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Journal of Clinical Medicine Dec 2023Amyloid deposits can be the cause of many chronic diseases. Primary localized cutaneous amyloidosis (PLCA) is a chronic dermatologic condition with amyloid deposits in...
Amyloid deposits can be the cause of many chronic diseases. Primary localized cutaneous amyloidosis (PLCA) is a chronic dermatologic condition with amyloid deposits in the papillary dermis. The most common types of the keratinocyte-derived form of PLCA include macular (MA), lichen (LA), and biphasic (BA) amyloidosis. The estimated prevalence of PLCA in the Asian population is 0.98/10,000, which is higher than in the European population; thus, epidemiologic data on PLCA in the Caucasian population are limited. We performed a retrospective single-center study analyzing epidemiologic characteristics of a Central European PLCA population. Epidemiologic data regarding age, sex, skin phototype (Fitzpatrick scale I-VI), disease duration, comorbidities, history of atopy, and family history of PLCA were collected. Clinical characteristics, localization of PLCA lesions, applied therapies and treatment outcomes were also analyzed. Dermoscopic characteristics were also evaluated. A total of 41 patients diagnosed with PLCA were included, with 22 presenting with macular, 18 with lichen, and 1 with biphasic amyloidosis. The male/female ratio was 16/25, and mean age at diagnosis was 54.6 ± 15.2 years (range 27-87 years). The mean age at the onset of PLCA was 53 ± 16.1 years (range 19-79 years) in MA, 46.7 ± 18.2 years (range 14-73 years) in LA, and 26 years in BA. The interscapular region in MA and the extensor surface of the lower extremities in LA proved to be localization-related areas. In our center, a wide range of therapeutic options was applied, with the most prescribed being topical corticosteroids in all types of PLCA. We presented a retrospective, monocentric study on the epidemiology of PLCA in the Central European region. By examining the medical data of a significant number of PLCA patients, we compared our epidemiologic data with that of the Asian PLCA population. Due to the rarity of the condition, further randomized controlled trials and guidelines are needed to improve therapeutic outcomes.
PubMed: 38137741
DOI: 10.3390/jcm12247672 -
Biology of Sex Differences Sep 2023The amyloid-β (Aβ) cascade is one of the most studied theories linked to AD. In multiple models, Aβ accumulation and dyshomeostasis have shown a key role in AD onset,...
BACKGROUND
The amyloid-β (Aβ) cascade is one of the most studied theories linked to AD. In multiple models, Aβ accumulation and dyshomeostasis have shown a key role in AD onset, leading to excitatory/inhibitory imbalance, the impairments of synaptic plasticity and oscillatory activity, and memory deficits. Despite the higher prevalence of Alzheimer's disease (AD) in women compared to men, the possible sex difference is scarcely explored and the information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data regarding the early stages of amyloidosis in female mice, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of Aβ on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse, in both male and female mice.
METHODS
To do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings as well as encoding and retrieval of spatial (working, short- and long-term) and exploratory habituation memories using Barnes maze and object location, or open field habituation tasks, respectively.
RESULTS
Aβ administration impaired all forms of memory evaluated in this work, regardless of sex. This effect was displayed in a long-lasting manner (up to 17 days post-injection). LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underlie memory deficits.
CONCLUSIONS
In conclusion, our results provide further evidence on the shifting of LTP/LTD threshold due to a single icv. Aβ injection, which underly cognitive deficits in the early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.
Topics: Female; Male; Humans; Mice; Animals; Neuronal Plasticity; Amyloidosis; Alzheimer Disease; Mice, Transgenic; Memory Disorders
PubMed: 37716988
DOI: 10.1186/s13293-023-00545-4 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023The Phase 3 IKEMA study (NCT03275285) demonstrated isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) significantly improved progression-free... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Phase 3 IKEMA study (NCT03275285) demonstrated isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in patients with relapsed multiple myeloma (MM) compared with Kd. A post-hoc analysis of East Asian patients in IKEMA evaluated the efficacy and safety of Isa-Kd versus Kd in this population and was previously published.
PATIENTS AND METHODS
Patients with relapsed MM who had received 1 to 3 prior lines of therapy were randomized 3:2 to receive Isa-Kd or Kd. The primary endpoint was PFS, and key secondary endpoints included rate of very good partial response or better (≥VGPR), complete response (CR) rate, and minimal residual disease (MRD) negativity. Of the IKEMA overall population, 46 patients were of East Asian descent. This is an updated analysis of the efficacy and safety of Isa-Kd in East Asian patients, including data through 14 January 2022.
RESULTS
Isa-Kd continued to demonstrate improved efficacy and safety versus Kd in East Asian patients with relapsed MM, with improved PFS, rate of ≥VGPR, CR rate, and MRD negativity, that was consistent with the overall IKEMA population. The rate of Grade ≥3 treatment-emergent adverse events was also consistent with the prior analysis and overall IKEMA population.
