Large Cohort Of Patients Research Articles

Late outcomes of Fontan operation from the EUROFONTAN experience

Abstract Background Fifty years after the first Fontan operation, the persisting challenges and evolving landscape of post-Fontan complications are explored in the EUROFONTAN experience. Aim of the study is the evaluation of long term outcomes of a large cohort of Fontan patients, focusing on age at Fontan and onset of Fontan-associated liver disease (FALD). Methods A retrospective clinical study across 21 european congenital cardiac centers across Europe. Clinical and operative data of patients who underwent Fontan operation between January 1990 and December 2022 were gathered through a RedCap online database. Results 2606 patients were included in this analysis (M/F: 59%/41%, median age and median weight at Fontan of 4.3 y.o (IQR 3.3-6.4), and 16kg (IQR 14-20), respectively. Most frequent cardiac anomaly were tricuspid atresia and pulmonary atresia with intact ventricular septum (781, 30%). Ventricular morphology was left in 1379 patients (53%), and right in 1029 patients (40%). Extra cardiac conduit (ECC) was performed in the majority of patients (2335, 90%), with a median conduit size of 20mm (IQR 18-20). Early post-operative complications were present in 52% (1340), with an early reintervention in 349 patients (249 surgical , 99 catheter driven) At a median follow-up median of 10 years (IQR 4-15), there were 79 late deaths (3%). Adverse events occurred in 49% (1288 , non-surgical in 962 , surgical in 249). The clinical status was stage A in 60% (1288 patients), while only a minority (1.3%) was in status D. Systemic Ventricular function was normal in 1898 patients (73%), while absent or mild Atrioventricular Valve regurgitation was presnet in 86% (1816). Of note, FALD was detected in 388 (15 %) , and sinus rhythm was present in 99%. Statistical analysis shows that late death and adverse events are significantly associated right ventricular morphology of the systemic ventricle (p-value 0.019). Of note, when compared to lateral tunnel, TCPC extracardiac conduit demonstrated lower late mortality (2.3% vs 8.2%, p-value <0.001) and complication rates (60% vs 48%, p-value 0.001). Analyzing age at Fontan, a linear relationship exists between age and late mortality, whereby mortality increases with advancing age (graph 1). However, concerning the development of late adverse events, the risk decreases with age at Fontan up to 7 years; beyond 7 years, the risk increases with advancing age (graph 2). The analysis demonstrated growing FALD-prevalence with increasing time from Fontan completion (significant especially after 10 years). Conclusion current long term outcomes of Fontan operation are highly satisfactory. However, the longer survival is associated to an increasing incidence of late term extracardiac complications (namely FALD) which are more evident if Fontan is performed at older age.Data of Fontan PatientsCorrelation between age at Fontan and AE

Predictors of discordance in estimating the presence of chronic kidney disease among patients with atrial fibrillation and impact on prescription of anticoagulants and cardiovascular outcomes

Abstract Background In patients with atrial fibrillation (AF), the prevalence, predictors and clinical implications of a potential discordance in estimating the presence/absence of chronic kidney disease (CKD) according to Cockroft-Gault (CG) and CKD-EPI formulas remain unclear. Objective To examine patients characterized by discordance in evaluation of renal function, specifically with regard to the threshold for defining the presence of CKD according to an estimated glomerular filtration rate (eGFR) < 60 ml/min, in a large cohort of European AF patients, and to assess the association with prescriptions of oral anticoagulants (OAC) and the risks of adverse outcomes. Methods Data related to AF patients enrolled in a large European observational prospective registry with an average follow up of 645.2 days were analysed. We evaluated renal function for assessing the presence of CKD according to CG and CKD-EPI formulas and we categorized the population in four groups: eGFR ≥ 60 ml/min according both to CG and CKD-EPI (Concordant ≥ 60); < 60 ml/min according to both formulas (Concordant <60); CG <60 ml/min and CKD-EPI ≥60 ml/min (Discordant-CKD-EPI), CG ≥ 60 ml/min and CKD-EPI <60 ml/min (Discordant-CG). Logistic regression analyses were used to assess factors associated with a Discordant assessment of CKD and its association with OAC therapy. Cox regression analysis was used to determine association between categories and the risk of adverse outcome. The primary endpoint was a composite of all-cause death and major adverse cardiovascular events (MACEs). Results 8.786 patients with AF (mean age 68.70, SD 11.58 years; 40.9% female) were included in the analysis. 1360 (15.5%) of them had Discordant CKD assessment: 577 (6.6%) with Discordant-CKD-EPI and 783 (8.9%) with Discordant-CG. Increasing age, female sex and coronary artery disease (CAD) were associated with Discordant-CKD-EPI, while BMI and heart failure (HF) showed an inverse association (Figure 1). Conversely, BMI and HF were factors significantly associated with Discordant-CG. Discordant-CKD-EPI patients showed lower odds of being prescribed with OAC therapy (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.54-0.95) with no significant differences regarding the type of OAC therapy (warfarin or direct oral anticoagulants). At Cox regression analysis, patients with Discordant-CKD-EPI showed a higher risk of composite endpoint events (Figure 2) and both Discordant-CKD-EPI and Discordant-CG patients were associated with a higher risk of all-cause death. Conclusions Age, BMI, female sex and comorbidities associated with AF (CAD and HF) significantly influenced the probability of having a discordant assessment of the presence of CKD, according to estimation of renal function impairment using CG or CKD-EPI formulas, respectively. A discordant assessment of CKD influenced the probability of being prescribed with OAC and was associated with a higher risk of adverse outcomes.Figure 1Figure2

