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Cancers Apr 2024Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light...
Outcomes of Modified Mayo Stage IIIa and IIIb Cardiac Light-Chain Amyloidosis: Real-World Experience in Clinical Characteristics and Treatment-67 Patients Multicenter Analysis.
Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50-70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment.
PubMed: 38672674
DOI: 10.3390/cancers16081592 -
Mayo Clinic Proceedings Jul 2024To evaluate the association of carpal tunnel syndrome (CTS) with incident heart failure and incident amyloidosis and to assess the risk of CTS in pathogenic TTR genetic...
OBJECTIVE
To evaluate the association of carpal tunnel syndrome (CTS) with incident heart failure and incident amyloidosis and to assess the risk of CTS in pathogenic TTR genetic variant carriers.
METHODS
This prospective cohort study included multiethnic US adults 18 years of age and older without prevalent heart failure and amyloidosis with available genotypic data from the All of Us Research Program. The primary outcomes were incident heart failure and incident amyloidosis. The association of incident heart failure and incident amyloidosis with CTS was assessed using multivariable adjusted Cox models accounting for age, sex, race and ethnicity, obesity, hypertension, diabetes, statin use, and smoking status.
RESULTS
Of the 166,987 individuals included, the median age was 54 (38 to 66) years; 105,279 (63.0%) were female, and 92,780 (55.6%) were non-Hispanic White individuals; CTS was identified in 12,407 (7.4%) individuals. Compared with individuals without CTS, the adjusted hazard ratio for incident heart failure was 1.13 (95% CI, 1.02 to 1.26) in individuals with CTS. The risk of amyloidosis was ∼3-fold higher (adjusted hazard ratio, 2.86; 95% CI, 1.71 to 4.77) in individuals with CTS compared with those without CTS. Individuals carrying a pathogenic TTR variant had an approximately 40% higher risk (adjusted hazard ratio, 1.38; 95% CI, 1.16 to 1.65) for development of CTS compared with noncarriers.
CONCLUSION
Cardiac amyloidosis screening programs may use CTS as a sentinel event and use genetic testing to identify individuals at a higher risk of TTR amyloidosis.
Topics: Humans; Carpal Tunnel Syndrome; Female; Male; Middle Aged; Amyloid Neuropathies, Familial; Prospective Studies; United States; Heart Failure; Aged; Adult; Incidence; Prealbumin; Risk Factors
PubMed: 38661598
DOI: 10.1016/j.mayocp.2023.11.016 -
American Heart Journal Plus :... May 2024Patients with carpal tunnel syndrome (CTS) show manifestations of arterial abnormalities, including carotid intimal thickening and increased vascular stiffness. As...
STUDY OBJECTIVES
Patients with carpal tunnel syndrome (CTS) show manifestations of arterial abnormalities, including carotid intimal thickening and increased vascular stiffness. As carpal tunnel syndrome is associated with amyloidosis, we hypothesized that previously observed abnormalities can largely be related with concomitant amyloidosis rather than CTS itself.
DESIGN
Prospective observational study.
SETTING
Medeniyet University Goztepe Hospital.
PARTICIPANTS
61 patients with CTS (of whom 32 had biopsy-proven amyloidosis) and 36 healthy controls.
INTERVENTIONS
Subjects underwent ultrasound examinations for the measurement of coronary flow velocity reserve (CFVR), flow-mediated vasodilatation (FMD) and carotid intimal-media thickness (CIMT).
MAIN OUTCOME MEASURES
Comparison of CFVR, FMD and CIMT in CTS patients with or without amyloidosis.
RESULTS
Patients with either CTS or CTS with concomitant amyloidosis (CTS-A) had significantly lower FMD (9.7 % ± 4.0 % in CTS and 10.3 % ± 4.6 % in CTS-A groups, < 0.05 for both) and CFVR (2.4 (2.1-2.8) in CTS and 1.8 (1.6-2.1) in CTS-A groups, < 0.001 for both) as compared to controls, while CIMT was only increased in CTS-A group (0.70 (0.60-0.80), p < 0.001). The reduction in CFVR was solely related to an increased basal flow velocity in CTS patients while there was also a reduced hyperemic flow velocity in patients with CTS-A.
CONCLUSION
Most arterial phenomena in CTS patients could be attributable to concomitant amyloidosis, although endothelial dysfunction was present even in patients with CTS without amyloidosis.
PubMed: 38655035
DOI: 10.1016/j.ahjo.2024.100393 -
Indian Journal of Nephrology 2024Monoclonal gammopathy of renal significance (MGRS) has gained importance because identifying the monoclonal deposit and addressing it, rather than treating renal...
Monoclonal gammopathy of renal significance (MGRS) has gained importance because identifying the monoclonal deposit and addressing it, rather than treating renal dysfunction as the primary pathology, has salvaged the patients from progressing into end-stage renal disease. Since it affects elderly population, there could be a propensity to misdiagnose them with cardiorenal syndrome. We present four patients of MGRS diagnosed from our center. They presented with proteinuria or unexplained renal dysfunction. Three of the patients were diagnosed to have amyloidosis, of which two had lambda-type and one had kappa amyloidosis. The fourth patient had fibrillary glomerulonephritis with kappa restriction, further evaluation of which led to diagnosis of chronic lymphocytic leukemia. Absence of "M" band in protein electrophoresis and a normal bone marrow study should not stop physicians from further evaluation. Quantitative serum immunofixation electrophoresis and electron microscopic examination of renal biopsy have become a comprehensive diagnostic tool in such patients.
