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Scientific Reports Sep 2023The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a...
The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a variety of proteins/peptides, which ultimately leads to cell toxicity and tissue damage. Understanding how amyloid aggregation occurs and developing compounds that impair this process is a major challenge in the health science community. Here, we demonstrate that pathogenic proteins associated with Alzheimer's disease, diabetes, AL/AA amyloidosis, and amyotrophic lateral sclerosis can aggregate within stress-inducible physiological amyloid-based structures, termed amyloid bodies (A-bodies). Using a limited collection of small molecule inhibitors, we found that diclofenac could repress amyloid aggregation of the β-amyloid (1-42) in a cellular setting, despite having no effect in the classic Thioflavin T (ThT) in vitro fibrillation assay. Mapping the mechanism of the diclofenac-mediated repression indicated that dysregulation of cyclooxygenases and the prostaglandin synthesis pathway was potentially responsible for this effect. Together, this work suggests that the A-body machinery may be linked to a subset of pathological amyloidosis, and highlights the utility of this model system in the identification of new small molecules that could treat these debilitating diseases.
Topics: Humans; Diclofenac; Amyloidogenic Proteins; Amyloidosis; Prostaglandin-Endoperoxide Synthases; Immunoglobulin Light-chain Amyloidosis
PubMed: 37660155
DOI: 10.1038/s41598-023-41712-2 -
Cells Dec 2023Human body cells are stem cell (SC) derivatives originating from bone marrow. Their special characteristics include their capacity to support the formation and... (Review)
Review
Human body cells are stem cell (SC) derivatives originating from bone marrow. Their special characteristics include their capacity to support the formation and self-repair of the cells. Cancer cells multiply uncontrollably and invade healthy tissues, making stem cell transplants a viable option for cancer patients undergoing high-dose chemotherapy (HDC). When chemotherapy is used at very high doses to eradicate all cancer cells from aggressive tumors, blood-forming cells and leukocytes are either completely or partially destroyed. Autologous stem cell transplantation (ASCT) is necessary for patients in those circumstances. The patients who undergo autologous transplants receive their own stem cells (SCs). The transplanted stem cells first come into contact with the bone marrow and then undergo engraftment, before differentiating into blood cells. ASCT is one of the most significant and innovative strategies for treating diseases. Here we focus on the treatment of Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, and AL amyloidosis, using ASCT. This review provides a comprehensive picture of the effectiveness and the safety of ASCT as a therapeutic approach for these diseases, based on the currently available evidence.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Multiple Myeloma; Immunoglobulin Light-chain Amyloidosis; Transplantation, Autologous; Lymphoma, Non-Hodgkin; Stem Cell Transplantation
PubMed: 38132175
DOI: 10.3390/cells12242855 -
Blood Advances Oct 2023Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but...
Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but predictors of these outcomes have yet to be clarified. We report on 142 patients with newly diagnosed stage IIIb AL amyloidosis. After a median follow-up of 60 months, the median overall survival (OS) was 9 months. Independent baseline factors associated with shorter OS were symptom onset to diagnosis >6 months (hazard ratio [HR], 1.94; P = .003); bone marrow plasmacytosis ≥ 10% (HR, 1.98; P = .01); troponin I > 0.635 ng/mL (HR, 1.62; P = .04); New York Heart Association class III or IV (HR, 1.67; P = .04); and 6-minute walk test distance < 200 m (HR, 1.85; P = .01). Early hematologic (within 1 month) and cardiac (within 3 months) responses were significantly associated with longer survival. In a 1-month landmark analysis, patients with a hematologic very good partial response, partial response, and no response had a median OS of 47, 25, and 5 months, respectively (P < .0001). Patients with cardiac response at 3 months had significantly longer OS (47 vs 11 months; P < .0001). On multivariable modeling, bortezomib use was associated with early hematologic and cardiac responses and longer OS. Symptom onset to diagnosis duration of >6 months and difference between the involved and uninvolved free light chain > 350 mg/L were independently associated with lower odds of an early cardiac response. This study identified factors predictive of treatment outcomes and survival in advanced cardiac AL amyloidosis.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Retrospective Studies; Immunoglobulin Light Chains; Treatment Outcome; Proportional Hazards Models
PubMed: 37581513
DOI: 10.1182/bloodadvances.2023010324 -
Cancers Apr 2024Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to... (Review)
Review
Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.
PubMed: 38672686
DOI: 10.3390/cancers16081605 -
BMJ Open Sep 2023Hereditary transthyretin-mediated amyloidosis is a rare, progressive and potentially life-limiting multisystem disease, affecting every aspect of a patient's life.