Generalizability of SELECT to a contemporary cohort of cardiac surgical patients: analysis of the TRICS III Randomized Trial

Abstract Background The SELECT trial reported a significant reduction in cardiovascular (CV) outcomes with semaglutide amongst patients without diabetes who had pre-existing CV disease and a body-mass index (BMI) of 27 or greater. Patients undergoing cardiac surgery represent a high-risk subset of those with established CV disease, and may benefit from treatment with semaglutide. Purpose This study evaluated the generalizability of SELECT to a contemporary international cohort of cardiac surgical patients, and assessed whether differences between SELECT-eligible and non-eligible patients translated to altered risks of CV outcomes. Methods Present data was gathered from the TRICS III trial, a multicentre, randomized trial of restrictive versus liberal red-cell transfusion thresholds amongst 5243 cardiac surgical patients with a EuroSCORE I of ≥6. The proportion of cardiac surgical patients eligible for SELECT was determined by applying its selection criteria to the TRICS III cohort. Finally, baseline characteristics and outcomes stratified by SELECT eligibility were compared. Results A total of 4887 patients from the TRICS III cohort had available data for analysis, of which 452 (9.2%) were deemed to have been eligible for the SELECT trial. A comparison of baseline characteristics between SELECT-eligible and non-eligible patients are presented in Table 1; while SELECT-eligible patients were more likely to have preserved left ventricular function (71.7% vs. 61.0%), EuroSCORE I values were comparable between the two groups (7.8±2.1 vs. 7.9±1.9). The rate of a 3-point MACCE of Death, MI or stroke in the present cohort of SELECT-eligible patients undergoing cardiac surgery (16.6%) was numerically higher than those enrolled in SELECT receiving semaglutide (8.1%) or placebo (10.0%), despite the shorter follow-up (6 months vs. 39.8 months). Six month outcomes following cardiac surgery were similar regardless of SELECT eligibility (Figure 1); no difference in risk of outcomes was documented for the 3-point MACCE [SELECT Eligible vs. Non-eligible – 16.6% vs. 14.5%; OR 1.17 (0.9-1.53); P=0.24] and the TRICS III primary composite of Death, MI, Stroke, or New-Onset Renal Failure with Dialysis [17.0% vs. 17.0%; OR 1.0 (0.77-1.29); P=0.98]. There was a trend towards higher rates of MI at 6 months amongst SELECT-eligible patients, but this difference failed to reach statistical significance [8.5% vs. 6.3%; OR 2.0 (0.96-1.39); P=0.08). Conclusions In this large international cohort of contemporary cardiac surgical patients, nearly 10% would have met eligibility for SELECT. SELECT-eligible patients undergoing cardiac surgery in TRICS III had a numerically higher rate of MACCE than those enrolled in SELECT, highlighting the high risk nature of this patient subgroup. However, amongst SELECT-eligible and non-eligible patients undergoing cardiac surgery, no significant difference in CV outcomes was uncovered.

The effect of Glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in type 2 diabetes mellitus patients with coronary artery disease

Abstract Background Cardiovascular disease is the primary cause of mortality in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCT) have shown that Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in T2DM patients, with greater therapeutic benefits observed in patients with established atherosclerotic cardiovascular disease. However, the effect of GLP1-RA therapy on cardiovascular outcomes has been inconsistent and the RCT have not been sufficiently powered to examine the effect of GLP1-RA on mortality or their therapeutic effect in different subgroups of T2DM patients. Purpose This study aimed to examine the effect of GLP1-RA therapy on cardiovascular outcomes and mortality in a real-world cohort of T2DM patients with coronary artery disease (CAD). Methods This study included T2DM patients with CAD who were treated with metformin at a daily dose of ≥ 1g for a period of ≥ 180 days. CAD was defined as ≥ 50% luminal stenosis in any coronary artery segment according to a nationwide angiography and angioplasty registry. We performed sequential emulated target trials at monthly intervals between January 1, 2013 and December 31, 2020 to examine the effect of GLP1-RA therapy on major adverse cardiovascular outcomes (MACE), a composite of myocardial infarction, ischemic stroke and all-cause mortality. Secondary outcomes included the individual components of MACE. Marginal structural models were used to compute pooled effect estimates. This was an intention-to-treat analysis with 5 years of follow-up for each emulated target trial. Inverse probability of treatment weighting was used to adjust for confounding due to differences in patient demographics at baseline. Results This study consisted of 26,746 individuals who were treated with GLP1-RA and 74,638 controls. The 5-year cumulative risk of MACE was 27.7 % in the GLP1-RA group and 32.7 % in the control group (risk ratio 0.85 [95% confidence interval 0.82 – 0.88]). GLP1-RA therapy was associated with a lower risk of all-cause mortality (risk ratio 0.76 [95% confidence interval 0.72 – 0.79]) and myocardial infarction (risk ratio 0.95 [95% confidence interval 0.89 – 1.00]). We found little or no effect of GLP1-RA therapy on the risk of ischemic stroke (risk ratio 1.13 [95% confidence interval 0.97 – 1.27]). Conclusions In this large real-world cohort of T2DM patients with established CAD, we observed that GLP1-RA therapy was associated with a lower risk of MACE, myocardial infarction and all-cause mortality.