PubMed: 38645913
DOI: 10.4103/ijn.ijn_329_22 -
Current Heart Failure Reports Jun 2024Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection... (Review)
Review
PURPOSE OF REVIEW
Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection fraction (HFmrEF). Since patients with CA show early exhaustion, we aimed to investigate whether non-exertional variables of cardiopulmonary exercise testing (CPET) provide additional information in comparison to traditional peak oxygen consumption (VO).
RECENT FINDINGS
We retrospectively investigated CPET variables of patients with HFpEF and HFmrEF with (n = 21) and without (n = 21, HF) CA at comparable age and ejection fraction. Exertional and non-exertional CPET variables as well as laboratory and echocardiographic markers were analyzed. The primary outcome was the difference in CPET variables between groups. The secondary outcome was rehospitalization in patients with CA during a follow-up of 24 months. Correlations between CPET, NTproBNP, and echocardiographic variables were calculated to detect patterns of discrimination between the groups. HF patients with CA were inferior to controls in most exertional and non-exertional CPET variables. Patients with CA were hospitalized more often (p = 0.002), and rehospitalization was associated with VE/VCO (p = 0.019), peak oxygen pulse (p = 0.042), the oxygen equivalent at the first ventilatory threshold (p = 0.003), circulatory (p = 0.024), and ventilatory power (p < .001), but not VO (p = 0.127). Higher performance was correlated with lower E/e' and NTproBNP as well as higher resting heart rate and stroke volume in CA. Patients with CA displayed worse non-exertional CPET performance compared to non-CA HF patients, which was associated with rehospitalization. Differences between correlations of resting echocardiography and CPET variables between groups emphasize different properties of exercise physiology despite comparable ejection fraction.
Topics: Humans; Heart Failure; Exercise Test; Stroke Volume; Amyloidosis; Retrospective Studies; Oxygen Consumption; Male; Female; Aged; Echocardiography; Exercise Tolerance; Middle Aged; Cardiomyopathies
PubMed: 38635117
DOI: 10.1007/s11897-024-00661-1 -
Journal of the European Academy of... Apr 2024
PubMed: 38634739
DOI: 10.1111/jdv.20039 -
Therapeutic Innovation & Regulatory... Jul 2024Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To... (Review)
Review
Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Clinical Trials as Topic; Drug Development; Endpoint Determination; United States
PubMed: 38632158
DOI: 10.1007/s43441-024-00641-6 -
Cureus Mar 2024Macular amyloidosis is primary localized cutaneous amyloidosis (PLCA). It is described by the extracellular accumulation of heterogenic amyloid proteins in the skin that...
Macular amyloidosis is primary localized cutaneous amyloidosis (PLCA). It is described by the extracellular accumulation of heterogenic amyloid proteins in the skin that does not affect the systemic immune system, causing hyperpigmented patches. It is a prevalent skin disorder of young female adults, especially in India, since it affects the population with darker skin. History of frictional rub on the skin is typically present, such as using loofah or bathing scrubs or stones. The case presented below is of a 23-year-old female who presented with a hyperpigmented patch on the upper back of both sides and extensor surface of arms and did not have any history of usage of loofah on those areas, compelling us to research more on the other causative factors (genetic predisposition, infectious agents, and UV radiation are probable causative factors) for macular amyloidosis. This condition is not entirely cured; it is managed symptomatically only to improve cosmetic outcomes.
PubMed: 38623100
DOI: 10.7759/cureus.56248 -
Minimal residual disease in systemic light chain amyloidosis: a systematic review and meta-analysis.Journal of Cancer Research and Clinical... Apr 2024Minimal residual disease (MRD) is a validated prognostic factor in several hematological malignancies. However, its role in systemic light chain (AL) amyloidosis remains... (Meta-Analysis)
Meta-Analysis
PURPOSE
Minimal residual disease (MRD) is a validated prognostic factor in several hematological malignancies. However, its role in systemic light chain (AL) amyloidosis remains controversial, and this systematic review and meta-analysis aims to fill this gap.
METHODS
We searched for relevant studies on Pubmed, Embase, and Cochrane Controlled Register of Trials, nine studies involving 451 patients were included and meta-analyzed. This systematic review has been registered in PROSPERO (CRD42023494169).
RESULTS
Our study found that in the group of patients who achieved very good partial response (VGPR) or better, MRD negativity was correlated with higher cardiac and renal response rates [pooled risk ratio (RR) = 0.74 (95% CI 0.62-0.89), 0.74 (95% CI 0.64-0.87), respectively]. Patients with MRD positivity had a higher hematologic progression rate within two years after MRD detection [pooled RR = 10.31 (95% CI 2.02-52.68)]; and a higher risk of hematologic + organ progression in the first year [pooled RR = 12.57 (95% CI 1.73-91.04)]. Moreover, MRD negativity was correlated with a better progression-free survival (PFS) [pooled hazard ratio (HR) = 0.27 (95% CI 0.17-0.45)]; but it did not significantly improve the overall survival (OS) [pooled HR = 0.34 (95% CI 0.11-1.07)].
CONCLUSION
In AL amyloidosis, our study supports that MRD negativity correlates with higher cardiac or renal response rates and indicates a better PFS in the follow-up. However, the correlation between OS and the status of MRD is not significant.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Neoplasm, Residual; Amyloidosis; Hematologic Neoplasms; Kidney
PubMed: 38619663
DOI: 10.1007/s00432-024-05733-2 -
International Journal of Molecular... Mar 2024Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is... (Review)
Review
Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (v) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 v carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.
Topics: Humans; Prealbumin; Intermediate Filaments; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Polyneuropathies; Biomarkers
PubMed: 38612579
DOI: 10.3390/ijms25073770