CONCLUSION
Based on the results of this analysis, Isa-Kd is a novel treatment option for East Asian patients with relapsed MM.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; East Asian People; Multiple Myeloma; Recurrence
PubMed: 37479547
DOI: 10.1016/j.clml.2023.06.011 -
Frontiers in Cardiovascular Medicine 2023Cardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting...
BACKGROUND
Cardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting major cardiac adverse events recommend genetic testing for inherited cardiovascular conditions such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), hereditary amyloidosis, and familial hypercholesterolemia (FH); however, little is known about how consistently practitioners order genetic testing for these conditions in routine clinical practice. This study aimed to assess the adoption of guideline-directed genetic testing for patients diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH.
METHODS
This retrospective cohort study captured real-world evidence of genetic testing from ICD-9-CM and ICD-10-CM codes, procedure codes, and structured text fields of de-identified patient records in the Veradigm Health Insights Ambulatory EHR Research Database linked with insurance claims data. Data analysis was conducted using an automated electronic health record analysis engine. Patient records in the Veradigm database were sourced from more than 250,000 clinicians serving over 170 million patients in outpatient primary care and specialty practice settings in the United States and linked insurance claims data from public and private insurance providers. The primary outcome measure was evidence of genetic testing within six months of condition diagnosis.
RESULTS
Between January 1, 2017, and December 31, 2021, 224,641 patients were newly diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH and included in this study. Substantial genetic testing care gaps were identified. Only a small percentage of patients newly diagnosed with DCM (827/101,919; 0.8%), HCM (253/15,507; 1.6%), LQTS (650/56,539; 1.2%), hereditary amyloidosis (62/1,026; 6.0%), or FH (718/49,650; 1.5%) received genetic testing.
CONCLUSIONS
Genetic testing is underutilized across multiple inherited cardiovascular conditions. This real-world data analysis provides insights into the delivery of genomic healthcare in the United States and suggests genetic testing guidelines are rarely followed in practice.
PubMed: 37915745
DOI: 10.3389/fcvm.2023.1272433 -
Frontiers in Cardiovascular Medicine 2023Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan...
BACKGROUND
Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan therapeutic strategies and follow-ups. Cardiac biomarkers, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (Hs-cTnT), remain the cornerstone of the prognostic assessment. An increased level of soluble suppression of tumorigenesis-2 (sST2) is predictive of adverse events [all-cause death and heart failure (HF) hospitalizations] in patients with HF. This study aimed to evaluate the prognostic value of circulating sST2 levels in AL-CA and ATTR-CA.
METHODS
We carried out a multicenter study including 133 patients with AL-CA and 152 patients with ATTR-CA. During an elective outpatient visit for the diagnosis of CA, Mayo Clinic staging [NT-proBNP, Hs-cTnT, differential of free light chains (DFLCs)] and sST2 were assessed for all AL patients. Gillmore staging [including estimated glomerular filtration rate (eGFR), NT-proBNP] and Grogan staging (including NT-proBNP and Hs-cTnT) were assessed for TTR-CA patients.
RESULTS
The median age was 73 years [interquartile range (IQR) 61-81], and 53% were men. The endpoint was the composite of all-cause death or first HF-related hospitalization. The median follow-up was 20 months (IQR 3-34) in AL amyloidosis and 33 months (6-45) in TTR amyloidosis. The primary outcome occurred in 70 (53%) and 99 (65%) of AL and TTR patients, respectively. sST2 levels were higher in patients with AL-CA than in patients with ATTR-CA: 39 ng/L (26-80) vs. 32 ng/L (21-46), < 0.001. In AL-CA, sST2 levels predicted the outcome regardless of the Mayo Clinic score (HR: 2.16, 95% CI: 1.17-3.99, < 0.001). In TTR-CA, sST2 was not predictive of the outcome in multivariate models, including Gillmore staging and Grogan staging (HR: 1.17, CI: 95% 0.77-1.89, = 0.55).
CONCLUSION
sST2 level is a relevant predictor of death and HF hospitalization in AL cardiac amyloidosis and adds prognostic stratification on top of NT-proBNP, Hs cTnT, and DFLC.
PubMed: 37600055
DOI: 10.3389/fcvm.2023.1179968 -
Circulation Apr 2024The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin...
BACKGROUND
The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome.
METHODS
Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality.
RESULTS
Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; <0.001), whereas Perugini grade was not associated with survival (=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; <0.001), presence of the p.(V142I) variant (HR, 1.42 [95% CI, 1.20-1.81]; =0.004), National Amyloidosis Centre stage (each category, <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; =0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (<0.001 and =0.02, respectively).
CONCLUSIONS
Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.