Clinical validation of the 2021 European Society of Cardiology guidelines on pre-existing right bundle branch block patients undergoing transcatheter aortic valve replacement

Abstract Introduction The management of patients with right bundle branch block (RBBB) undergoing transcatheter aortic valve replacement (TAVR) remains challenging. In these patients, the 2021 ESC guidelines recommend early pacemaker (PM) implantation in case of PR prolongation, QRS axis change or transient high-degree atrioventricular block (HAVB). However, evidence for the proposed criteria is scarce. Purpose Our aim was to evaluate the ESC recommendation for risk stratification of RBBB patients undergoing TAVR. Methods We retrospectively analyzed patients with pre-existing RBBB undergoing TAVR at our institution between 2011-2023. A surface 12-lead electrocardiogram (ECG) was available before and after procedure in all patients. The following, proposed ESC criteria were validated: ΔPR interval ≥ 20ms, QRS axis change or transient HAVB < 24 hours after TAVR. Results Of a total 1412 patients undergoing TAVR, 109 had pre-existing RBBB and were eligible for final analysis (mean age 83±5 years, 39% female). Of 109 RBBB patients, 36 (33%) developed persistent HAVB and received a permanent PM. Among the other 73 patients (67%), 17 patients (23%) suffered delayed HAVB during 30-days FU. When applying the ESC Guidelines, PM placement would have been indicated in 52% (38/73) of patients with RBBB after TAVR: due to transient HAVB in 17 (23%), due to PR prolongation ≥ 20ms in 19 (26%) and due to QRS axis change in 20 patients (27%). The proposed ESC criteria identified 82% of patients (14/17) with delayed HAVB during 30-day FU, while missing 3 patients (18%, 2.8% of overall cohort, Figure). This resulted in a sensitivity of 82% and a negative predictive value of 91%. Among the 17 patients with delayed HAVB, 12 patients (71%) displayed transient atrioventricular (AV) block within 24 hours after TAVR. Conclusion In this large cohort of RBBB patients undergoing TAVR with contemporary valves and techniques, the proposed ESC criteria of PR prolongation, QRS axis change or transient HAVB correctly identified 4/5 patients developing HAVB during 30-day FU. Prospective studies are warranted to confirm these findings.

Small heart size and premature death in 366,484 individuals with normal ejection fraction

Abstract Background In patients with preserved left ventricular ejection fraction (LVEF), small ventricular size has been associated with reduced functional capacity, but its impact on clinical outcomes is unclear. Purpose The goal of this study was to determine the relationship between small heart size and premature mortality within a large multi-centre adult patient cohort with transthoracic echocardiographic examinations. Methods We divided 366,484 individuals with LVEF ≥ 50% (including a sub-set of 279,442 individuals with high-normal LVEF ≥ 60%) by sex and increasing quartiles for LV end-diastolic volume (LVEDV), LVEDV indexed to body surface area (LVEDVi) and LV end-diastolic diameter to assess associations with 5-year mortality through linkage with the National Death Index. Results During 2-million person-years of follow-up, 65,241 deaths occurred. Increasing LV chamber size was associated with reduced odds of 5-year all-cause mortality, particularly for higher LVEF. As compared with the larger quartiles, the smallest cardiac size quartiles were associated with higher 5-year all-cause mortality, even after adjusting for age (Figure 1). The smallest LVEDVi quartile was associated with a 14% and 18% higher odds of 5-year all-cause mortality for males and females, respectively, with a greater effect with high-normal LVEF. For cardiovascular-related mortality, females in the smallest quartile for LVEDVi had a 17% increased odds of mortality, which increased to 30% in those with LVEF was ≥ 60%. In men, there was no significant association between smallest cardiac size and cardiovascular-related mortality. Conclusions In individuals with normal LVEF, small ventricular size is associated with increased mortality, particularly among females and those with higher LVEF.

Tricuspid regurgitation in the context of severe concomitant left-sided valvular heart disease: patients characteristics and long-term clinical and interventional outcomes

