Citations

Rosai-Dorfman Disease (RDD) is an uncommon histiocytic disorder that can affect lymph nodes and/or extranodal sites. It is marked by the accumulation of abnormal histiocytes that demonstrate emperipolesis—the active, non-destructive engulfment of other leukocytes. RDD exhibits considerable variability in clinical presentation, pathology, genetics, treatment response, and patient outcomes. In this report, we describe 2 rare cases of RDD that underwent sarcomatous transformation and harbored MAP2K1 mutations, both of which demonstrated poor responses to multiple lines of therapy. Additionally, we review 3 other similar cases from the literature.

Patients with ineffective esophageal motility continue to experience significant symptoms years after diagnosis. In this survey of 47 patients diagnosed ≥5 years earlier, 45% reported GERD symptoms and 75% reported dysphagia. Greater numbers of failed swallows correlated with worse GERD and dysphagia scores, highlighting the long-term clinical impact of IEM and its association with esophageal symptom burden.

During severe exercise, expiratory and inspiratory muscle fatigue develops by ∼50% of the tolerable exercise duration. The magnitude of expiratory and inspiratory muscle fatigue increases progressively toward exercise intolerance but is not different between muscle groups; this is despite the expiratory muscles being less fatigue-resistant. Inspecting esophageal and gastric twitches via cervical stimulation, we speculate that the progressive magnitude of exercise-induced inspiratory muscle fatigue is a function of recruitment and fatigue of the accessory inspiratory muscles.

ABSTRACT Objective Identifying risk factors enables stratification of patients’ susceptibility to inflammatory arthritis immune-related adverse events (IA-irAE). This retrospective study examines whether preexisting osteoarthritis (OA) increases the likelihood of de novo IA in patients treated with immune checkpoint inhibitors (ICIs). Methods The prevalence of OA among ICI–treated patients who developed IA-irAE, those who developed other types of irAEs but not IA (non-IA irAE), and those who did not develop any irAEs (non-irAE) were compared. Electronic medical records were reviewed to extract demographic, clinical and laboratory data. Group comparisons and logistic regression analyses were performed. Results 181 de novo IA-irAE patients, 140 non-IA irAE patients and 170 non-irAE patients were included. The prevalence of OA was significantly higher in the IA-irAE group (69%) than the non-IA irAE group (48%) and the non-irAE group (48%) (both p < 0.001). The IA-irAE group demonstrated a higher frequency of multisite OA, with predominant hand involvement (62%) than the non-IA irAE with OA group (13%) and the non-irAE with OA group (13%) (both p < 0.001). A family history of autoimmune disease (AID) (OR 2.03, 95% CI 1.02–4.05), preexisting OA (OR 2.88, 95% CI 1.85–4.52) and melanoma (OR 2.63, 95% CI 1.56–4.47) were identified as risk factors for the development of IA-irAE. Conclusions OA was more prevalent among ICI-treated patients developing IA-irAE than those who did not. Hand OA was the most common OA pattern in IA-irAE patients. Preexisting OA, melanoma and a family history of AID were risk factors for IA-irAE.

Abstract Background Electronic health record (EHR)–based prognostic modeling is increasingly used in oncology, yet incorporating pharmacogenomic (PGx) knowledge derived from experimental systems into clinical prediction frameworks remains challenging. This gap is driven by fundamental mismatches between controlled drug–mutation assays and heterogeneous, incomplete real-world clinical data. Methods We propose a representation transfer framework that integrates PGx embeddings learned from large-scale in vitro pharmacogenomic screens into patient-level EHR models. A frozen pharmacogenomic encoder is used to generate interaction-aware embeddings from patient mutation profiles and administered therapies, which are aggregated into a fixed-length PGx Complementarity Representation. These representations are incorporated into multimodal survival prediction models alongside standard clinical features. Performance was evaluated using systematic modality ablation analyses, attribution analyses, and exploratory unsupervised representation analyses. Results Integrating PGx embeddings yielded consistent performance improvements across all evaluated modality combinations. Relative gains were largest in modality-sparse settings, where baseline EHR features encode limited biological context, and were attenuated—but remained significant—in biologically enriched configurations. Attribution analyses indicated that PGx embeddings contributed non-redundant predictive signal beyond standard clinical features. Exploratory unsupervised analyses further demonstrated that the learned representations exhibit interpretable association patterns aligned with known therapeutic exposures and pathway-level associations. Conclusion These findings suggest that externally learned pharmacogenomic representations can be transferred into real-world EHR models as a context-dependent, non-redundant augmentation. By framing PGx knowledge as an interaction-aware representation rather than a mechanistic model, this work provides an informatics framework for integrating experimental pharmacogenomic data into clinical prediction tasks in a reproducible and interpretable manner.

