Light chain amyloidosis

轻链淀粉样变性
  • 文章类型: Journal Article
    轻链(AL)淀粉样变性是系统性淀粉样变性最普遍的亚型,包括一组罕见的疾病。这里,我们评估了AL淀粉样变性的科学前景,以调查研究趋势并确定该领域的热点。
    在过去20年中发表的关于AL淀粉样变性的相关研究从WebofScienceCoreCollection检索。2005年至2024年的出版物进行了文献计量分析,利用包括CiteSpace在内的工具,VOSviewer,RStudio和MSExcel分析和可视化年度出版物趋势,共现模式,国家之间的合作网络,组织,和作者。还检查了突发关键词和参考文献,以获得研究历史,和新兴热点。
    文献计量分析包括2005年至2024年之间发表的2864篇文章。最有成效的杂志是淀粉样蛋白折叠疾病杂志。美国,以及几个发达国家,成为国际AL淀粉样变性研究的主导力量。“AL淀粉样变性”和“心脏淀粉样变性”是过去二十年来的主要热点,和“生物标志物,心脏淀粉样变性,“和”治疗“将是未来的趋势。
    该文献计量分析使用文献计量软件检查了过去二十年来AL淀粉样变性的研究进展。该领域的最新研究主要集中在两个主要领域:AL淀粉样变性的临床诊断和治疗,以及心脏淀粉样变性.重点是理解免疫球蛋白轻链聚集和沉积以减轻器官参与的潜在机制。
    UNASSIGNED: Light chain (AL) amyloidosis stands as the most prevalent subtype of systemic amyloidosis, encompassing a group of rare diseases. Here, we evaluated the scientific landscape of AL amyloidosis to investigate research trends and identify hotspots within the field.
    UNASSIGNED: Relevant studies on AL amyloidosis published over the past two decades were retrieved from the Web of Science Core Collection. The publications between 2005 and 2024 were subjected to bibliometric analyses, leveraging tools including CiteSpace, VOSviewer, RStudio and MS Excel to analyse and visualize the annual publication trend, co-occurrence patterns, collaborative networks among countries, organizations, and authors. Burst keywords and references were also examined to obtain the research history, and emerging hotspots.
    UNASSIGNED: The bibliometric analysis included 2,864 articles published between 2005 and 2024. The most productive journal is Amyloid-Journal of Protein Folding Disorders. The United States, along with several developed nations, emerges as a dominant force in international AL amyloidosis research. \"AL amyloidosis\" and \"cardiac amyloidosis\" were the primary hotspots over the past two decades, and \"Biomarkers,\" \"Cardiac amyloidosis,\" and \"treatment\" would be future trends.
    UNASSIGNED: This bibliometric analysis examined the research developments in AL amyloidosis over the past two decades using bibliometric software. Recent research in this field primarily focuses on two main areas: clinical diagnosis and treatment of AL amyloidosis, as well as cardiac amyloidosis. Emphasis is placed on understanding the mechanisms underlying immunoglobulin light chain aggregation and deposition to mitigate organ involvement.
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  • 文章类型: Journal Article
    系统性轻链(AL)淀粉样变性是一种多系统疾病,其特征是错误折叠的不溶性淀粉样原纤维在细胞外沉积,导致进行性器官功能障碍。AL.淀粉样变性最常见的影响心脏,肾脏,胃肠道和周围神经。早期死亡率主要取决于心脏受累的程度。治疗的目的是通过靶向潜在的克隆血浆或淋巴瘤细胞群体来快速减少淀粉样变性轻链的产生。使用美法仑的高剂量治疗,然后进行自体外周血干细胞移植(ASCT)仍然是一种非常有效的治疗方法,被认为是符合移植条件的患者的标准护理。为AL淀粉样变性患者提供长期疾病控制。近年来,已经出现了几种新的治疗选择(包括抗CD38单克隆抗体),它们单独或联合治疗在根除克隆性浆细胞方面非常有效.在这次审查中,我们讨论了ASCT在目前AL淀粉样变性患者快速发展的治疗环境中的作用,并提供了我们的实践建议.