Abstract Background The clinical features, therapeutical management and outcome of patients with significant tricuspid regurgitation (TR) in the context of multiple valvular disease (VD) are poorly defined. Purpose To assess the characteristics, management and long-term prognosis of a large cohort of patients with multiple VD, focusing on the context of significant TR and concomitant severe mitral or aortic disease. Methods Clinical and echocardiographic data were collected in 1183 patients with ≥moderate TR diagnosed at our centers from January 2012 to June 2020: after propensity score matching for age to create matched cohort with < 10% of absolute difference, 975 patients were included in this study and divided in 4 groups as shown in Figure 1. Primary endpoint was all-cause death (ACD), secondary endpoint was the composite of heart failure (HF) hospitalization+any valvular intervention. Results Patients with isolated TR (356, 37%) had more history of atrial fibrillation and were more often asymptomatic and with preserved left-ventricular ejection fraction (LVEF). TR+ severe MR patients (466, 48%) showed higher rates of concomitant coronary artery disease, NYHA class III/IV symptoms and larger left atrial volumes. The group of TR+ severe AS (131 patients, 13%) was characterized by older age, more comorbidities and lower LVEF. Patients with TR and severe AR (22, 2%) were younger, with larger LV dimensions and higher pulmonary pressures. Overall, in 37(4%) patients tricuspid intervention was performed: no differences were found between groups in term of frequency of concomitant or staged tricuspid valve surgical treatment (p=0.444 and p= 0.624, respectively), while left-valve only surgical treatment was more common among patients with TR and severe MR and left-valve transcatheter treatment among patients with TR and severe AS (both p<0.001). After a median follow-up of 2.8 years, the primary endpoint occured in 374 (38%) of patients, and was significantly more frequent in the group of patients with TR and severe AS (p<0.001, Figure 2). In this group, after multivariate analysis, indexed stroke volume remained independenty associated with ACD (OR 0.96, CI 0.93-0.98, p =0.040). Eventually, the secondary endpoint too was more common in patients with TR and severe AS (p<0.001, Figure 2). Conclusions In the context of significant TR, concomitant severe left-sided VD is common, and each subtype presents with different clinical features and echocardiographic phenotypes; in this scenario, TR was profoundly underteated. Long-term, patients with significant TR+ severe AS have considerable worse prognosis.Figure 1Figure 2

Mycophenolate mofetil for the treatment of cicatrizing conjunctivitis secondary to ocular pemphigoid

PurposeTo characterize the use of mycophenolate mofetil (MMF) in a large cohort of patients undergoing treatment for ocular mucous membrane pemphigoid (ocMMP). DesignThis was a retrospective consecutive observational chart review of patients with cicatrizing conjunctivitis associated with pemphigoid (ocMMP) at the University of Texas Southwestern Medical Center in Dallas, TX from 2016 to 2023 who underwent treatment with MMF. MethodsData collection included patient demographics, medical and ocular history, clinical findings, slit lamp photographs, biopsy results, additional testing, disease stage, time on MMF, patient response to treatment, and side effects of treatment. The data was analyzed with logistic regression using IBM SPSS (version 29). The dependent variable was remission status. ResultsA total of 52 patients with cicatrizing conjunctivitis associated with pemphigoid were treated with MMF, of which 37 (71.2 %) patients had biopsy proven disease. Of the cohort, 29 (55.8 %) patients were female and 23 (44.2 %) patients were male. The mean age at initiation of MMF therapy was 65.1 years (range 35–93). The best degree of response achieved by each patient in our cohort was as follows: no response (4, 7.7 %), partial response (28, 53.8 %), clinical remission with steroids (4, 7.7 %), steroid-free remission (14, 26.9 %), and durable drug-free remission (2, 3.8 %). The mean time of treatment with MMF was 35.5 months (range 2–118), with a mean follow up time of 42.7 months (range 3–123). The mean time to clinical remission was 6.7 months (range 1–18), while the mean time to steroid-free remission was 7.2 months (range 2–18). Of the entire cohort, 16 (30.8 %) patients reported side effects. The most common side effect was nausea (7 patients). There was one adverse event (anemia, 1, 1.9 %). Overall, 30 (57.7 %) patients discontinued MMF, most commonly due to side effects (11 patients) or inadequate disease control (11 patients). ConclusionMycophenolate mofetil (MMF) can be beneficial in ocMMP as a steroid-sparing alternative. Although effective, side effects and discontinuation of treatment were common.

Incidence of acute pericarditis after pulsed-field ablation for the treatment of atrial fibrillation

Abstract Introduction Pulsed-field ablation (PFA) has emerged as a novel treatment strategy for patients with atrial fibrillation (AF). While traditional thermal ablation modes such as radiofrequency energy or cryoballoon energy showed an acute pericarditis rate of 0.5 – 4%, little is known about the incidence of acute pericarditis after PFA. Purpose To assess the incidence of acute pericarditis using PFA for the treatment of AF. Method Patients undergoing catheter ablation for AF using PFA were consecutively enrolled in a prospective registry in a tertiary referral center between January 2022 and January 2024. After PFA, all patients received a clinical assessment for cardiothoracic symptoms including cardiac auscultation, 12-lead ECG and transthoracic echocardiography. A clinical diagnosis of acute pericarditis was established according to the 2015 European Society of Cardiology (ESC) guidelines by the presence of at least 2 of the following criteria within 90 days after PFA: 1) pleuritic chest pain; 2) friction rub; 3) new widespread ST-elevation or PR depression on ECG; 4) pericardial effusion. Suspected acute pericarditis was diagnosed if 1 criterion was fulfilled. Results A total of 388 patients with AF (median age 67.5 years, 32% female) underwent pulmonary vein isolation using PFA. 0 (0%) patients fulfilled ≥ 2 ESC criteria required for diagnosis of acute pericarditis. Suspected acute pericarditis within 90 days after the procedure was found in 17 (4.4%) patients. 29 (7.5%) patients reported some sort of cardiothoracic symptoms (chest pain, chest tightness, chest discomfort, shortness of breath or pleuritic chest pain). Among them, 6 (1.5%) patients received anti-inflammatory drug treatment due to suspected pericarditis. 0 (0%) patients had a friction rub, 6 (1.5%) patients showed PR depression (no ST-elevation) and 5 (1.3%) patients demonstrated pericardial effusions. None of the pericardial effusions required drainage. Conclusion In this large cohort of patients undergoing PFA for AF, no patients suffered acute pericarditis according to current ESC criteria. Any type of cardiothoracic symptoms after PFA were noted in 7.5% of patients with 1.5% of patients requiring drug therapy.Graphical Abstract

Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers

BackgroundCancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile.MethodsWe develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in oncogenic processes.ResultsOur strategy successfully captures complex dynamics in developmental tissue bulks, reveals remarkable cellular heterogeneity in adult tissues, and resolves the ambiguity of cell identities in in vitro transformations. Applying it to large patient cohorts of bulk RNA-seq, we identify clinically relevant cell-of-origin patterns and observe that decomposed fetal cell signals significantly increase in tumors versus normal tissues and metastases versus primary tumors. Across cancer types, the inferred fetal-state strength outperforms published stemness indices in predicting patient survival and confers substantially improved predictive power for therapeutic responses.ConclusionsOur study not only provides a general approach to quantifying developmental-status-aware cell states of bulk samples but also constructs an information-rich, biologically interpretable, cell-state panorama of human cancers, enabling diverse translational applications.

Fully automated detection of anomalous aortic origin of the coronary arteries in coronary CT images: a novel artificial intelligence-based screening tool

Abstract Background Anomalous Aortic Origin of the Coronary Artery (AAOCA) is a rare congenital disease that can be easily overlooked during contrast-enhanced Coronary Computed Tomography Angiography (CCTA) image analysis. Objective In this study, we aimed to develop a novel artificial intelligence-based screening tool to automate the detection of AAOCA in CCTA images. Method We enrolled 127 patients from the coronary artery anomaly registry from two centers with AAOCA diagnosis based on CCTA as well as 413 normal cases. A deep learning model was developed to automatically segment the aorta and the left ventricle (LV), after which the images were automatically cropped to the aortic root and LV intersection with a box size of 6 cm3. The images were then clipped to Hounsfield Units ranging from -400 to 750 and normalized to -1 to1. These cropped regions were fed into different residual convolutional neural networks (ResNet, with different depths 10, 18, 34 and 50) to detect AAOCA. Model development (parameter and hyperparameters optimization) was performed on the training and validation sets (70/10%), and finally, it was tested on the 20% untouched test set. Various classification metrics were reported for the detection of AAOCA. Results ResNet-10 achieved an AUC of 0.91 (sensitivity: 0.89, specificity: 0.86), while ResNet-18 showed improved performance with an AUC of 0.95 (sensitivity: 0.89, specificity: 0.95). ResNet-34 achieved an AUC of 0.94 (sensitivity: 0.83, specificity: 0.96), and ResNet-50 excelled with the highest AUC of 0.96 (sensitivity: 0.89, specificity: 0.95), indicating its superior capability in accurately identifying AAOCA. Conclusion We developed a high-performance AI tool for the fully automated detection of AAOCA using CCTA images. This tool can be used to evaluate large patient cohorts and detect AAOCA in extensive databases. Moreover, it can operate seamlessly alongside clinical assessments of CCTA scans, providing real-time alerts to medical personnel about potential AAOCA findings. This enhances diagnostic efficiency and supports early intervention in cardiovascular care.

The value of a multimodal approach combining radical surgery and intraoperative radiotherapy in the recurrence treatment of gynecological malignancies - analysis of a large patient cohort in a tertiary care center

BackgroundRecurrent and locally advanced gynecological malignancies have a poor prognosis. In particularly, pelvic local recurrence after previous radiotherapy and/or positive resection margins during surgical treatment for recurrent disease result in low survival rates. Consequently, locoregional control is of utmost importance in this cohort of patients. The aim of this study was to analyze treatment outcomes and determine prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for recurrent and locally advanced gynecological malignancies.Methods40 patients who underwent surgical treatment and IORT between 2010 and 2022 were eligible for inclusion. The median follow-up time was 22 months. The outcomes measured were locoregional control (LRC), overall survival (OS), and survival without distant metastases (DMFS). The Cox proportional hazards model was used for univariate and multivariate analysis to assess the impact of patient variables and treatment factors on the endpoints mentioned. The following variables were analyzed: age at surgical treatment and IORT and initial diagnosis (< 65 vs. ≥65 years, each), disease-free interval (DFI) between initial diagnosis and first recurrence, DFI to surgical treatment and IORT, grading, histology, IORT dose (≤ 13 vs. >13 Gy) and technique (high dose radiotherapy (HDR) vs. IORT using electrons, (IOERT)). Survival curves were generated using the Kaplan-Meier method.ResultsThe mean IORT dose was 13.8 Gy (range 10–18 Gy). Cervical carcinoma was most frequently found in 27.5% of patients followed by endometrial carcinoma and vulvar carcinoma in 25% respectively. The final histopathologic results after surgery with IORT showed no residual tumour in 24 patients (60%), microscopic residual disease in 5 patients (12.5%), resection status could not be evaluated in three patients (7.5%) and the resection status was unknown in eight patients (20%). Subsequently, 27.5% of patients also received adjuvant radiotherapy of the local recurrence bed. However, after IORT, 65% of the women suffered a recurrence. Of these, the recurrences were localized: in-field 32.5%, out-of-field 22.5% and margin-of-field 12.5%. The 3- and 5-year OS was 69% and 55% respectively. The 3- and 5-year LRC was 56% respectively. The 3- and 5-year DMFS was 66% and 49%. Whereas the comparison between groups by IORT dose level (≤ 13 vs. >13 Gy) showed a non-significant trend in favor of the higher dose only for OS (p = 0.094), but not in LRC and DMFS (p > 0.05). OS and DMFS, but not LRC, differed significantly between the HDR-IORT and IOERT groups (p = 0.06 and p = 0.03,) in favor of the HDR-IORT technique. For HDR-IORT technique a trend towards superior OS and LRC was observed in the univariate analysis: HR 3.76, CI 95%: 0.95–14.881, p = 0.059 and HR 2.165 CI 95%: 0.916–5.114, p = 0.078ConclusionsThe survival rate for pelvic recurrence in gynecological malignancies remains poor and comparable with historical data from the last two decades. Particularly HDR-IORT, appears to provide a long-term oncological benefit in carefully selected patients.