PURPOSE Detection of molecular residual disease using circulating tumor DNA (ctDNA) may enable postoperative risk stratification and guide adjuvant therapy. We evaluated the prognostic value of a tissue-free, epigenomic ctDNA assay in patients with stage III colon cancer (CC) enrolled in a phase III adjuvant chemotherapy trial. METHODS Plasma samples were collected after surgery and before adjuvant infusional fluorouracil, leucovorin, and oxaliplatin alone or combined with cetuximab. ctDNA was analyzed using a tissue-free assay; in ctDNA-positive patients, tumor fraction (TF) was quantified and genotyping was performed with a 739-gene panel. Associations with disease-free survival (DFS), time to recurrence (TTR), and overall survival (OS) were assessed using multivariable Cox models adjusted for covariates. RESULTS Among 2,260 evaluable patients, 461 (20.4%) were ctDNA-positive with significantly higher detection in advanced T-/N-stage, high-grade, obstruction/perforation, and BRAF V600E tumors. At a median follow-up of 6.1 years, ctDNA positivity was independently associated with shorter TTR (hazard ratio [HR], 5.96 [95% CI, 5.11 to 6.96]), DFS (HR, 5.03 [95% CI, 4.36 to 5.81]), and OS (HR, 4.45 [95% CI, 3.76 to 5.27]; all P < .0001). The 5-year DFS was 27.7% (95% CI, 23.8 to 32.2) v 77.1% (95% CI, 75.1 to 79.1) in ctDNA-positive versus ctDNA-negative patients, and adverse prognostic impact was greater in lower T/N stage, low-risk, and dMMR subsets (interaction P = .0012-.041). Among ctDNA-positive patients, TF was nearly double in those who recurred or died ( P = .0002) and stratified patients for TTR, DFS, and OS (all adjusted P < .002). Genotyping identified mutations in FLT1 (OR, 8.99) and PREX2 (OR, 7.73) genes that were most strongly associated with recurrence ( P < .03). CONCLUSION Evaluation of ctDNA in resected stage III CC using a tissue-free assay provided robust and independent prognostic value. Higher ctDNA burden, dMMR, and specific mutations defined poor prognostic groups among ctDNA-positive patients.

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&lt;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 Background Myocardial strain derived from cardiovascular magnetic resonance (CMR) using feature tracking (FT) offers incremental prognostic value beyond traditional imaging markers. However, its broader clinical application is hindered by the lack of population-specific reference ranges. This study establishes age-, sex-, and ethnicity-specific normative data for FT-CMR-derived myocardial strain metrics from the Healthy Hearts Consortium (HHC). Methods The HHC is a large, international, multicohort initiative comprising CMR data from 9,088 rigorously screened healthy adults across six centers. The cohort spans the full adult age range and includes greater ethnic diversity than any comparable dataset. CMR scans were acquired using standardized protocols. Image analysis followed pre-specified standard operating procedures and was performed by two experienced readers using two commercial platforms (CVI42®, Circle Cardiovascular Imaging; suiteHEART®, Neosoft). Metrics extracted included: (i) global longitudinal, circumferential, and radial FT strain for both ventricles and atria; (ii) strain rate; (iii) annular plane systolic excursion (MAPSE, TAPSE); and (iv) rapid strain metrics (long-axis, junctional strain) for the left ventricle and atria. Comprehensive quality control involved visual review and exclusion of biologically implausible or extreme outlier values. Reference ranges were calculated using the 95% prediction interval method, stratified by age deciles (20–80 years), sex, and ethnicity (White, Black, Chinese, South Asian, Mixed/Other). The impact of technical factors—scanner vendor, field strength (1.5T vs 3.0T), and software platform—was also assessed. Results The study included 4,452 men (49%) and 4,636 women (51%), aged 18 to 83 years (mean 61 ± 13). The cohort was ethnically diverse: White (81.7%), South Asian (5.6%), Mixed/Other (5.3%), Black (3.7%), and Chinese (3.7%). Women consistently exhibited higher absolute strain values than men. A clear age-related decline in strain was observed, particularly in left ventricular global circumferential and longitudinal strain. Ethnic differences were most pronounced between White and Black, and White and Chinese individuals for RV and LV strain metrics; in contrast, RA, LA, and rapid strain metrics showed minimal ethnic variation. Conclusion This study delivers the most comprehensive age-, sex-, and ethnicity-specific reference ranges to date for FT-CMR-derived myocardial strain. These normative values support improved clinical interpretation, aiding diagnosis and risk stratification in diverse populations. The findings mark a pivotal advancement towards the routine integration of myocardial strain assessment in cardiovascular imaging practice.

