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Brain and Nerve = Shinkei Kenkyu No... May 2024AL amyloidosis, derived from amyloidogenic immunoglobulin light chains, is a common type of systemic amyloidosis. Peripheral neuropathy has been identified in 10%-40% of... (Review)
Review
AL amyloidosis, derived from amyloidogenic immunoglobulin light chains, is a common type of systemic amyloidosis. Peripheral neuropathy has been identified in 10%-40% of patients with systemic AL amyloidosis. Definitive diagnosis requires tissue biopsies, including skin, fat, and gastrointestinal samples, as well as amyloid typing. Disease-modifying therapies have been shown to improve patient survival and prevent progressive organ dysfunction.
Topics: Humans; Amyloidosis; Immunoglobulin Light-chain Amyloidosis; Immunoglobulin Light Chains
PubMed: 38741500
DOI: 10.11477/mf.1416202647 -
European Journal of Heart Failure Sep 2023Left ventricular (LV) hypertrophy consists in an increased LV wall thickness. LV hypertrophy can be either secondary, in response to pressure or volume overload, or...
Diagnosis and management of patients with left ventricular hypertrophy: Role of multimodality cardiac imaging. A scientific statement of the Heart Failure Association of the European Society of Cardiology.
Left ventricular (LV) hypertrophy consists in an increased LV wall thickness. LV hypertrophy can be either secondary, in response to pressure or volume overload, or primary, i.e. not explained solely by abnormal loading conditions. Primary LV hypertrophy may be due to gene mutations or to the deposition or storage of abnormal substances in the extracellular spaces or within the cardiomyocytes (more appropriately defined as pseudohypertrophy). LV hypertrophy is often a precursor to subsequent development of heart failure. Cardiovascular imaging plays a key role in the assessment of LV hypertrophy. Echocardiography, the first-line imaging technique, allows a comprehensive assessment of LV systolic and diastolic function. Cardiovascular magnetic resonance provides added value as it measures accurately LV and right ventricular volumes and mass and characterizes myocardial tissue properties, which may provide important clues to the final diagnosis. Additionally, scintigraphy with bone tracers is included in the diagnostic algorithm of cardiac amyloidosis. Once the diagnosis is established, imaging findings may help predict future disease evolution and inform therapy and follow-up. This consensus document by the Heart Failure Association of the European Society of Cardiology provides an overview of the role of different cardiac imaging techniques for the differential diagnosis and management of patients with LV hypertrophy.
Topics: Humans; Hypertrophy, Left Ventricular; Heart Failure; Cardiac Imaging Techniques; Echocardiography; Cardiology; Ventricular Function, Left
PubMed: 37581253
DOI: 10.1002/ejhf.2997 -
Seminars in Nephrology Jan 2024Amyloidosis is a heterogeneous disorder characterized by abnormal protein aggregate deposition that often leads to kidney involvement and end-stage kidney disease. With... (Review)
Review
Amyloidosis is a heterogeneous disorder characterized by abnormal protein aggregate deposition that often leads to kidney involvement and end-stage kidney disease. With advancements in diagnostic techniques and treatment options, the prevalence of patients with amyloidosis requiring chronic dialysis has increased. Kidney transplantation is a promising avenue for extending survival and enhancing quality of life in these patients. However, the complex and heterogeneous nature of amyloidosis presents challenges in determining optimal referral timing for transplantation and managing post-transplantation course. This review focuses on recent developments and outcomes of kidney transplantation for amyloidosis-related end-stage kidney disease. This review also aims to guide clinical decision-making and improve management of patients with amyloidosis-associated kidney disease, offering insights into optimizing patient selection and post-transplant care for favorable outcomes.
Topics: Kidney Transplantation; Humans; Kidney Failure, Chronic; Amyloidosis; Patient Selection; Immunoglobulin Light-chain Amyloidosis
PubMed: 38490903
DOI: 10.1016/j.semnephrol.2024.151496 -
Revista Espanola de Cardiologia... Jan 2024Cardiac amyloidosis (CA) refers to an infiltrative process involving amyloid fibril deposition in the myocardium causing restrictive cardiomyopathy. While various types... (Review)
Review
Cardiac amyloidosis (CA) refers to an infiltrative process involving amyloid fibril deposition in the myocardium causing restrictive cardiomyopathy. While various types can affect the heart, the predominant forms are immunoglobulin light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. This review article explores the expanding field of imaging techniques used to diagnose AL-CA and ATTR-CA, highlighting their usefulness in prognostication and disease surveillance. Echocardiography is often the initial imaging modality to suspect CA and, since the incorporation of nonbiopsy criteria using bone scintigraphy, diagnosing ATTR-CA has become more attainable following exclusion of plasma cell dyscrasia. Cardiac magnetic resonance is progressively emerging as a vital tool for imaging CA, and is used in diagnosis, prognostication, and disease surveillance. The use of cardiac magnetic resonance in AL-CA is discussed, as it has been shown to accurately evaluate organ response to chemotherapy. As novel drug treatments emerge in the realm of ATTR-CA, the use of cardiovascular imaging surveillance to monitor disease progression is discussed, as it is gaining prominence as a critical consideration. The ongoing phase III trials investigating treatments for patients with ATTR-CA, will undoubtedly enhance our understanding of cardiac imaging surveillance.