Consensus recommendations on holistic care in hereditary ATTR amyloidosis: an international Delphi survey of patient advocates and multidisciplinary healthcare professionals.
BACKGROUND
Hereditary transthyretin-mediated amyloidosis is a rare, progressive and potentially life-limiting multisystem disease, affecting every aspect of a patient's life.
OBJECTIVES
This online international Delphi survey aimed to evolve clinical-patient-led practical guidance, to inspire and encourage a holistic approach to care that is managed in specialist settings by multidisciplinary teams and supported by allied healthcare professionals (HCPs) and patient advocacy groups (PAGs).
DESIGN
A 14-member joint patient advocate-HCP primary panel was convened including representation from PAGs and key clinical specialties (neurology, cardiology, internal medicine, physiotherapy, clinical psychology, dietetics and specialist nursing). Guidance evolved on the care provision needed to support seven core goals: early diagnosis and treatment; disease monitoring and organisation of care; maintenance of physical and mental health; family-centred care and caregiver support; patient-doctor dialogue; access to social support and social networking.
PARTICIPANTS
From June to October 2022, 252 HCPs and 51 PAG representatives from 27 countries were invited to participate in a Delphi survey. Of the 122 respondents who answered at least one survey question, most were HCPs (100, 82%) from specialist centres; the remainder were PAG representatives (22, 18%).
MAIN OUTCOME MEASURE
Both level of agreement and feasibility in practice of each recommendation was tested by two anonymised online Delphi voting rounds.
RESULTS
Based on an a priori threshold for consensus of ≥75% agreement, the clinical-patient community endorsed all but one recommendation. However, only 17/49 (35%) recommendations were identified by most HCPs as a core part of routine care; the remainder (32/49 (65%)) were identified as part of core care by <50% of HCPs respondents, or as largely achievable by 30%-45% of HCPs. By comparison, PAGs recorded lower implementation levels.
CONCLUSIONS
Further consideration is needed on how to evolve multidisciplinary services (supported by allied HCPs and PAGs) to address the complex needs of those affected by this disease.
Topics: Humans; Patient Advocacy; Consensus; Amyloid Neuropathies, Familial; Internal Medicine; Delivery of Health Care
PubMed: 37669844
DOI: 10.1136/bmjopen-2023-073130 -
JACC. Cardiovascular Imaging Aug 2023Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume...
BACKGROUND
Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume (ECV) mapping provides a surrogate measure of the myocardial, liver, and spleen amyloid burden.
OBJECTIVES
The purpose of this study was to assess multiorgan response to treatment using ECV mapping, and assess the association between multiorgan treatment response and prognosis.
METHODS
The authors identified 351 patients who underwent baseline serum amyloid-P-component (SAP) scintigraphy and cardiac magnetic resonance at diagnosis, of which 171 had follow-up imaging.
RESULTS
At diagnosis, ECV mapping demonstrated that 304 (87%) had cardiac involvement, 114 (33%) significant hepatic involvement, and 147 (42%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial HR: 1.03 [95% CI: 1.01-1.06]; P = 0.009; liver HR: 1.03; [95% CI: 1.01-1.05]; P = 0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R = 0.751; P < 0.001; R = 0.765; P < 0.001, respectively). Serial measurements demonstrated ECV correctly identified changes in liver and spleen amyloid load derived from SAP scintigraphy in 85% and 82% of cases, respectively. At 6 months, more patients with a good hematologic response had liver (30%) and spleen (36%) ECV regression than myocardial regression (5%). By 12 months, more patients with a good response demonstrated myocardial regression (heart 32%, liver 30%, spleen 36%). Myocardial regression was associated with reduced median N-terminal pro-brain natriuretic peptide (P < 0.001), and liver regression with reduced median alkaline phosphatase (P = 0.001). Changes in myocardial and liver ECV, 6 months after initiating chemotherapy, independently predict mortality (myocardial HR: 1.11 [95% CI: 1.02-1.20]; P = 0.011; liver HR: 1.07 [95% CI: 1.01-1.13]; P = 0.014).
CONCLUSIONS
Multiorgan ECV quantification accurately tracks treatment response and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. Baseline myocardial and liver ECV and changes at 6 months independently predict mortality, even after adjusting for traditional predictors of prognosis.
Topics: Humans; Contrast Media; Predictive Value of Tests; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Myocardium; Amyloid; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging, Cine
PubMed: 37178079
DOI: 10.1016/j.jcmg.2023.02.019 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of...
Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of cardiac amyloidosis are monoclonal immunoglobulin light chain amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). Nuclear medicine examinations can be accurate, rapid, and non-invasive to help diagnose diseases and can effectively predict the prognosis of patients with CA. Technetium (Tc)-labeled bisphosphonate imaging has been included in the consensus of experts and has become the first-line imaging method for the diagnosis of ATTR-CA. I-metaiodoenzylguanidine (MIBG) as a norepinephrine analogue can effectively assess cardiac sympathetic innervation in patients with CA. Aβ- amyloid imaging agents such as C-pittsburgh compound B and F-flubetaben are expected to be new techniques for diagnosing AL-CA and incorporating them into cardiac staging systems for AL-CA patients in the future. New imaging agents such as F-NaF has been widely used in the diagnosis, treatment response monitoring, and prognosis assessment of CA. Summarizing the research value of nuclide imaging in CA may provide new ideas for clinical realization of early detection of CA and accurate assessment of disease prognosis.
Topics: Humans; Prognosis; Radionuclide Imaging; Amyloidosis; Consensus; Diphosphonates
PubMed: 38432865
DOI: 10.11817/j.issn.1672-7347.2023.230176 -
Targeted Oncology Nov 2023Daratumumab, an anti-CD38 monoclonal antibody, is used for treatment of multiple myeloma (MM) and light chain amyloidosis at an intravenous dosage of 16 mg/kg or at a...
BACKGROUND
Daratumumab, an anti-CD38 monoclonal antibody, is used for treatment of multiple myeloma (MM) and light chain amyloidosis at an intravenous dosage of 16 mg/kg or at a subcutaneous fixed dose of 1800 mg. However, the subcutaneous formulation has only recently been approved in Europe, and real-life data on its safety are still few.
OBJECTIVE
In this multicenter retrospective real-life experience, we provided evidence for the safety of subcutaneous daratumumab in plasma cell disorders.
PATIENTS AND METHODS
A total of 189 patients diagnosed with MM or light chain amyloidosis were included in this retrospective study, and all subjects were daratumumab-naïve. Primary endpoint was safety of subcutaneous daratumumab, especially for infusion-related reaction (IRR) incidence and severity. All patients received premedication with dexamethasone, paracetamol, and antihistamine, with montelukast usage in 85% of cases.
RESULTS
Eight patients (4%) experienced IRRs, mainly of grade I-II, and other frequent toxicities were: hematological (thrombocytopenia, 4%; neutropenia, 5%; lymphopenia, 6%) and non-hematological (pneumonia, 4%; diarrhea, 2%; and cytomegalovirus reactivation, 0.5%). In our multicenter retrospective real-life experience, subcutaneous daratumumab was well-tolerated with an excellent safety profile with a very low (4%) IRR incidence, even in frailer MM patients with severe renal impairment or increased body weight.
CONCLUSIONS
Subcutaneous daratumumab was safe in a real-life setting including patients with severe renal failure and advanced disease. However, further studies on larger and prospective cohorts are required to confirm our real-life observations.
Topics: Humans; Retrospective Studies; Plasma Cells; Prospective Studies; Antineoplastic Agents; Multiple Myeloma; Antibodies, Monoclonal; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37747623
DOI: 10.1007/s11523-023-01001-4 -
Indian Journal of Dermatology,... Oct 2023
PubMed: 38031688
DOI: 10.25259/IJDVL_427_2023 -
Biomarker Research Oct 2023Light chain amyloidosis (AL) is a rare disease caused by the generalized deposition of misfolded free light chains. Patients with immunoglobulin M gammopathy (IgM) and...
Light chain amyloidosis (AL) is a rare disease caused by the generalized deposition of misfolded free light chains. Patients with immunoglobulin M gammopathy (IgM) and indolent B-cell lymphoma such as marginal zone lymphoma (MZL) may in some instances develop AL amyloidosis. So far, CAR T cells for AL amyloidosis have only been reported utilizing the B cell maturation antigen as target, while CD19 has so far not been used in AL amyloidosis.We report the case of a 71-year-old male, diagnosed with systemic AL kappa amyloidosis and MZL, receiving third-generation CAR T cell therapy targeting CD19. Prior treatment included bendamustine/rituximab and cyclophosphamide/ dexamethasone with subsequent autologous stem cell transplantation. CAR T application was well tolerated despite heart and kidney amyloid manifestations, and only early low-grade procedure-specific toxicities were observed. A continuous decrease in IgM, kappa light chains and kappa-to-lambda light chain difference was observed in the patient from day + 30 on, resulting in a deep hematological response six months after treatment.In summary, we present a novel case of CAR T cell treatment with third generation CD19 directed infusion for AL amyloidosis with an underlying secretory active B cell lymphoma, showing that this is an effective treatment modality and can be applied to patients with subsequent AL amyloidosis.
PubMed: 37838756
DOI: 10.1186/s40364-023-00532-2