OBJECTIVE: 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)].
CONCLUSIONS: 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.

Aggregation of antibody light chain proteins is associated with the progressive disease light chain amyloidosis. Patient-derived amyloid fibrils are formed from light chain variable domain residues in non-native conformations, highlighting a requirement that light chains unfold from their native structures in order to aggregate. However, mechanistic studies of amyloid formation have primarily focused on the self-assembly of natively unstructured peptides, and the role of native state unfolding is less well understood. Using a well-studied light chain variable domain protein known as WIL, which readily aggregates in vitro under conditions where the native state predominates, we asked how the protein concentration and addition of pre-formed fibril \"seeds\" alter the kinetics of aggregation. Monitoring aggregation with thioflavin T fluorescence revealed a distinctly non-linear dependence on concentration, with a maximum aggregation rate observed at 8 μM protein. This behavior is consistent with formation of alternate aggregate structures in the early phases of amyloid formation. Addition of N- or C-terminal peptide tags, which did not greatly affect the folding or stability of the protein, altered the concentration dependence of aggregation. Aggregation rates increased in the presence of pre-formed seeds, but this effect did not eliminate the delay before aggregation and became saturated when the proportion of seeds added was greater than 1 in 1600. The complexity of aggregation observed in vitro highlights how multiple species may contribute to amyloid pathology in patients.

(1) Background: To evaluate the predictive value of Holter monitoring for overall survival (OS) of patients with light chain amyloidosis (AL amyloidosis). (2) Methods: 137 patients with newly diagnosed AL amyloidosis who underwent Holter monitoring within 6 months of diagnosis were included. The primary outcome was OS. Landmark analysis was conducted at one-year follow-up. Independent predictors were determined using the log-rank test and multivariate Cox regression analysis. (3) Results: 131 (95.6%) patients received non-transplant therapy, and 32 (23.4%) underwent daratumumab-based chemotherapy. After a median follow-up of 20.3 months, 47 deaths occurred. Atrial tachycardia (AT), conduction delay, and non-sustained ventricular tachycardia (NSVT) were associated with poor OS one year beyond diagnosis in univariate analyses (patients with vs. without AT: 57.3% [95% confidence interval (CI): 47.2-67.4] vs. 81.0% (95% CI: 74.8-87.2), p = 0.039; patients with vs. without NSVT: 33.3% (95% CI: 8.5-58.1) vs. 75.3% (95% CI: 69.8-80.8), p = 0.024; patients with vs. without conduction delay: 41.7% (95% CI: 24.4-59.0) vs. 75.4% (95% CI: 69.7-81.1), p = 0.003]. AT [hazard ratio (HR): 2.6; 95% CI: 1.0-6.5; p = 0.049) and conduction delay (HR: 4.3; 95% CI: 1.3-14.3; p = 0.016) were independent predictors of OS after accounting for age and 2012 Mayo stage. (4) Conclusion: AT and conduction delay in Holter monitoring are independent predictors of poor OS one year beyond diagnosis in AL amyloidosis.

BACKGROUND: Systemic light chain (AL) amyloidosis is a rare and multisystem disease associated with increased morbidity and a poor prognosis. Delayed diagnoses are common due to the heterogeneity of the symptoms. However, real-world insights from Chinese patients with AL amyloidosis have not been investigated.
OBJECTIVE: This study aimed to describe the journey to an AL amyloidosis diagnosis and to build an in-depth understanding of the diagnostic process from the perspective of both clinicians and patients to obtain a correct and timely diagnosis.
METHODS: Publicly available disease-related content from social media platforms between January 2008 and April 2021 was searched. After performing data collection steps with a machine model, a series of disease-related posts were extracted. Natural language processing was used to identify the relevance of variables, followed by further manual evaluation and analysis.
RESULTS: A total of 2204 valid posts related to AL amyloidosis were included in this study, of which 1968 were posted on haodf.com. Of these posts, 1284 were posted by men (median age 57, IQR 46-67 years); 1459 posts mentioned renal-related symptoms, followed by heart (n=833), liver (n=491), and stomach (n=368) symptoms. Furthermore, 1502 posts mentioned symptoms related to 2 or more organs. Symptoms for AL amyloidosis most frequently mentioned by suspected patients were nonspecific weakness (n=252), edema (n=196), hypertrophy (n=168), and swelling (n=140). Multiple physician visits were common, and nephrologists (n=265) and hematologists (n=214) were the most frequently visited specialists by suspected patients for initial consultation. Additionally, interhospital referrals were also commonly seen, centralizing in tertiary hospitals.
CONCLUSIONS: Chinese patients with AL amyloidosis experienced referrals during their journey toward accurate diagnosis. Increasing awareness of the disease and early referral to a specialized center with expertise may reduce delayed diagnosis and improve patient management.