    Systemic light chain (AL) amyloidosis is a multisystem disorder characterized by extracellular deposition of misfolded insoluble amyloid fibrils resulting in progressive organ dysfunction. AL. amyloidosis most commonly affects the heart, kidneys, gastrointestinal tract and peripheral nerves. Early mortality is chiefly determined by the degree of cardiac involvement. The aim of therapy is to rapidly reduce amyloidogenic light chain production by targeting the underlying clonal plasma or lymphoma cell population. High dose therapy with melphalan followed by autologous peripheral blood stem cell transplant (ASCT) continues to remain a highly effective treatment and is considered a standard of care for transplant eligible patients, which offers long term disease control in patients with AL amyloidosis. In recent years, several new therapeutic options have emerged (including anti-CD38 monoclonal antibodies) which are very effective alone or in combination in eradicating clonal plasma cells. In this review, we discuss the role of ASCT in the current setting of a rapidly evolving treatment landscape for patients with AL amyloidosis and provide our practice recommendations.
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  • 文章类型: Journal Article
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  • 文章类型: Journal Article
    轻链淀粉样变性(AL),被归类为浆细胞发育不良,由此突变的浆细胞不受控制地增殖并分泌大量的无免疫球蛋白轻链(FLC)片段。这些FLC经历了一个错误折叠和聚集成淀粉样纤维的过程,这可能会导致整个系统不可逆转的损害。目前的治疗集中于消耗潜在的浆细胞克隆通常耐受性差,特别是在严重心脏受累的患者中,意味着患者预后较差。目前正在探索的替代治疗方法是通过稳定天然构象异构体来抑制FLC聚集。这里,我们旨在鉴定和表征靶向FLC结构域并促进其稳定性的抗体片段。使用噬菌体展示筛选方法,我们确定了一个可变重(VH)域,称为VH1,靶向FLC。使用差示扫描荧光法和表面等离子体共振,VH1的特征是结合并在动力学上稳定淀粉样FLC,由此注意到热稳定性>5.5°C增加。这种改善的稳定性对应于原纤维形成的抑制,其中10:1LC:VH1浓度将聚集降低至基线水平。LC:VH1络合物在原子分辨率下的X射线晶体学结构显示以1:1的比例结合,模拟天然免疫球蛋白分子和天然LC同二聚体的二聚体抗原结合位点。
    Light chain amyloidosis (AL), is classified as a plasma cell dyscrasia, whereby a mutant plasma cell multiplies uncontrollably and secretes enormous amounts of immunoglobulin-free light chain (FLC) fragments. These FLCs undergo a process of misfolding and aggregation into amyloid fibrils, that can cause irreversible system-wide damage. Current treatments that focus on depleting the underlying plasma cell clone are often poorly tolerated, particularly in patients with severe cardiac involvement, meaning patient prognosis is poor. An alternative treatment approach currently being explored is the inhibition of FLC aggregation by stabilisation of the native conformer. Here, we aimed to identify and characterise antibody fragments that target FLC domains and promote their stabilisation. Using phage-display screening methods, we identified a variable heavy (VH) domain, termed VH1, targeted towards the FLC. Using differential scanning fluorimetry and surface plasmon resonance, VH1 was characterised to bind and kinetically stabilise an amyloidogenic FLC, whereby a > 5.5 °C increase in thermal stability was noted. This improved stability corresponded to the inhibition of fibril formation, where 10 : 1 LC : VH1 concentration reduced aggregation to baseline levels. X-ray crystallographic structures of the LC : VH1 complex at atomic resolution revealed binding in a 1 : 1 ratio, mimicking the dimeric antigen binding sites of the native immunoglobulin molecule and the native LC homodimer.