Abstract Background While type 2 diabetes (T2DM) is a known risk factor for aortic valve calcification (AVC) and aortic stenosis (AS), the specific mechanisms remain unclear. The aim of this study was to determine early factors associated with AVC in patients with T2DM. Methods This cross-sectional study is a pre-specified substudy of an ongoing multicenter randomized controlled trial, the STENO INTEN-CT trial (Screening and Intervention for Subclinical Coronary Artery Disease in Patients With Type 2 Diabetes). Eligibility criteria are patients with diagnosed T2DM without prior ischemic heart disease, and age between 55-69 years (male) and 60-74 years (female). All patients underwent a non-contrast cardiac computed tomography scan and AVC was measured in Agatston units. Results Of the 3635 patients included in this study, nearly half (n = 1694) demonstrated an AVC &gt; 0 (n=1502 with 0 &lt; AVC &lt; 300 and n = 192 with AVC ≥ 300). With increasing AVC, patients were elder, predominantly males, and had significantly more comorbidities (obesity, hypertension, chronic obstructive pulmonary disease, and kidney dysfunction). Patients with higher AVC were more likely to be treated with statins (AVC = 0: n = 1509 (78%), 0 &lt; AVC &lt; 300: n = 1217 (81%), AVC ≥ 300: n = 163 (85%), p = 0.009). Higher body mass index (OR: 1.03 (1.02-1.04), p &lt; 0.001), statin use (OR: 1.49 (1.24-1.80), p &lt;0.001), low-density lipoprotein (OR: 1.24 (1.12 - 1.37), p &lt; 0.001), and kidney dysfunction, measured as urine albumine-creatinine ratio (OR: 1.00 (1.00-1.00), p &lt;0.001), were independently associated with increasing AVC (Figure 1). However, T2DM severity, measured as the duration of T2DM, HbA1c levels, and the number of antidiabetic drugs used, was not associated with increasing AVC severity (Figure 1+2). Conclusion AVC is highly prevalent, affecting nearly half of patients with T2DM. However, early factors driving AVC are not associated with T2DM severity, but rather to diabetes-related comorbidities and complications.

Abstract Background The presence of the significant left ventricular outflow tract gradient (LVOTG) changes clinical symptoms, prognosis and treatment in hypertrophic cardiomyopathy enabling the classification into its obstructive (HOCM) and non-obstructive form (non-HOCM). However, the more detailed functional characteristics and comparison of these forms remains poorly known. Purpose To compare the demographic, clinical and echocardiographic features between non-HOCM (defined as LVOTG &lt; 30 mmHg) and HOCM patients enrolled into multi-centred study in years 1996-2024 as well as to analyse their long –term prognosis in relation to registered LVOTG. Methods We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 27 centers, nevertheless quantitative assessment of LVOTG was available in 1252 patients. Survival analysis was performed in a subset of 1200 patients with follow-up information. Beyond standard TTE, the number of B-lines, the maximal diastolic velocity of coronary flow in left anterior descending artery (LAD) as well as left ventricular force defined as the ratio of systolic blood pressure plus LVOTG divided by left ventricular end-systolic volume was assessed with specification of hypercontractile phenotype (HP) as the highest force quartile. Additionally age and sex matched control group was included. Results Compared to non-HOCM patients, HOCM showed a bit higher body mass index (27 ± 4 vs 26 ± 4 kg/m2, p = 0.001), were often burdened with diabetes and hypertension, presented more advanced NYHA class and higher risk of SCD, see Table. In the echocardiographic assessment HOCM presented lower end-systolic left ventricular volume (LV ESV: 27 ± 14 vs 29 ± 13 ml, p = 0.014) although maintained equal stroke volume and even higher ejection fraction (EF: 69 ± 8% vs 67 ± 7%, p &lt; 0.001), cardiac output (CO: 4.3 ± 1.7 vs 4.0 ± 1.4 l/min, p &lt; 0.001) and force in comparison to counterparts without LVOTG. This high-contractility performance was however sustained at the cost of larger left atrium volume index (LAVI: 49 ± 19 vs 40 ± 15 ml/m2, p &lt; 0.001), higher coronary flow velocity (43 ± 12 vs 27 ± 13 cm/s, p &lt; 0.001) as well as more frequent B-lines in the lung assessment. During a median follow-up of 87 months (interquartile range 45 – 143 months), 131 all-cause deaths occurred and not only patients with HOCM but also those with HP showed the worse long-term survival, see Figure. Conclusion HOCM remains the form of HCM burdened with more overt clinical symptoms, signs and prognosis. On the other hand LVOTG seems to be important but not always necessary element of this presentation, which seems to be related even more tightly to general hypercontractility phenotype reflected by higher force and resting coronary flow.Table.Non-HOCM vs HOCM comparison Figure.Force and LVOTG prognostic value