Aggregation of antibody light chain proteins is associated with the progressive disease light chain amyloidosis. Patient-derived amyloid fibrils are formed from light chain variable domain residues in non-native conformations, highlighting a requirement that light chains unfold from their native structures in order to aggregate. However, mechanistic studies of amyloid formation have primarily focused on the self-assembly of natively unstructured peptides, and the role of native state unfolding is less well understood. Using a well-studied light chain variable domain protein known as WIL, which readily aggregates in vitro under conditions where the native state predominates, we asked how the protein concentration and addition of pre-formed fibril \"seeds\" alter the kinetics of aggregation. Monitoring aggregation with thioflavin T fluorescence revealed a distinctly non-linear dependence on concentration, with a maximum aggregation rate observed at 8 μM protein. This behavior is consistent with formation of alternate aggregate structures in the early phases of amyloid formation. Addition of N- or C-terminal peptide tags, which did not greatly affect the folding or stability of the protein, altered the concentration dependence of aggregation. Aggregation rates increased in the presence of pre-formed seeds, but this effect did not eliminate the delay before aggregation and became saturated when the proportion of seeds added was greater than 1 in 1600. The complexity of aggregation observed in vitro highlights how multiple species may contribute to amyloid pathology in patients.

Objective: To analyze the value of (11)C-PiB PET/MRI for evaluating organ involvement in patients with primary light chain amyloidosis (pAL) . Methods: The clinical data of 20 patients with pAL and 3 healthy volunteers from January 2019 to October 2021 were retrospectively analyzed. The correlation between the organ involvement evaluated by clinical standards and PET/MRI was compared. The relationship between cardiac-related biological indicators, disease stage, and the maximum standardized uptake value (SUVmax) were analyzed. The relationship between 24-hour urinary protein quantification and kidney SUVmax was analyzed. Results: ①In 20 patients (18 newly diagnosed patients and 2 non-newly diagnosed patients) ,(11)C-PiB positive uptake was observed in the heart (15 patients, 75%) , lung (8 patients, 40%) , bone marrow (10 patients, 50%) , muscle (10 patients, 50%) , tongue muscle (7 patients, 35%) , thyroid (6 patients, 30%) , salivary gland (4 patients, 20%) , spleen (2 patients, 10%) , and stomach wall (1 patient, 5%) . ②Organ involvement on (11)C-PiB PET/MRI showed good correlations with the clinical evaluation criteria for the heart and bone marrow. The positive rate of PET/MRI evaluation in the lung, spleen, gland, muscle, and tongue muscle was significantly higher than the clinical criteria. However, (11)C-PiB PET/MRI has limitations in the evaluation of the nervous system and fat tissue. ③To analyze the relationship between cardiac-related biological indexes and the SUVmax of the heart in 13 newly diagnosed patients. Patients with left ventricular ejection fraction (LVEF) <50% and interventricular septal thickness (ISV) ≥1.2 cm showed a higher SUVmax than patients with LVEF ≥50% and ISV<1.2 cm (P<0.05) .There are significant differences in the SUVmax of the heart between the Mayo2004 stage and the Mayo2012 stage. The later the disease stage, the higher the SUVmax (P<0.05) . The SUVmax of the heart was positively correlated with cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P<0.01) .There was no significant correlation between renal SUVmax and 24-hour urine protein (P>0.05) . Conclusion: Whole body (11)C-PiB PET/MRI, as a visualization system of amyloid protein, is used to qualitatively evaluate organ involvement, which can improve the level of early non-invasive diagnosis. Whole body (11)C-PiB PET/MRI can be used to perform quantitative evaluation of organ levels, especially the heart, which is expected to evaluate organ function and predict disease prognosis more accurately.
目的： 分析(11)C标记的匹兹堡化合物B（(11)C-PiB）PET/MRI在原发性系统性轻链型淀粉样变（pAL）中评估器官受累的价值。 方法： 回顾性分析2019年1月至2021年10月在华中科技大学同济医学院附属协和医院就诊的20例pAL患者及3名健康志愿者的临床资料，比较临床标准评估器官受累和PET/MRI评估的相关性，分析心脏相关生物学指标、疾病分期与心脏最大标准摄取值（SUVmax）之间的关系及24 h尿蛋白定量与肾脏SUVmax之间的关系。 结果： ①纳入20例患者，初诊患者18例，非初诊患者2例。观察到(11)C-PiB摄取阳性的脏器分别为：心脏15例（75%），肺部8例（40%），骨髓10例（50%），肌肉10例（50%），舌肌7例（35%），甲状腺6例（30%），唾液腺4例（20%），脾脏2例（10%），胃壁1例（5%）。②(11)C-PiB在心脏及骨髓摄取的阳性率与临床评估标准具有很好的相关性。在肺组织、脾脏、腺体、肌肉和舌肌中，(11)C-PiB PET/MRI评估的阳性率明显高于临床标准。但对于神经系统受累和脂肪组织的评估(11)C-PiB PET/MRI具有局限性。③分析18例初诊患者心脏相关生物学指标与心脏SUVmax之间的关系。左心室射血分数（LVEF）<50%且室间隔厚度（ISV）≥1.2 cm的患者相较LVEF≥50%且ISV<1.2 cm的患者其心脏SUVmax更高（P<0.05）。心脏SUVmax值在Mayo2004分期、Mayo2012分期各期之间差异有统计学意义，分期越晚，SUVmax值越高（P<0.05）。心脏SUVmax与心肌肌钙蛋白酶Ⅰ、N末端前体脑钠肽水平呈明显正相关（P<0.01），肾脏SUVmax与24 h尿蛋白定量无明显相关性（P>0.05）。 结论： 全身(11)C-PiB PET/MRI作为一种淀粉样蛋白的可视化系统，若用于器官水平的定性评估，具有提高早期无创性诊断pAL水平的潜力；用于器官水平（尤其是心脏）的定量评估，有望更精准评估器官功能和预测疾病预后。.