Future directions in myelodysplastic syndromes/neoplasms and acute myeloid leukaemia classification: from blast counts to biology.

Myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukaemia (AML) are neoplastic haematopoietic cell proliferations that are diagnosed and classified based on a combination of morphological, clinical and genetic features. Specifically, the percentage of myeloblasts in the blood and bone marrow is a key feature that has historically separated MDS from AML and, together with several other morphological parameters, defines distinct disease entities within MDS. Both MDS and AML have recurrent genetic abnormalities that are increasingly influencing their definitions and subclassification. For example, in 2022, two new MDS entities were recognised based on the presence of SF3B1 mutation or bi-allelic TP53 abnormalities. Genomic information is more objective and reproducible than morphological analyses, which are subject to interobserver variability and arbitrary numeric cut-offs. Nevertheless, the integration of genomic data with traditional morphological features in myeloid neoplasm classification has proved challenging by virtue of its sheer complexity; gene expression and methylation profiling also can provide information regarding disease pathogenesis, adding to the complexity. New machine-learning technologies have the potential to effectively integrate multiple diagnostic modalities and improve on historical classification systems. Going forward, the application of machine learning and advanced statistical methods to large patient cohorts can refine future classifications by advancing unbiased and robust previously unrecognised disease subgroups. Future classifications will probably incorporate these newer technologies and higher-level analyses that emphasise genomic disease entities over traditional morphologically defined entities, thus promoting more accurate diagnosis and patient risk stratification.

A long-term follow-up study of gastric peroral endoscopic myotomy (G-POEM) in a large cohort of patients with postsurgical gastroparesis.

Postoperative gastroparesis occurs after surgeries which affect the upper digestive tract. Gastric peroral endoscopic myotomy (G-POEM) is a treatment for postoperative gastroparesis. The present study boasts the long-term efficacy and safety of G-POEM in a large cohort of patients. Gastroparesis Cardinal Symptom Index (GCSI) and Gastroesophageal Reflux Disease Questionnaire (GERDQ) were utilized for the assessment of postsurgical gastroparesis symptoms. Gastroscope was used to observe the anastomotic site. Three-dimensional ultrasound was used to measure the morphological structure of the gastric antrum and pylorus tube. Gastric emptying time was calculated by analyzing the volume change of gastric antrum. Significant clinical effectiveness of G-POEM was observed. The GCSI score, including each subscale score, showed significant decrease after G-POEM. Before G-POEM, there was a negative correlation between GCSI score and the inner diameter of pylorus, as well as a positive correlation with the length of pyloric tube. The similar results were found in the scores of nausea/vomiting and postprandial fullness/early satiety subscales. No correlation was observed between GCSI score and the emptying time, nor between the emptying time and the parameters of antrum morphology. After G-POEM, no correlation was found between GCSI (including subscales) score, the emptying time, and the parameters of antrum morphology. Patients who exhibited as clinical non-responders often accompanied with GERD symptoms. After G-POEM, the score of GERDQ decreased significantly. Either before or after G-POEM, no correlation was noticed between GERDQ scores, the emptying time and the parameters of antrum morphology. The technique of G-POEM was demonstrated as a minimally invasive approach with the long-term efficacy and safety in therapying postoperative gastroparesis.

