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Indian Dermatology Online Journal 2024
PubMed: 38550837
DOI: 10.4103/idoj.idoj_217_23 -
Journal of the Formosan Medical... Mar 2024To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with...
BACKGROUND AND OBJECTIVES
To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy.
METHODS
The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M.
RESULTS
Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population.
CONCLUSIONS
This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy.
TRIAL REGISTRATION INFORMATION
The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.
PubMed: 38548524
DOI: 10.1016/j.jfma.2024.03.008 -
Haematologica Jul 2024
Efficacy and safety of daratumumab plus bortezomib and dexamethasone in newly diagnosed Mayo 2004 stage IIIA or IIIB light-chain amyloidosis: a prospective phase II study.
Topics: Humans; Bortezomib; Dexamethasone; Immunoglobulin Light-chain Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal; Male; Female; Prospective Studies; Aged; Treatment Outcome; Middle Aged; Neoplasm Staging
PubMed: 38546676
DOI: 10.3324/haematol.2024.285145 -
Journal of Clinical Pathology Mar 2024The digital transformation of the pathology laboratory is being continuously sustained by the introduction of innovative technologies promoting whole slide image...
AIM
The digital transformation of the pathology laboratory is being continuously sustained by the introduction of innovative technologies promoting whole slide image (WSI)-based primary diagnosis. Here, we proposed a real-life benchmark of a pathology-dedicated medical monitor for the primary diagnosis of renal biopsies, evaluating the concordance between the 'traditional' microscope and commercial monitors using WSI from different scanners.
METHODS
The College of American Pathologists WSI validation guidelines were used on 60 consecutive renal biopsies from three scanners (Aperio, 3DHISTECH and Hamamatsu) using pathology-dedicated medical grade (MG), professional grade (PG) and consumer-off-the-shelf (COTS) monitors, comparing results with the microscope diagnosis after a 2-week washout period.
RESULTS
MG monitor was faster (1090 vs 1159 vs 1181 min, delta of 6-8%, p<0.01), with slightly better performances on the detection of concurrent diseases compared with COTS (κ=1 vs 0.96, 95% CI=0.87 to 1), but equal concordance to the commercial monitors on main diagnosis (κ1). Minor discrepancies were noted on specific scores/classifications, with MG and PG monitors closer to the reference report (r=0.98, 95% CI=0.83 to 1 vs 0.98, 95% CI=0.83 to 1 vs 0.91, 95% CI=0.76 to 1, κ=0.93, 95% CI=077 to 1 vs 0.93, 95% CI=0.77 to 1 vs 0.86, 95% CI=0.64 to 1, κ=1 vs 0.50, 95% CI=0 to 1 vs 0.50, 95% CI=0 to 1, for IgA, antineutrophilic cytoplasmic antibody and lupus nephritis, respectively). Streamlined Pipeline for Amyloid detection through congo red fluorescence Digital Analysis detected amyloidosis on both monitors (4 of 30, 13% cases), allowing detection of minimal interstitial deposits with slight overestimation of the Amyloid Score (average 6 vs 7).
CONCLUSIONS
The digital transformation needs careful assessment of the hardware component to support a smart and safe diagnostic process. Choosing the display for WSI is critical in the process and requires adequate planning.
PubMed: 38538076
DOI: 10.1136/jcp-2024-209418 -
Therapeutic Advances in Neurological... 2024We describe here the first case of exposure to patisiran treatment, a small interfering RNA molecule, during early pregnancy of a 36-year-old woman with symptomatic...
