No evidence of disease activity-3 (NEDA-3) constitutes a crucial target for relapsing-remitting multiple sclerosis (RRMS). Long-term predictors of its attainment remain insufficiently characterized. This study aimed to assess the prevalence and the predictors of long-term NEDA-3 status in a large real-world RRMS cohort. This retrospective monocentric study analyzed RRMS patients strictly followed for up to six years. Treatment exposure was classified based on the efficacy of the first therapy in moderate (ME) and high efficacy (HE) disease modifying treatments (DMTs). Percentages of patients exposed to ME and HE DMTs reaching NEDA-3 were compared. Logistic regression models were applied to identify predictors of NEDA-3 achievement at 2 and 5 years. EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) were also analyzed in a small sub-cohort. 485 RRMS patients were included. Subjects starting treatment with HE DMTs were associated with significantly higher rates of NEDA-3 across all time-points. Significant risk factors for not achieving NEDA-3 included multifocal onset, delayed treatment initiation and spinal cord lesions. Conversely, treatment initiation with HE DMT was a significant protective factor for NEDA-3 status achievement at 2 and 5 years of follow-up. Early initiation of HE DMTs significantly improves long-term control of disease activity. Multifocal onset, delayed treatment initiation, presence of spinal cord lesions and oligoclonal bands were identified as risk factors of not achieving NEDA-3 status.

BackgroundSecondary progressive multiple sclerosis (SPMS) encompasses heterogeneous phenotypes that may or may not exhibit disease activity.ObjectivesTo characterize a cohort of non-relapsing SPMS (nrSPMS) identified through a data-driven definition adapted from the HERCULES trial criteria, compared with neurologist-defined (ND) SPMS.MethodsRelapsing MS patients were retrospectively extracted from the Italian Multiple Sclerosis Register (RISM). ND was defined according to clinical criteria for SPMS and the HERCULES cohort adapting the trial inclusion criteria. Progression independent from relapse activity (PIRA) and relapse-associated worsening (RAW) events were assessed. Diagnostic performances of SPMS definitions were evaluated.ResultsAmong 20,306 patients, 866 (4.26%) were classified as SPMS by ND and 1603 (7.89%) by HERCULES criteria. The HERCULES group included older patients, less likely to relapse post-conversion. PIRA occurred in 88.8% of ND and 88.5% of HERCULES-defined cases, with a shorter median time to first PIRA in the latter. The HERCULES definition showed high specificity (93.4%) and low sensitivity (37.6%).ConclusionsHERCULES-adapted criteria identified a subgroup of 7.9% nrSPMS patients in the real-world cohort of RISM, characterized by fewer post-conversion relapses and earlier PIRA onset. These findings reinforce the value of applying standardized algorithmic definitions of SPMS in registry-based studies.

OBJECTIVE:To evaluate the long-term impact of early intensive treatment (EIT) versus escalation (ESC) strategies using high-efficacy disease-modifying therapies (HE-DMTs) on disability progression in relapsing multiple sclerosis (RMS). METHODS:This observational study included 4878 RMS patients from the Italian Multiple Sclerosis Register. Eligible participants initiated their first disease-modifying therapy (DMT) within 3 years of disease onset and had ≥ 5 years of follow-up with at least three Expanded Disability Status Scale (EDSS) evaluations. Patients were categorized into the EIT group if they started with HE-DMTs and into the ESC group if HE-DMTs were initiated after ≥ 1 year of moderate-efficacy therapy. Propensity score matching was performed to balance baseline characteristics. Outcomes included disability trajectories assessed using linear mixed models for repeated measures and risks of confirmed disability accrual (CDA), progression independent of relapse activity (PIRA), and relapse-associated worsening (RAW) evaluated using Cox proportional hazards models. RESULTS:Post-matching analysis of 908 pairs revealed significantly slower disability progression in the EIT group compared to the ESC group. At 10 years, the delta-EDSS difference between groups was -0.63 (95% CI: -0.83 to -0.43; p < 0.0001). ESC was associated with higher risks of CDA (HR 1.36, 95% CI: 1.20-1.54; p < 0.0001), PIRA (HR 1.22, 95% CI: 1.05-1.40; p = 0.0074), and RAW (HR 1.55, 95% CI: 1.17-2.05; p = 0.0021). INTERPRETATION:EIT significantly reduces long-term disability progression in RMS compared to ESC. These findings underscore the potential of EIT to optimize long-term outcomes in RMS patients.

