Citations

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Abstract Background Treatment with immune-checkpoint inhibitors (ICI) may be associated with adverse cardiac events. Troponin elevation is part of the diagnostic criteria for ICI related myocarditis (ICIrM) and myocardial infarction (MI), however there is limited data for causes of troponin elevation independent of MI and ICIrM and their clinical outcomes with ICI therapy. Purpose To assess the diagnostic and prognostic value of high-sensitivity troponin T (hs-TnT) in patients treated with ICI based on different etiologies and association with cardiac events. Methods All patients treated with ICI who had hs-TnT measured at a multi-center institution from 2011 to 2022 were included. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death and MACE (MI, stroke, heart failure [HF]), and cause of hs-TnT elevation. Risk of cardiac events and mortality were compared for the different etiologies of hs-TnT elevation. Results Of 5,423 patients treated with ICI, 1669 had post-ICI hs-TnT measurement. Mean age was 68.7±11.3 years, 58.3% were male, with follow-up through one year from ICI first administration. Elevated hs-TnT was seen in 1136 patients, with the different causes for elevation depicted in Figure 1, panel A. ICIrM patients exhibited the highest median hs-TnT value of 364 ng/L (IQR 1096), followed by a median of 98 ng/L for MI/Type 2 ischemia, 61 ng/L for infection/sepsis, 51 ng/L for pulmonary embolus, 50 ng/L for HF and 27 ng/L for indeterminate causes, Figure 1, panel B. Additionally, median time from first ICI dose to hs-TnT elevation according to each of the diagnoses are depicted in Figure 1, panel C, with ICIrM showing the shortest median time of 44 days (IQR 74). Hs-TnT elevation in patients with ICIrM had the highest risk for cardiac death (HR 52.7, 95% CI 11.7-238.0, p<0.001), followed by hs-TnT elevation due to HF (HR 15.9, 95% CI 2.9-87.0, p=0.001), MI/type 2 ischemia (HR 11.6, 95% CI 2.4-56.1, p=0.002), and infection/sepsis (HR 5.7, 95% CI 1.0-31.0, p=0.045) compared to those with no hs-TnT elevation, Figure 2, panel A. Similarly, patients with ICIrM had highest risk for MACE (HR 8.2, 95% CI 4.4-15.3, p<0.001), followed by increased hs-TnT due to MI/type 2 ischemia (HR 8.1, 95% CI 5.0-13.1, p<0.001), HF (HR 7.6, 95% CI 4.2-13.7, p<0.001), pulmonary embolism (HR 5.1, 95% CI 2.5-10.8, p<0.001), infection/sepsis (HR 4.1, 95% CI 2.4-7.0, p<0.001), and indeterminate cause (HR 2.4, 95% CI 1.5-3.8, p<0.001), Figure 2, panel B. Conclusions Hs-TnT measurements have prognostic value for cardiac events in cancer patients receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs-TnT levels and the poorest outcomes, with a graded response observed; the worst prognosis was seen in patients with hs-TnT elevation due to ICIrM, followed by other causes, and those without hs-TnT elevation had the best prognosis.Figure 1 Figure 2

Abstract Background Mitral valve prolapse (MVP) is the most common valvular abnormality in the population. Emerging evidence suggests that MVP is associated with left ventricular (LV) remodelling and dysfunction regardless of mitral regurgitation (MR) severity mimicking an early stage of dilated cardiomyopathy. However, prior studies have provided scattered results and were limited by small sample size and poor adjustment for confounders. Purpose To assess early cardiac chamber remodelling associated with MVP in absence of significant MR. Methods This multicentre, retrospective case-control study included patients with isolated MVP without significant MR undergoing CMR including late gadolinium enhancement (LGE). Healthy controls (HC) were selected from local databases and included subjects without cardiovascular pathology or significant comorbidities, with normal CMR parameters defined as comprised within normality ranges reported in the literature. Propensity-score-matching (PSM) was performed in a 1:1 nearest neighbour without replacement method (calliper 0.1), based on age, sex, body-surface-area, hypertension, and diabetes. The impact of MVP on cardiac remodelling was quantified using absolute standardized mean differences (SMDs). Results A total of 587 MVP patients and 583 HC were included, with 517 pairs successfully matched after PSM. Compared to HC, MVP patients showed greater left atrial (LA) area (12.2 [10.5 – 14.1] vs. 11.0 [9.5 – 12.4] cm²/m²), left ventricular (LV) end-diastolic-volume (86.3 [72.4–101.4] vs. 76.3 [66.1–86.0] ml/m²), and lower LV ejection-fraction (60.0% [55.2–65.6] vs. 61.0% [58.0–66.0], all p<0.001). MVP patients also showed greater right atrial area, right ventricular end-diastolic-volume, and higher right ventricular ejection-fraction compared to HC (Figure 1). The greatest impact of MVP on remodelling was observed for LV-end-diastolic volume and left atrial size (SMD ~0.55–0.62, respectively), (Figure 2). Among patients with MVP, remodelling was most pronounced in patients with bi-leaflet MVP and LGE. Conclusions In the absence of significant MR, MVP is associated with cardiac chambers’ remodelling with a particular emphasis on LV and LA dilatation.Cardiac chamber parameters in HC vs. MVP Effect size of MVP on cardiac remodeling

