other non-inflammatory diseases (NID). All samples were analyzed for the presence of oligoclonal bands and ELISA was performed for detection of: INF gamma, IL-6, neurofilaments light chain (NF-L), GFAP, CHI3L1, CXCL13, and osteopontin.ResultsThe level of IL-6 (p = 0.024), osteopontin (p = 0.0002), and NF-L (p = 0.002) was significantly different among groups. IL-6 (p = 0.0350) and NF-L (p = 0.0015) level was significantly higher in SID compared to NID patients. A significantly higher level of osteopontin (p = 0.00026) and NF-L (p = 0.002) in MS compared to NID population was noted. ROC analysis found weak diagnostic power for osteopontin and NFL-L.ConclusionsThe classical and non-standard markers of inflammatory process and neurodegeneration do not allow for sufficient differentiation between MS and non-MS inflammatory CNS disorders. Weak diagnostic power observed for the osteopontin and NF-L needs to be further investigated.
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Project description:Primary central nervous system lymphoma (PCNSL) is a rare, highly aggressive, extranodal form of non-Hodgkin lymphoma, predominantly diagnosed as primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL). Fast and precise diagnosis of PCNSL is critical yet challenging. microRNAs, important regulators in physiology and pathology are potential biomarkers. In 131 patients with CNS DLBCL and with non-malignant brain lesions (n-ML), miR-21, miR-19b and miR-92a, miR-155, miR-196b, miR-let-7b, miR-125b, and miR-9 were examined by RT-qPCR in brain biopsy samples (formalin-fixed paraffin-embedded tissues, FFPET; CNS DLBCL, n = 52; n-ML, n = 42) and cerebrospinal fluid samples (CSF; CNS DLBCL, n = 30; n-ML, n = 23) taken for routine diagnosis. FFPET samples were split into study and validation sets. Significantly higher CSF levels of miR-21, miR-19b, and miR-92a were identified in PCNSL but not in n-ML, and differentiated PCNSL from n-ML with 63.33% sensitivity and 80.77% specificity. In FFPETs, miR-155 and miR-196b were significantly overexpressed and miR-let-7b, miR-125b, and miR-9 were downregulated in PCNSL as compared to n-ML. Combined miR-155 and miR-let-7b expression levels in FFPETs discriminated PCNSL and n-ML with a 97% accuracy. In conclusion, tissue miR-155, miR-196b, miR-9, miR-125b, and miR-let-7b expression profiles differentiate PCNSL from n-ML. PCNSL CSFs and the relevant biopsy samples are characterized by specific, different microRNA profiles. A logistic regression model is proposed to discriminate between PCNSL and non-malignant brain lesions. None of the examined microRNAs influenced overall survival of PCNSL patients. Further ongoing developments involve next generation sequencing-based profiling of biopsy and CSF samples.
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Project description:PurposePrimary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses.Experimental designWe performed targeted next-generation sequencing of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single-nucleotide variants (SNV), and small insertions/deletions (indel) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available.ResultsCases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), nonmalignant (n = 17), and nondiagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/or cancer-specific alterations in 75.0% (n = 24) of glioblastoma and 52.6% (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26%-48%) and SNVs at predefined gene loci (44%), followed by SNVs/indels identified via uninformed variant calling (8%-14%). A molecular-guided tumor classification was possible for 23.5% (n = 4) of nondiagnostic cases.ConclusionsWe developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma. See related commentary by Abdullah, p. 2860.
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