Topics: Humans; Amyloid Neuropathies, Familial; Heart; Myocardium; Magnetic Resonance Imaging; Amyloid; Cardiomyopathies
PubMed: 37696332
DOI: 10.1016/j.rec.2023.06.014 -
The Lancet. Haematology Oct 2023Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of... (Randomized Controlled Trial)
Randomized Controlled Trial
Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.
BACKGROUND
Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.
METHODS
GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022.
FINDINGS
Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy.
INTERPRETATION
Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies.
FUNDING
Janssen Oncology.
Topics: Humans; Male; Multiple Myeloma; Bortezomib; Lenalidomide; Thalidomide; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thrombocytopenia
PubMed: 37708911
DOI: 10.1016/S2352-3026(23)00217-X -
EXCLI Journal 2023Amyloidosis is a protein deposition disorder in which insoluble fibril structures accumulate in the bodily tissues damaging the organ function. Cardiac amyloidosis is a... (Review)
Review
Amyloidosis is a protein deposition disorder in which insoluble fibril structures accumulate in the bodily tissues damaging the organ function. Cardiac amyloidosis is a severe but under-reported medical condition characterized by the accumulation of amyloid in the extracellular area of the myocardium, which results in thickening and stiffening of ventricular walls. Cardiac amyloidosis has recently gained much attention with its slowly surging incidence. With this study, we seek to comprehensively compile the pathophysiology and clinical picture of cardiac amyloidosis subtypes, extending a clinically oriented, up-to-date clinical approach to diagnosis and therapy. Cardiac amyloidosis can be caused by rare genetic mutations which may be inherited or acquired. The growing incidence can be attributed to advancements in imaging methods and other diagnostic modalities. Most occurrences of cardiac amyloidosis result from two forms of precursor protein: transthyretin [TTR] amyloid and immunoglobulin-derived light-chain amyloid. Prompt identification of cardiac amyloidosis can facilitate the implementation of evolving therapeutic interventions to enhance the outcomes. The modalities for the management of CA have evolved significantly in the last ten years. Apart from therapies for modifying disease and heart failure, a myriad of novel therapeutic approaches that target specific aspects of the disease, including gene therapies, are being researched. These aim at impeding its progression and improving clinical outcomes. See also Figure 1(Fig. 1).
PubMed: 37720240
DOI: 10.17179/excli2023-6284 -
European Journal of Heart Failure Mar 2024Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes...
AIMS
Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment.
METHODS AND RESULTS
Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density.
CONCLUSION
Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.
Topics: Humans; Male; Female; Middle Aged; Coronary Circulation; Aged; Cardiomyopathies; Amyloidosis; Magnetic Resonance Imaging, Cine; Myocardium; Immunoglobulin Light-chain Amyloidosis; Myocardial Ischemia; Amyloid Neuropathies, Familial; Myocardial Perfusion Imaging; Coronary Vessels; Biopsy
PubMed: 38247182
DOI: 10.1002/ejhf.3137 -
Ophthalmology Nov 2023
PubMed: 37999679
DOI: 10.1016/j.ophtha.2023.10.028 -
Internal and Emergency Medicine Oct 2023Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA).... (Review)
Review
Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA). AL-CA is a medical urgency for which a diagnostic delay can be catastrophic for patients' outcome. In this manuscript, we focus on the pearls and pitfalls that are relevant to achieve a correct diagnosis and to avoid diagnostic and therapeutical delays. Through the aid of three unfortunate clinical cases, some fundamental diagnostic aspects are addressed, including the following: first, a negative bone scintigraphy does not exclude CA, with patients with AL-CA frequently showing no or mild cardiac uptake, and its execution should not delay hematological tests; second, fat pad biopsy does not have a 100% sensitivity for AL amyloidosis and, if negative, further investigations should be performed, particularly if the pre-test probability is high. Third, Congo Red staining is not sufficient to reach a definitive diagnosis and amyloid fibrils typing with mass spectrometry, immunohistochemistry, or immunoelectron microscopy is crucial. To achieve a timely and correct diagnosis, all the necessary investigations must be performed, always considering the yield and diagnostic accuracy of each examination.
Topics: Humans; Delayed Diagnosis; Amyloidosis; Immunoglobulin Light-chain Amyloidosis; Biopsy; Congo Red; Cardiomyopathies
PubMed: 37338717
DOI: 10.1007/s11739-023-03335-3