UNASSIGNED: The main objective of treatment in systemic light chain amyloidosis (AL amyloidosis) is to achieve the best hematological response. Deeper responses are associated with better organ responses and survival. In this study, we analysed the efficacy of prolonged duration treatment after first line in patients with AL amyloidosis.
UNASSIGNED: Retrospective analysis that included patients older than 18 years with AL amyloidosis. We excluded patients with more than 30% marrow plasmacytosis or concurrent multiple myeloma. Two cohorts identified accordingly if they received or not prolonged treatment after the first line. Survival analysis regarding progression free survival (PFS) and overall survival (OS) estimated with Kaplan-Meier and comparisons between groups with log-rank.
UNASSIGNED: Thirty-eight patients were included in the analysis with a median age of 55 years. Twenty-one patients received prolonged duration treatment and 17 did not. In the prolonged duration group, after a median duration of 12 months, the median PFS was 58.8 months. In the fixed duration treatment group, PFS was 30.6 months. The difference was significant with p = .0045 favouring prolonged duration treatment. Organ response was sustained for a longer period in the prolonged duration treatment group. For OS, the difference was not significant.
UNASSIGNED: Prolonged duration treatment in patients with systemic light chain amyloidosis correlated with better PFS and deeper organ responses. Prospective studies are needed to analyse this further.

Aims: Systemic light-chain (AL) amyloidosis is a multisystemic disorder leading to multiple organ dysfunction and mortality that is often caused by cardiac involvement. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker identified for risk stratification of heart disease. The aim of this study was to investigate the value of circulating sST2 levels in prognosis and mortality risk assessments for the AL amyloidosis population. Methods and Results: A total of 56 patients diagnosed with AL amyloidosis were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2018. The relationships between the clinical parameters and overall survival (OS) and risk factors for disease progression were assessed. Additionally, receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox hazard models were performed to explore the predictive value of sST2 in mortality rates. We found that the median OS of all patients was 7.3 [interquartile range (IQR) 4.4, 15.9] months. The median baseline sST2 level was 12.2 (IQR 5.1, 31.1) ng/ml, and the sST2 high group had more severe patients with a higher Mayo stage. In the ROC analysis, the area under the curve (AUC) was 0.728 [95% confidence interval (CI) 0.603-0.853] for sST2 to predict the outcomes of AL amyloidosis patients, and the optimal cutoff value was 12.34 ng/ml (sensitivity 80.2%, specificity 61.1%). Moreover, in multivariate Cox proportional hazards regression analysis, sST2 acted as an independent predictor of poor functional outcome in patients with AL amyloidosis. Conclusion: In AL amyloidosis patients, sST2 was a strong and independent prognostic biomarker for all-cause mortality, providing complementary prognostic information of a novel scoring system for risk stratification.