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  • 文章类型: Journal Article
    淀粉样变是一种以淀粉样蛋白原纤维的局部和全身细胞外沉积为特征的疾病,其中淀粉样蛋白原纤维在组织中的过度积累和对降解的抗性可导致器官衰竭。由于大约36种不同的淀粉样蛋白亚型,诊断具有挑战性。成像方法,如免疫组织化学和使用刚果红染色淀粉样蛋白进行激光捕获显微切割结合液相色谱串联质谱(LMD/LC-MS/MS)是目前使用的两种诊断方法,具体取决于病理学实验室的专业知识。这里,我们通过基质辅助激光解吸电离-质谱成像(MALDI-MSI)结合陷阱离子迁移谱技术对潜在的转甲状腺素蛋白(ATTR)淀粉样变性亚型进行了简化的原位淀粉样肽空间定位。虽然我们利用标准LMD/LC-MS/MS工作流程对来自不同器官的31个样本进行淀粉样蛋白亚型分型,我们还评估了MS工作流程中数据采集参数变化的潜在引入,如动态排除,或测试数据相关采集结合高场非对称波形离子迁移谱(DDAFAIMS)与数据独立采集(DIA)相结合,以在更短的采集时间内增强淀粉样蛋白识别。我们还证明了Mascot的容错搜索和PEAKS从头测序用于淀粉样变性标本的序列变异分析。
    Amyloidosis is a disease characterized by local and systemic extracellular deposition of amyloid protein fibrils where its excessive accumulation in tissues and resistance to degradation can lead to organ failure. Diagnosis is challenging because of approximately 36 different amyloid protein subtypes. Imaging methods like immunohistochemistry and the use of Congo red staining of amyloid proteins for laser capture microdissection combined with liquid chromatography tandem mass spectrometry (LMD/LC-MS/MS) are two diagnostic methods currently used depending on the expertise of the pathology laboratory. Here, we demonstrate a streamlined in situ amyloid peptide spatial mapping by Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI) combined with Trapped Ion Mobility Spectrometry for potential transthyretin (ATTR) amyloidosis subtyping. While we utilized the standard LMD/LC-MS/MS workflow for amyloid subtyping of 31 specimens from different organs, we also evaluated the potential introduction in the MS workflow variations in data acquisition parameters like dynamic exclusion, or testing Data Dependent Acquisition combined with High-Field Asymmetric Waveform Ion Mobility Spectrometry (DDA FAIMS) versus Data Independent Acquisition (DIA) for enhanced amyloid protein identification at shorter acquisition times. We also demonstrate the use of Mascot\'s Error Tolerant Search and PEAKS de novo sequencing for the sequence variant analysis of amyloidosis specimens.
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  • 文章类型: Journal Article
    Daratumumab在轻链(AL)淀粉样变性的前期治疗中的掺入导致了Daratumumab(Dara)在疾病过程早期的难治性。经历复发或对基于dara的治疗反应欠佳的患者,选择有限。
    本研究旨在评估以前dara失败的t(11;14)阳性AL患者的基于维奈托克的治疗结果。
    这项双机构回顾性分析纳入了31例AL患者。
    Dara失败是由于20(65%)患者的反应不足,血液学复发7例(22%),4例(13%)均出现血液学和器官复发。对基于维奈托克的治疗的总体血液学反应率为97%,VGPR≥91%。在19名可评估的心脏受累患者中,14(74%)取得器官反响。在13名可评估的肾脏受累患者中,6(46%)取得器官反响。中位随访时间为22个月,未达到中位下一次治疗时间(TTNT)和总生存期(OS).12个月和24个月的TTNT发生率分别为74%和56%,分别。在数据截止时,四名病人死亡,全部来自AL相关器官并发症。12个月和24个月的OS率分别为89%和85%,分别。26%的患者发生≥3级不良事件,6%是由于感染。
    这些发现对于使用维奈托克作为达拉失败后的抢救治疗是令人鼓舞的。
    UNASSIGNED: Daratumumab\'s incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options.
    UNASSIGNED: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara.
    UNASSIGNED: Thirty-one patients with AL were included in this bi-institutional retrospective analysis.
    UNASSIGNED: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections.
    UNASSIGNED: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.
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  • 文章类型: Case Reports
    背景:免疫球蛋白轻链(AL)淀粉样变性表现为多个器官的不同表现和受累,对医生构成了重大的诊断挑战。
    结果:我们介绍了一例因反复咳嗽和痰而入院的患者,最初被诊断为难治性结核病。在他住院期间,患者出现了痛苦的症状,包括无法控制的胸闷,低血压,和发烧。值得注意的观察包括心脏生物标志物的持续升高,指示心脏损伤。支气管肺泡灌洗显示存在各种病原微生物,而骨髓流式细胞术显示存在克隆性浆细胞。此外,无尿轻链测定检测到M蛋白的存在,腹壁脂肪活检的阳性刚果红染色证实了淀粉样蛋白在组织中的沉积。考虑到患者的临床表现和检查结果,我们对免疫球蛋白轻链(AL)淀粉样变性进行了结论性诊断。
    结论:此案例提醒医生,当患者出现涉及心脏等多器官系统的症状时,应考虑罕见疾病,如AL淀粉样变性,对常规治疗方案无反应的肺和肾。
    BACKGROUND: Immunoglobulin light chain (AL) amyloidosis presents a clinical spectrum characterized by diverse manifestations and involvement of multiple organs, posing a significant diagnostic challenge for physicians.