ABSTRACT Introduction/Aims Accurate needle electromyography (EMG) of the short head of the biceps femoris (SHBF) is often important to localize nerve damage when proximal to the fibular head. Techniques have been proposed for accurate SHBF EMG; however, needle placement accuracy is low and with the risk of inadvertent needle placement into the long head (LHBF) potentially resulting in false localization and inappropriate operative management. This study aimed to define the optimal window for accurate SHBF needle EMG placement through ultrasound (US) investigation of the anatomical relationships of the SHBF, LHBF, and common fibular nerve (CFN) in the distal posterolateral thigh. Methods Forty lower limbs from 20 healthy adults were evaluated using US. Distances from the popliteal crease (PC) to the SHBF and LHBF myotendinous junctions and position of the CFN in the popliteal fossa were recorded. The “SHBF window” was defined as the region where the SHBF muscle body is present in the absence of the LHBF. Results The SHBF was located anterolateral to the LHBF tendon/muscle and the CFN medial to the SHBF in all limbs. The average distances from the PC to SHBF and LHBF muscles were 0.6 and 6.4 cm, respectively. The optimal “SHBF window” was identified to be 3–4 cm (2–3 fingerbreadths) proximal to the PC, anterolateral to the LHBF tendon in the distal thigh. Discussion SHBF examination within this optimized window results in increased accuracy of needle placement, aiding in the electrodiagnostic localization of fibular nerve lesions.

Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.

Abstract Background Dementia with Lewy Bodies (DLB) is often misdiagnosed or conflated with Alzheimer's Disease (AD) due to overlapping clinical presentations and neuropathological features. The presence of AD‐like features correlates with accelerated cognitive decline and a worse overall prognosis. Compared to AD, studies suggest that amyloid uptake in DLB may spare the occipital lobe. This project aims to investigate whether amyloid PET could be leveraged to differentiate between AD and DLB patients, with the goal of improving diagnostic accuracy and supporting patient stratification and safety in anti‐amyloid trials. Method This study involves collaboration across six centres (University of Geneva, BioFINDER, AMPLE, AMYPAD PNHS, MCSA, GEHC), each contributing amyloid PET imaging data from patients diagnosed with DLB based on clinical or neuropathological assessments. Moreover, each center provided an additional subset of AD and healthy controls, then matched to DLB samples based on age/sex/APOE genotype/education for comparison. A sub analysis will be performed on patients with evidence of both DLB and AD markers. Given the relatively small sample size, key aspect of the methodological approach is to reduce technical sources of variability. The processing workflow includes rigorous quality control, formatting, normalisation to MNI space, harmonisation (differential smoothing), and MRI‐based segmentation. Result The dataset currently includes amyloid PET scans (acquired using [ 11 C]PiB, [ 18 F]Flutemetamol or [ 18 F]Florbetapir) and MRI scans from ∼130 DLB patients, along with ∼150 AD patients and ∼150 controls. In addition, 99 patients positive for the CSF α‐Synuclein Seeding Amplification Assay were included. Patient data were anonymized, and a harmonised database was created, including demographic characteristics, clinical history, and results from neuropsychological assessments. Conclusion The creation of a standardized, multi‐centre amyloid PET dataset for DLB will enable the study of amyloid PET patterns at the global, regional and voxel level, in comparison with uptake in AD patients and controls. This dataset will serve as a valuable resource for investigating the neuropathological underpinnings of DLB, improving diagnostic accuracy, and potentially guiding patient stratification in anti‐amyloid trials. Efforts to integrate [ 18 F]Florbetaben and additional data are ongoing.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.

Abstract Background Dementia with Lewy Bodies (DLB) is often misdiagnosed or conflated with Alzheimer’s Disease (AD) due to overlapping clinical presentations and neuropathological features. The presence of AD‐like features correlates with accelerated cognitive decline and a worse overall prognosis. Compared to AD, studies suggest that amyloid uptake in DLB may spare the occipital lobe. This project aims to investigate whether amyloid PET could be leveraged to differentiate between AD and DLB patients, with the goal of improving diagnostic accuracy and supporting patient stratification and safety in anti‐amyloid trials. Method This study involves collaboration across six centres (University of Geneva, BioFINDER, AMPLE, AMYPAD PNHS, MCSA, GEHC), each contributing amyloid PET imaging data from patients diagnosed with DLB based on clinical or neuropathological assessments. Moreover, each center provided an additional subset of AD and healthy controls, then matched to DLB samples based on age/sex/APOE genotype/education for comparison. A sub analysis will be performed on patients with evidence of both DLB and AD markers. Given the relatively small sample size, key aspect of the methodological approach is to reduce technical sources of variability. The processing workflow includes rigorous quality control, formatting, normalisation to MNI space, harmonisation (differential smoothing), and MRI‐based segmentation. Result The dataset currently includes amyloid PET scans (acquired using [ 11 C]PiB, [ 18 F]Flutemetamol or [ 18 F]Florbetapir) and MRI scans from ∼130 DLB patients, along with ∼150 AD patients and ∼150 controls. In addition, 99 patients positive for the CSF α‐Synuclein Seeding Amplification Assay were included. Patient data were anonymized, and a harmonised database was created, including demographic characteristics, clinical history, and results from neuropsychological assessments. Conclusion The creation of a standardized, multi‐centre amyloid PET dataset for DLB will enable the study of amyloid PET patterns at the global, regional and voxel level, in comparison with uptake in AD patients and controls. This dataset will serve as a valuable resource for investigating the neuropathological underpinnings of DLB, improving diagnostic accuracy, and potentially guiding patient stratification in anti‐amyloid trials. Efforts to integrate [ 18 F]Florbetaben and additional data are ongoing.

Abstract The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary ( de novo ) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (46%), post-myelodysplastic syndrome (MDS) (19%), post-myeloproliferative neoplasm (MPN) (12%), post-MDS/MPN (6%), therapy-related (17%) and AML with myelodysplasia-related genetic abnormalities (AML-MR; 46%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including in AML-MR (60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p = 0.02), or CEBPA MUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1 MUT (not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.