We describe here the first case of exposure to patisiran treatment, a small interfering RNA molecule, during early pregnancy of a 36-year-old woman with symptomatic hereditary transthyretin-related amyloidosis. There were no major complications during pregnancy and delivery, except for a postpartum hemorrhage due to uterine atony. Vitamin A levels had to be closely monitored during pregnancy, and vitamin A substitution adapted accordingly. There was no sign of minor or major congenital abnormalities of the baby. One month after delivery, the patient showed slight clinical and electrophysiological signs of neuropathy progression due to patisiran treatment withdrawal. Patisiran infusions were resumed 3 months after delivery. Due to the unknown teratogenic potential of patisiran, the risk of neuropathy worsening associated with withholding treatment must of course be weighed against a potential teratogenic risk of treatment during pregnancy. Vitamin A levels need to be closely assessed, and substitution must be adapted accordingly, to avoid embryofetal adverse outcome due to vitamin A deficiency or toxicity.
PubMed: 38532802
DOI: 10.1177/17562864241239755 -
American Heart Journal Plus :... Nov 2023To assess temporal changes in clinical profile and in-hospital outcome of patients with amyloidosis presenting with non-ST elevation myocardial infarction, NSTEMI.
STUDY OBJECTIVE
To assess temporal changes in clinical profile and in-hospital outcome of patients with amyloidosis presenting with non-ST elevation myocardial infarction, NSTEMI.
DESIGN/SETTING
We conducted a retrospective observational study using the National Inpatient Sample (NIS) database from January 1, 2010, to December 31, 2020.
MAIN OUTCOMES
Primary outcome of interest was trend in adjusted in-hospital mortality in patients with amyloidosis presenting with NSTEMI from 2010 to 2020. Our secondary outcomes were trend in rate of coronary revascularization, and trend in duration of hospitalization.
RESULTS
We identified 272,896 hospitalizations for amyloidosis. There was a temporal increase in incidence of NSTEMI among patients aged 18-44 years from 15.5 % to 28.0 %, a reverse trend was observed in 45-64 years: 22.1 % to 17.7 %, = 0.043. There was no statistically significant difference in rate of coronary revascularization from 2010 to 2020; 16.3 % to 14.2 %, = 0.86. We observed an increased odds of all-cause in-hospital mortality in patients with NSTEMI compared to those without NSTEMI (aOR = 2.2, 95 % CI: 1.9-2.6, < 0.001) but there was a decrease trend in mortality from 21.5 % to 11.3 %, = 0.013 for trend. Hospitalization duration was also observed to decreased from 14.1 days to 10.9 days during the study period ( = 0.055 for trend).
CONCLUSION
In patients with amyloidosis presenting with NSTEMI, there was increased incidence of NSTEMI among young adults, a steady trend in coronary revascularization, and a decreasing trend of adjusted all-cause in-hospital mortality and length of hospitalization from 2010 to 2020 in the United States.
PubMed: 38511180
DOI: 10.1016/j.ahjo.2023.100336 -
ESC Heart Failure Mar 2024The primary objectives of this study were to analyse the nationwide healthcare trajectories of heart failure (HF) patients in France, 2 years after their first...
AIMS
The primary objectives of this study were to analyse the nationwide healthcare trajectories of heart failure (HF) patients in France, 2 years after their first hospitalization, and to measure sequence similarities. Secondary objectives were to identify the association between trajectories and the risk of mortality.
METHODS AND RESULTS
A retrospective, observational study was conducted using data extracted from the Echantillon Généraliste des Bénéficiaires database, covering the period from 1 January 2008 to 31 December 2018. Follow-up concluded upon death or at the end of the study. We developed a methodology specific to healthcare data by extracting frequent healthcare trajectories and measuring their similarity for use in a survival machine learning analysis. In total, 11 488 HF patients were included and followed up for an average of 2.9 ± 1.3 years. The mean age of the patients was 78.0 ± 13.2 years. The first-year mortality rate was 31.7% and increased to 78.8% at 5 years. Fifty per cent of patients experienced re-hospitalization for reasons related to cardiovascular diseases. We identified 1707 hospitalization sequences, and 21 sequences were associated with survival, while 15 sequences were linked to mortality. In all our models, age and gender emerged as the most significant predictors of mortality (permutation feature importance: 0.099 ± 0.00078 and 0.0087 ± 0.00018, respectively; weights could be interpreted in relative terms). Specifically, the age at initial hospitalization for HF was positively associated with mortality. Gender (male: 49.5%) was associated with poorer prognoses. Healthcare trajectories, including non-surgical device treatments, valve replacements, and atrial fibrillation ablation, were associated with a better prognosis (permutation feature importance: 0.0047 ± 0.00011, 0.0014 ± 0.000073, and 0.00095 ± 0.000097, respectively), except in cases where these invasive treatments preceded or followed hospitalization for cardiac decompensation. The predominant negative prognosis sequences were mostly those that included HF-related hospitalizations before or after other-related hospitalizations (permutation feature importance: 0.0007 ± 0.000091 and 0.00011 ± 0.000045, respectively).