The role of transforming growth factor-β in lung damage in COVID-19: clinical and diagnostic parallels

BACKGROUND: Coronavirus 2 (SARS-CoV-2), which causes severe acute respiratory syndrome in COVID-19, leads to complex immune reactions, hyperactivation of immunocompetent cells, including increased degranulation activity of mast cells and the release of their secretome products. The SARS-CoV-2 virus and the subsequent strong immune and inflammatory response, as well as a violation of the regulation of coagulation and fibrinolytic pathways, cause massive activation of latent TGF-β in the lungs, as well as the latent pool of TGF-β in the blood of patients with COVID-19. AIMS: To assume the participation of transforming growth factor-β (TGF-β) in lung damage in patients with COVID-19 by determining its quantitative level in autopsy lung samples in patients with COVID-19 and to conduct a correlation analysis with clinical and laboratory parameters. MATERIALS AND METHODS: The study included samples of lung autopsy material obtained from patients who died from severe COVID-19. A correlation analysis of TGF-β-positive cells and clinical and laboratory parameters was also performed. RESULTS: Extensive representation of TGF-β-positive cells was found in lung tissues of patients who died from COVID-19.A negative correlation was revealed: between TGF-β and the content of nucleated neutrophils in the blood (r = - 0,617; p = 0,033); between TGF-β and the level of C-reactive protein (CRP) according to the results of blood biochemistry (r = - 0,491; p = 0,013). A positive correlation was revealed between TGF-β and the content of blood platelets (r = 0,384; p =0,012);TGF-β with the level of erythrocyte sedimentation rate (ESR) (r = 0,409; p = 0,025). A positive correlation was also found between TGF-β and the presence of cough in the patient at the beginning of hospitalization (r = 0,367; p = 0,046). CONCLUSIONS: Activation of TGF-β in the lungs of patients who died from severe COVID-19 correlates with the level of neutrophils, platelets, ESR, CRP and the presence of cough in the patient. Further research is needed on the activation, release of TGF-β and its interactions in larger cohorts of patients. These correlations suggest the negative involvement of the transforming growth factor and consider the therapeutic possibilities of regulatory influence on its activation.

Catheter-Directed Thrombolysis for (Not Immediately) Threatened Acute Lower Limb Ischemia: Clinical Outcome and Efficacy.

The objective of this study was to examine the short- and midterm outcomes of catheter-directed thrombolysis (CDT) for acute lower limb ischemia (ALI), classes Rutherford 1 and 2, with specific attention to functional outcome. This retrospective study included patients with ALI treated with CDT from 2 vascular centers between May 2018 and April 2021. Cases were analyzed in groups according to the Rutherford (1 and 2) classification. The primary endpoint was functional outcome during follow-up, assessed by Rutherford's chronic limb ischemia classification. Functional outcomes over time were analyzed by generalized estimating equations. Kaplan-Meier analysis was used to estimate reintervention, amputation, survival, and reintervention-free survival rates. Two hundred cases were included (Rutherford 1, n = 51; Rutherford 2, n = 149). Total median treatment duration was 27 hours in the Rutherford 1 group and 39 hours in the Rutherford 2 group (P= 0.120). Initial clinical success was high (Rutherford 1, 82% vs Rutherford 2, 89%; P= 0.253). Complications were comparable between the 2 groups: major bleeding 8% vs 10% (P= 0.634), major amputation 4% vs 7% (P= 0.603), and mortality 6% vs 6% (P= 0.967). Median follow-up was 32 months (0-63 months). During follow-up, there was a high number of reinterventions (43%) and amputations (20%) in patients with Rutherford 1 limb ischemia, which was comparable to patients with Rutherford 2 limb ischemia. Fifty-six percent of the patients with Rutherford 1 limb ischemia reaching 2 years of follow-up were asymptomatic, 20% had mild and 16% had moderate to severe claudication. Initial clinical success following CDT and not immediately threatened ischemia at presentation are associated with improved functional outcomes during follow-up (P < 0.001 and P= 0.009, respectively). In our cohort, CDT was effective in reestablishing arterial flow for not immediately threatened ALI. Patients with Rutherford 1 limb ischemia who receive CDT had a more favorable functional outcome than patients with more severe limb ischemia (Rutherford 2). However, reinterventions were required frequently, and there was a substantial risk of complications. Acute lower limb ischemia (ALI) does not immediately jeopardize limb survival in patients with Rutherford 1 limb ischemia but can induce disabling claudication. In such patients, catheter-directed thrombolysis (CDT) is often performed to improve functional outcome. However, previous reports warned about the complications of CDT, and so far, mid- and long-term functional outcomes have not been reported. This study, in which a large cohort of patients with ALI was included, demonstrates a high technical success of CDT for not immediately threatened ALI with more favorable functional outcomes when compared with those with threatened limbs. Nevertheless, major complications pose a serious risk, and the need for reinterventions in the long term is high.

Evaluation of metagenomic next-generation sequencing (mNGS) combined with quantitative PCR: cutting-edge methods for rapid diagnosis of non-invasive fungal rhinosinusitis.