    RESULTS: We present a case of a patient admitted to our hospital due to recurrent cough and sputum, which was initially diagnosed as refractory tuberculosis. Throughout his hospitalization, the patient experienced distressing symptoms, including uncontrollable chest tightness, hypotension, and fever. Noteworthy observations included a persistent elevation in cardiac biomarkers, indicative of cardiac damage. Bronchoalveolar lavage revealed the presence of various pathogenic microorganisms, while bone marrow flow cytometry demonstrated the existence of clonal plasma cells. Additionally, the urine free light chain assay detected the presence of M protein, and the positive congo red staining of the abdominal wall fat biopsy confirmed amyloid deposition in the tissues. Taking into account the patient\'s clinical presentation and the examination findings, we reached a conclusive diagnosis of immunoglobulin light chain (AL) amyloidosis.
    CONCLUSIONS: This case serves as a reminder for physicians to consider rare diseases like AL amyloidosis when patients present with symptoms involving multiple organ systems such as heart, lung and kidney that are unresponsive to conventional treatment options.
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  • 文章类型: Journal Article
    背景:目前心脏淀粉样变性(CA)预后的超声心动图危险因素无法区分两种主要亚型:甲状腺素运载蛋白心肌病(TTR)和免疫球蛋白轻链心肌病(AL),每个都需要不同的诊断和治疗方法。此外,只研究了传统的参数,很少有关于先进技术的数据。因此,我们试图通过综合方法确定CA亚型之间的2D经胸超声心动图(2DE)生存预测因子是否存在差异.
    方法:纳入220例(72±12年)确诊为CA的患者(AL=89,TTR=131),在诊断为CA时行2DE。左心室(LV)尺寸,指数质量(LVMi),全局纵向应变(LVGLS),根尖备用比(LVASR),非分解学,右心室(RV)大小和功能指标,包括三尖瓣环收缩偏移(TAPSE),RV自由壁(RVFWS)和全局(RVGLS)应变,左(LA)和右心房容积(LAVi和RAVi),测量LA应变(储层和助推器)和RV收缩压(RVSP)。在36个月的中位随访时间内,使用从NYHA分级和诊断时肾功能损害状态得出的倾向评分加权逐步变量选择Cox比例风险模型来确定2DE参数与CA亚型特有死亡率之间的关联。
    结果:调整年龄后,心房颤动和治疗,与生存相关的参数是在AL和LVASR(p=0.007,HR6.68,95%CI[1.75,25.492])和RAVi(p=0.049,HR1.03,95%CI[1.053,1.245])中的RVSP(p=0.03,HR1.03,95%CI[1.0063])和在1.00052中的RAVi(p=HR1.03,TCI)。
    结论:存活的超声心动图预测指标对心脏淀粉样蛋白亚型具有特异性。这些结果可能为这些患者的临床决策和随访提供关键信息。
    BACKGROUND: Current echocardiographic risk factors for prognosis in cardiac amyloidosis (CA) do not distinguish between the two main subtypes: transthyretin cardiomyopathy (TTR) and immunoglobulin light chain cardiomyopathy (AL), each of which require distinct diagnostic and therapeutic approaches. Additionally, only traditional parameters have been studied with little data on advanced techniques. Accordingly, we sought to determine whether differences exist in 2D transthoracic echocardiography (2DE) predictors of survival between the CA subtypes using a comprehensive approach.