Topics: Humans; Cardiomyopathies; Prealbumin; Prognosis; Tomography, Emission-Computed, Single-Photon
PubMed: 38328945
DOI: 10.1161/CIRCULATIONAHA.123.066524 -
Journal of the American Heart... Aug 2023Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a... (Comparative Study)
Comparative Study
Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; =0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; =0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; <0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; =0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; =0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; <0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart Failure; Prealbumin; Spironolactone; Stroke Volume; Treatment Outcome
PubMed: 37522238
DOI: 10.1161/JAHA.123.029705 -
Journal of Clinical Medicine May 2024Cardiac amyloidosis, a condition characterized by abnormal protein deposition in the heart, leads to restrictive cardiomyopathy and is notably associated with an... (Review)
Review
Cardiac amyloidosis, a condition characterized by abnormal protein deposition in the heart, leads to restrictive cardiomyopathy and is notably associated with an increased risk of arrhythmias and conduction disorders. This article reviews the current understanding and management strategies for these cardiac complications, with a focus on recent advancements and clinical challenges. The prevalence and impact of atrial arrhythmias, particularly atrial fibrillation, are examined, along with considerations for stroke risk and anticoagulation therapy. The article also addresses the complexities of managing rate and rhythm control, outlining the utility and limitations of pharmacological agents and interventions such as catheter ablation. Furthermore, it reviews the challenges in the treatment of ventricular arrhythmias, including the contentious use of implantable cardioverter-defibrillators for primary and secondary prevention. Individualized approaches, considering the unique characteristics of cardiac amyloidosis, are paramount. Continuous research and clinical exploration are essential to refine treatment strategies and improve outcomes in this challenging patient population.
PubMed: 38892799
DOI: 10.3390/jcm13113088 -
Leukemia Dec 2023Plasma cell disorders are clonal outgrowths of pre-malignant or malignant plasma cells, characterized by extensive chromosomal aberrations. Centrosome abnormalities are...
Plasma cell disorders are clonal outgrowths of pre-malignant or malignant plasma cells, characterized by extensive chromosomal aberrations. Centrosome abnormalities are a major driver of chromosomal instability in cancer but their origin, incidence, and composition in primary tumor cells is poorly understood. Using cutting-edge, semi-automated high-throughput electron tomography, we characterized at nanoscale 1386 centrioles in CD138 plasma cells from eight healthy donors and 21 patients with plasma cell disorders, and 722 centrioles from different control populations. In plasma cells from healthy individuals, over-elongated centrioles accumulated with age. In plasma cell disorders, centriole over-elongation was notably frequent in early, pre-malignant disease stages, became less pronounced in overt multiple myeloma, and almost entirely disappeared in aggressive plasma cell leukemia. Centrioles in other types of patient-derived B cell neoplasms showed no over-elongation. In contrast to current belief, centriole length appears to be highly variable in long-lived, healthy plasma cells, and over-elongation and structural aberrations are common in this cell type. Our data suggest that structural centrosome aberrations accumulate with age in healthy CD138 plasma cells and may thus play an important role in early aneuploidization as an oncogenic driver in plasma cell disorders.
Topics: Humans; Centrioles; Plasma Cells; Electron Microscope Tomography; Centrosome; Cell Cycle
PubMed: 37821581
DOI: 10.1038/s41375-023-02056-y -
Clinical, Cosmetic and Investigational... 2023To compare epidermal biophysical properties, indicators of epidermal function, in individuals with and without primary cutaneous amyloidosis (PCA).
PURPOSE
To compare epidermal biophysical properties, indicators of epidermal function, in individuals with and without primary cutaneous amyloidosis (PCA).
PATIENTS AND METHODS
This study incorporated 189 patients with PCA and 166 healthy individuals. The GPSkin Barrier was employed to measure transepidermal water loss (TEWL) rates and hydration levels of the stratum corneum. The Sebumeter and the Skin pH Meter were utilized to determine the skin surface's sebum content and pH, respectively. The severity of pruritus in participants was evaluated using the visual analog scale (VAS).
RESULTS
Compared to the control group without PCA, individuals with PCA displayed a notable increase in skin surface pH and TEWL and a decrease in the hydration levels of the stratum corneum (<0.0001 for all parameters). Additionally, the sebum content was markedly lower in those with PCA than in the controls (<0.0001). Of particular note, both TEWL and skin surface pH at the lesion sites on the back and the shin were more elevated in lichenoid amyloidosis (LA) and in macular amyloidosis (MA), whereas hydration levels of the stratum corneum and sebum levels were diminished in LA compared to MA (<0.05). In conclusion, both hydration levels of the stratum corneum and sebum content exhibited an inverse relationship with pruritus severity, whereas TEWL and skin surface pH demonstrated a positive correlation with pruritus intensity.
CONCLUSION
The function of the epidermis is compromised in individuals diagnosed with PCA. However, the mechanisms underlying these changes await further investigation.
PubMed: 37953856
DOI: 10.2147/CCID.S426209