CONCLUSIONS
We highlight the value of healthcare trajectories on frequent hospitalization sequences, mortality, and prognosis and indicate the necessary prognostic value of HF re-hospitalization. Our work may be an essential tool for better identification of at-risk patients in order to increase and improve personalized care in the future.
PubMed: 38509817
DOI: 10.1002/ehf2.14753 -
The Journal of Biological Chemistry Apr 2024AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo...
AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo remain unclear, several studies have highlighted the role that tissue environment and structural amyloidogenicity of individual light chains have in the disease pathogenesis. AL natural deposits contain both full-length light chains and fragments encompassing the variable domain (V) as well as different length segments of the constant region (C), thus highlighting the relevance that proteolysis may have in the fibrillogenesis pathway. Here, we investigate the role of major truncated species of the disease-associated AL55 light chain that were previously identified in natural deposits. Specifically, we study structure, molecular dynamics, thermal stability, and capacity to form fibrils of a fragment containing both the V and part of the C (133-AL55), in comparison with the full-length protein and its variable domain alone, under shear stress and physiological conditions. Whereas the full-length light chain forms exclusively amorphous aggregates, both fragments generate fibrils, although, with different kinetics, aggregate structure, and interplay with the unfragmented protein. More specifically, the V-C 133-AL55 fragment entirely converts into amyloid fibrils microscopically and spectroscopically similar to their ex vivo counterpart and increases the amorphous aggregation of full-length AL55. Overall, our data support the idea that light chain structure and proteolysis are both relevant for amyloidogenesis in vivo and provide a novel biocompatible model of light chain fibrillogenesis suitable for future mechanistic studies.
Topics: Amyloid; Humans; Immunoglobulin Light Chains; Molecular Dynamics Simulation; Immunoglobulin Constant Regions; Immunoglobulin Light-chain Amyloidosis; Kinetics; Protein Domains
PubMed: 38499153
DOI: 10.1016/j.jbc.2024.107174 -
The Journal of International Medical... Mar 2024Light chain deposition disease (LCDD) is an under-recognized condition characterized by deposition of abnormal monoclonal light chains in tissues, leading to organ... (Review)
Review
Light chain deposition disease (LCDD) is an under-recognized condition characterized by deposition of abnormal monoclonal light chains in tissues, leading to organ dysfunction. LCDD involving the gastrointestinal tract is very uncommon, and its diagnosis is challenging. We herein report two cases of LCDD that manifested as inflammatory bowel disease-like symptoms and protein-losing gastroenteropathy. Both patients were women in their early 60s. Tissue biopsies from the gastrointestinal mucosa demonstrated extracellular deposits, which were negative by Congo red staining but positive for κ-light chain by immunohistochemistry. The recent literature on LCDD was reviewed. When patients unexpectedly show extracellular deposits in gastrointestinal biopsy specimens, evaluation of immunoglobulin chains is recommended for diagnosis of LCDD after systemic amyloidosis has been excluded.
Topics: Humans; Female; Male; Immunoglobulin Light Chains; Multiple Myeloma; Immunoglobulin kappa-Chains; Amyloidosis; Gastrointestinal Diseases
PubMed: 38488658
DOI: 10.1177/03000605241233972