    METHODS: 220 patients (72±12 years) with confirmed CA (AL=89, TTR=131) who underwent 2DE at the time of CA diagnosis were enrolled. Left ventricular (LV) dimensions, indexed mass (LVMi), global longitudinal strain (LVGLS), apical-sparing ratio (LVASR), diastology, right ventricular (RV) size and function indices including tricuspid annular systolic excursion (TAPSE), RV free-wall (RVFWS) and global (RVGLS) strain, indexed left (LA) and right atrial volumes (LAVi and RAVi), LA strain (reservoir and booster) and RV systolic pressure (RVSP) were measured. A propensity-score weighted stepwise variable selection Cox proportional hazards model derived from NYHA class and renal impairment status at diagnosis was used to determine the associations between 2DE parameters and mortality specific to CA subtype over a median follow-up of 36-months.
    RESULTS: After adjusting for age, atrial fibrillation and treatment, parameters associated with survival were RVFWS (p=0.003, HR 1.15, 95% CI[1.053,1.245]) and RVSP (p=0.03, HR 1.03, 95% CI[1.004,1.063]) in AL and LVASR (p=0.007, HR 6.68, 95% CI[1.75,25.492]) and RAVi (p=0.049, HR 1.03, 95% CI[1.000,1.052]) in TTR.
    CONCLUSIONS: Echocardiographic prognosticators for survival are specific to cardiac amyloid subtype. These results potentially provide information critical for clinical decision-making and follow-up in these patients.
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  • 文章类型: Case Reports
    我们介绍了一名79岁的男性,其快速进行性肌病是与多发性骨髓瘤相关的轻链淀粉样变性的最初表现。患者出现进行性下肢无力,导致爬楼梯困难。辅助测试显示血清肌酸激酶水平略有升高。肌电图显示弥漫性肌源性模式,而肌肉MRI显示股四头肌脂肪置换。肌肉活检显示血管壁中存在淀粉样蛋白沉积物。检测到升高水平的λ(246mg/L)轻链。骨髓穿刺结果与多发性骨髓瘤诊断一致。总之,即使淀粉样蛋白肌病是一种罕见的疾病,肌肉活检中淀粉样蛋白沉积的常规筛查至关重要,应系统地进行。在目前的情况下,它能够快速诊断和开始治疗。
    We present the case of a 79-year-old man with rapidly progressive myopathy as the initial manifestation of light chain amyloidosis associated with multiple myeloma. The patient experienced progressive lower limb weakness resulting in difficulty climbing stairs. Ancillary tests revealed slightly elevated serum creatine kinase levels. The electromyogram revealed a diffuse myogenic pattern while muscle MRI indicated fatty replacement of the quadriceps muscles. Muscle biopsy revealed the presence of amyloid deposits in the vessel walls. An elevated level of lambda (246 mg/L) light chain was detected. The bone marrow aspiration results were consistent with the diagnosis of multiple myeloma. In conclusion, even if amyloid myopathy is a rare condition, routine screening for amyloid deposits in muscle biopsy is crucial and should be performed systematically. In the present case, it enabled a rapid diagnosis and the beginning of treatment.
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  • 文章类型: Journal Article
    背景:腱膜结构中的淀粉样蛋白沉积先于心脏受累长达20年。因此,在有心脏淀粉样变性(CA)腱鞘表现的患者中进行心脏筛查可能导致早期诊断的数量增加.
    方法:具有CA(腕管综合征,无创伤肱二头肌肌腱断裂,腰椎管狭窄)已由全科医生鉴定,并在CA转诊中心进行了评估。高度怀疑CA的患者接受了CA诊断途径。
    结果:在联系的50名全科医生中,10名(20%)同意参加该研究,共有5615名≥60岁的患者。一百四十五名病人符合纳入标准,其中2人已经被诊断为CA,和57同意接受心脏病评估(心电图,超声心动图,NTproBNP测定)。中位年龄为73[67-80]岁,31(54%)为女性。八名患者被建议启动CA诊断途径,其中五人接受了CA的完整诊断评估,三人拒绝完成诊断检查,也没有做出新的诊断。
    结论:对全科医生确定的有腱鞘表现的患者进行CA筛查是可行的,但可能不会产生高的新诊断率。在这项研究中,我们确定了两名已经诊断为CA的患者,在CA高危患者中,37%拒绝完成诊断途径。提高患者对CA的认识可能会增加筛查研究的参与度和诊断率。需要进一步验证该方案以评估其诊断性能。
    BACKGROUND: Amyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses.
    METHODS: Patients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway.
    RESULTS: Among 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67-80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made.
    CONCLUSIONS: A screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance.
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