Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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Clinical Trial
Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival.
Background: Amyloid light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibres derived from immunoglobulin that can lead to irreversible organ damage. Information about genomic profiles of AL amyloidosis is lacking. Methods: In this study, we adopted a two-step strategy to investigate the mutational profile of AL amyloidosis bone marrow plasma cells (PCs) and their clinical implications. ⋯ Results: Four recurrent mutations were identified by TGS and verified by Sanger sequencing: ASB15 (c. 844 C > T), ASCC3 (c. 1595 A > G), HIST1H1E (c. 311 C > T) and KRAS (c. 35 G > A), among which the first three mutations were associated with inferior overall survival (OS). Additionally, we found that the number of mutations identified by the TGS panel of 98 genes could be a prognostic predictor for OS. Conclusions: In summary, we revealed genomic profiling in AL amyloidosis and found mutation profiles associated with OS.
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Clinical Trial
The utility of repeat kidney biopsy in systemic immunoglobulin light chain amyloidosis.
Background: The diagnostic utility of repeat kidney biopsy in AL amyloidosis patients in complete (CR) or very good partial hematologic response (VGPR) but with renal organ relapse is not clear. Methods: We present eight patients with AL amyloidosis who had a repeat kidney biopsy performed. Results: AL amyloidosis was initially diagnosed by a kidney biopsy. ⋯ Amyloid deposits persist in the kidneys even after successful hematologic treatment and it is impossible to differentiate between new versus old amyloid deposits, which makes performing a repeat kidney biopsy unnecessary in most cases. Demonstration of amyloid deposits on repeat kidney biopsy would not aid in the decision making regarding re-initiation of hematologic treatment. A kidney biopsy should be considered only in cases when a specific alternative diagnosis is suspected.
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Background: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy. ⋯ At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres. Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.
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Response assessment in light chain (AL) amyloidosis is challenging given the low level of circulating free light chains usually seen. Multi-parametric flow cytometry (MFC) from a marrow aspirate was demonstrated to retain a prognostic significance in several recent studies. ⋯ Absence of clonal plasma cells by MFC compared with patients with detectable clonal plasma cells among deep responders was associated with lower level of involved light chain (involved free light chain (iFLC), median 1.1 vs. 1.7 mg/dL; p = .02) and higher frequency of renal response (100% vs. 68%; p = .005). Further studies are needed to determine if MFC should be incorporated into response criteria in AL amyloidosis.
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Pragmatic Clinical Trial
Immunoelectron microscopy and mass spectrometry for classification of amyloid deposits.
Amyloidosis is a shared name for several rare, complex and serious diseases caused by extra-cellular deposits of different misfolded proteins. Accurate characterization of the amyloid protein is essential for patient care. Immunoelectron microscopy (IEM) and laser microdissection followed by tandem mass spectrometry (LMD-MS) are new gold standards for molecular subtyping. ⋯ Concordance was 89.6-100% for different amyloid subtypes. Importantly, combined use of both methods increased the diagnostic classification to 100%. Some variety in performances at organ level was observed.