Fungal rhinosinusitis is a significant and growing health concern in arid regions, with an increasing incidence over recent decades. Without timely and appropriate management, it can lead to severe complications, including potential intracranial spread. This study aims to establish efficient and rapid diagnostics for non-invasive fungal rhinosinusitis (FRS), addressing the challenge of its difficult-to-culture diagnosis. Twenty-eight patients suspected of FRS were studied using endoscopic sinus surgery to obtain tissue samples for histopathology, direct microscopy, fungal culture, quantitative PCR (qPCR) and metagenomic next-generation sequencing (mNGS) detection. A patented qPCR targeting prevalent Aspergillus species was evaluated. The patient cohort had a male-to-female ratio of 9:14, with disease duration up to 50 years. Histopathologically, 23 out of 28 cases were positive. Fungal culture exhibited a sensitivity of 21.74%, with one false positive. qPCR and mNGS showed 100% sensitivity and specificity, with a 100% consistency rate for identification at the species level (23/23), and potential detection of cases with co-infections. The most common pathogen was A. flavus, followed by A. fumigatus and A. niger. Two cases involved mixed infections of A. fumigatus and A. flavus. qPCR and mNGS proved effective in rapidly identifying fungi from fresh sinus tissue that are challenging to culture, surpassing conventional methods. However, further evaluation and optimization with a larger cohort of patients are necessary. Histopathology is still recommended to confirm the clinical significance of the detected fungal species.

Neuroleptic malignant syndrome in Huntington disease.

Despite the wide use of dopamine receptor blocking agents (DRBAs) in Huntington disease (HD), neuroleptic malignant syndrome (NMS) is rarely described in this population. The aim of this study was to assess NMS prevalence in a large cohort of HD patients and explore the main associated risk factors. In 2023, an HD patient was admitted to our neurology department due to NMS. Starting from the case description, we performed a narrative review of the literature of NMS cases in HD, reviewed data from the fifth dataset of the Enroll-HD (a longitudinal, observational, global study of families with HD) study (PDS5) selecting HD patients treated with DRBAs and/or tetrabenazine (TBZ) who presented at least one of the core symptoms of NMS (rigidity and hyperthermia), and collected data to investigate prevalence of NMS and identify risk factors. In the Enroll-HD PDS5 dataset, we identified 5108 of 11,569 HD patients who were undergoing DRBA and/or TBZ treatment. Only one patient, a Caucasian man of 46 years, undergoing clozapine and valproate treatment, had a registered diagnosis of NMS. NMS in HD patients is seldom described. This could be due to an underestimation of this condition. There are no available objective NMS diagnostic criteria at present, and the existence of atypical forms of NMS further complicates diagnosis. Advanced disease stage, rigid-akinetic phenotype, abrupt therapy changes, polytherapy, and dehydration are key risk factors, most of which are preventable through awareness and caution in managing medications in the HD population.

Clinical Characteristics of Patients with Takayasu Arteritis Undergoing Open or Endovascular Operations in China.

The operation rate for different involved arteries and the manifestation of vessel involvement of patients with Takayasu arteritis undergoing open or endovascular operations remain unclear. We aimed to investigate the clinical characteristics, vessel involvement, angiographic classification and operations information in a large cohort of patients with Takayasu arteritis undergoing open or endovascular operations at a single centre in China. From January 2017 to October 2022, a total of 153 consecutive patients undergoing open or endovascular operations were recruited from the Department of Vascular Surgery of Beijing Hospital. The demographic characteristics, clinical presentations, pattern of vascular involvement and operation information were collected and analysed. The majority of patients were female (128/153, 83.7%). The most common vascular finding was hypertension (66.7%). The subclavian (74.2%), carotid (70.1%) and renal (68.9%) arteries were the most commonly involved arteries. Type V (40.5%) was the most common angiographic classification pattern. A total of 296 open or endovascular operations were performed, including 73 percutaneous transluminal angioplasties (PTAs), 50 stent placements and 173 bypass graft operations. Patients with renal (83.3%) or carotid (65.2%) artery involvement had markedly higher rates of undergoing operations. The subclavian and carotid arteries, as well as the type V (40.5%) pattern, exhibited the highest frequency of involvement among patients with Takayasu arteritis who underwent open or endovascular operations. Variations in angiographic features can result in differences in clinical manifestations and significantly impact the possibility and modality of operations.

A single-center case study series assessing the effect of selumetinib use in patients with neurofibromatosis-related plexiform neurofibromas

Abstract Background Neurofibromatosis type 1 (NF1) is a common genetic disorder of phenotypic variability with age-dependent penetrance. This study describes the diagnosis, clinical characterization, management, and outcomes of a large patient cohort with plexiform neurofibroma (PN) treated with selumetinib in a real-world clinical setting. Methods This single-center observational study consecutively enrolled patients with NF1-PN treated with selumetinib from April 2018 to April 2023. Data on clinical features, tumor types and locations, and results from genetic tests were recorded at baseline; details of disease management with selumetinib and surgical intervention and disease evolution including imaging data and evaluations of pain and function were documented. Results Overall, 54 patients with a median age (range) of 16.4 (4.5–58.0) years were enrolled. Most had cutaneous manifestations (88.9%), including cutaneous neurofibromas and PN. Patients underwent [18F]fluorodeoxyglucose (FDG)-PET/CT imaging before treatment to rule out malignant lesions. Initial evaluations included directed MRI, which facilitated future comparisons and allowed for the assessment of PN resectability. Pharmacological treatment with selumetinib (with surgery, without surgery) resulted in the following proportion of patients achieving stable disease (58.8%, 54.3%), partial response (29.4%, 28.6%), and improved pain (58.8%, 37.1%), deformity (17.6%, 20.0%), and functional (17.6%, 20.0%) outcomes, respectively. Conclusions Results from this study demonstrate that NF1-PN can be managed effectively with selumetinib with surgical intervention in some patients. Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.