UNASSIGNED: Although, doxycycline use is associated with improved outcomes in amyloidosis in retrospective studies, evidence from clinical trials is limited.
UNASSIGNED: This phase 2 trial of doxycycline (clinicaltrials.gov: NCT02207556) in newly diagnosed light chain (AL) amyloidosis enrolled 25 patients with systemic AL amyloidosis on treatment with doxycycline for 1 year along with chemotherapy. Outcomes of interest included mortality, organ response, and hematologic response rates at 1 year.
UNASSIGNED: The median age was 62 years, 64% were male, and 68% had the AL lambda subtype. Patients had Mayo 2012 stage 3 in 24% and stage 4 in 28%. Cardiac involvement was present in 60% of patients, renal involvement in 72%, and 60% patients had 3 or more organs involved. Target organ was cardiac in 14(56%), renal in 7(28%), hepatic in 1(4%) and soft tissue in 3(12%). At 1 year, mortality was 20% (95% confidence interval, 8.9-41.6%) and organ response was 36% (18-57%). Hematologic response in 1-year survivors was 100%, including 30% complete and 55% very good partial response. Autologous hematopoietic cell transplant was performed in 60%; among transplanted patients, day-100 transplant-related mortality was 0. Doxycycline use was safe and not attributed to any grade 2 or higher toxicity.
UNASSIGNED: In addition to a low 1-year mortality, doxycycline use was safe and associated with high transplant utilization rate. We thus contend that doxycycline should be studied in a placebo-controlled study in newly diagnosed AL patients in the first year, particularly among patients with advanced disease and cardiac involvement.

Objective: To investigate the characteristics of T cell immunophenotype and its relationship with clinical manifestation in patients with systemic light chain amyloidosis (AL) . Methods: The peripheral blood mononuclear cells from 36 patients with AL were collected and analyzed by multicolor flow cytometry, and the expression of surface antigen CD3, CD56, CD4, CD8, CD25, CD45RA, CD28, CD57 and nuclear antigen FOXP3 were examined. Samples from 28 age-matched healthy donors (HD) were also examined. Patients were divided by Mayo 2012 staging system and the difference between immunophenotype of Ⅰ-Ⅱ and Ⅲ-Ⅳ stage patients were analyzed. The correlations between the proportion of T-cell subpopulation and clinical manifestations in λ light chain type AL patients were analyzed. Results: The differences in the peripheral total T cells and T cell subsets, including CD4(+), CD8(+), regulatory T cells, and natural killer T cells were not significantly between AL and HD. The ratio of CD57(+) cells in CD8(+) T cells was lower in AL than in HD, and there was no significantly difference in the rate of CD45RA(+) and CD28(+)cells between these two groups. No differences were found in the ratio of total T cells or T cell subsets between stages Ⅰ-Ⅱ and Ⅲ-Ⅳaccording to the standard of Mayo 2012. Within λ light chain type AL patients, peripheral CD8(+) T cell ratio was positively correlated with 24-hour urine protein and creatinine level and negatively correlated with estimated glomerular filtration rate (eGFR) . Conclusion: The overall T cell distribution in the periphery is not significantly different between AL patients and age-matched healthy donors. However, the percentages of CD8(+) T cells are positively correlated with renal injury, indicating the importance of CD8(+) T cell subset in the prognostic evaluation of renal involvement.
目的： 探讨系统性免疫球蛋白轻链淀粉样变性（AL）初治患者的外周血免疫细胞表型特征及其与临床指标的相关性。 方法： 采用流式细胞仪多参数免疫荧光分析技术，对36例AL初诊患者和28名健康供者的外周血单个核细胞的表面抗原CD3、CD56、CD4、CD8、CD25、CD45RA、CD28、CD57及核内抗原FOXP3进行检测和比较。根据梅奥2012分期对AL患者进行分期，比较Ⅰ~Ⅱ、Ⅲ~Ⅳ期患者的免疫细胞表型差异。分析λ轻链型AL患者T细胞亚群比例与多项临床指标的相关性。 结果： AL患者的外周血T（CD3(+)CD56(-)）和NKT（CD3(+)CD56(+)）细胞比例，T细胞中的CD4(+)CD8(-)、CD4(-)CD8(+)、Treg（CD4(+)CD25(+)FOXP3(+)）细胞比例与健康供者相比差异无统计学意义（P>0.05）。AL患者的CD4(-)CD8(+)细胞中，CD57(+)细胞的比例较健康供者显著降低（P<0.05），但CD45RA(+)和CD28(+)细胞的比例在AL和健康供者间差异无统计学意义。Ⅰ~Ⅱ期和Ⅲ~Ⅳ期AL患者T细胞及其亚群的比例差异无统计学意义（P>0.05）。在λ轻链型AL患者中，外周血CD4(-)CD8(+)细胞的比例与24 h尿蛋白和血肌酐呈正相关（P<0.05），与eGFR呈负相关（P<0.05），与其他临床指标无显著相关性。与此相反，CD4(+)CD8(-)细胞的比例与eGFR呈正相关，而与24 h尿蛋白和血肌酐呈负相关（P<0.05）。 结论： AL患者外周血的T细胞亚群与健康供者相比差异无统计学意义，但CD8(+) T细胞的比例与肾脏损伤程度呈正相关，提示CD8(+) T细胞的比例在评估AL患者肾脏预后中具有一定的价值。.