Importance: Large multiple sclerosis (MS) registries provide crucial real-world evidence but often suffer from missing data, inconsistencies, and privacy limitations that restrict data sharing. The use of generative AI to create synthetic data (SD) is an emerging strategy to enhance real-world evidence research potentially overcoming these challenges. Objective: To evaluate the validity of AI-generated synthetic data (SD) in replicating real data collected in the Italian MS and Related Disorders Register (RISM), and to compare the risk of progression independent of relapse activity (PIRA) between early intensive treatment (EIT) versus escalation treatment strategy (ESC) in both real and synthetic MS cohorts. Design, Setting, and Participants: This validation study analyzed data from RISM. AI based generative models were trained on a subcohort of 1,666 patients with tabularized MRI data to generate a synthetic dataset of 4,878 patients. SD was evaluated using the Synthetic vAlidation FramEwork powered by Train (SAFE), assessing fidelity, utility, and privacy. Clinical Synthetic Fidelity (CSF) and Nearest Neighbor Distance Ratio (NNDR) were used for statistical and privacy validation. Treatment outcome comparisons between EIT and ESC strategies were conducted for clinical validation using both real and synthetic datasets, focusing on the risk of PIRA. Results: The synthetic dataset demonstrated high fidelity (CSF=97%) and privacy preservation (NNDR=0.61). Treatment effect estimates for ESCs vs EIT were consistent across real and synthetic datasets, with largely comparable trends, with increased statistical significance in SD. Cox proportional hazards models confirmed the robustness of synthetic data in estimating the risk of the first PIRA event. Conclusions and Relevance: AI-generated synthetic data reliably replicated treatment effect outcomes from real world RISM data, overcoming missing data and providing a privacy preserving alternative for data sharing and clinical research. ### Competing Interest Statement The authors report no conflicts of interest with respect to the contents of the current study, but note that the patients in the study were treated with a number of disease-modifying drugs and that authors have received advisory board, membership, speakers honoraria, travel support, research grants, consulting fees, or clinical trial support from the manufacturers of those drugs, including Actelion, Allergan, Almirall, Alexion, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Forward Pharma, Ipsen, Medday, Merck, Mylan, Novartis, Sanofi, Roche, Teva, and their local affiliates. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethical Committee of the Azienda Ospedaliero Universitaria Policlinico of Bari (Study REGISTRO SM001, approved on 8 July 2016) gave ethical approval for RISM studies. RISM study was also approved by this EC and by local ethics committees in all participating centers. Patients signed an informed consent allowing the collection and use of their clinical data for research purposes. The Scientific Committee of the Italian Multiple Sclerosis and Related Disorders Register approved this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data will be available upon reasonable request to the authors of a qualified investigator.

Extended follow-up data from real-world cohorts of patients with multiple sclerosis treated with ocrelizumab (OCR) are becoming widely available. This monocentric retrospective study aimed to evaluate the long-term effectiveness of OCR and its impact on immunoglobulin (Ig) levels, lymphocyte subsets, and infections in a cohort of patients with relapsing remitting, primary progressive, and secondary progressive multiple sclerosis. Patients followed at the Multiple Sclerosis Center of Bari with ≥ 2 years of OCR treatment were retrospectively recruited in 2024. Twelve-month confirmed disability worsening, improvement, and the annualized relapse rate before and after treatment start were estimated and follow-up magnetic resonance imaging scans were collected. Changes in IgG/IgM/IgA levels from baseline for up to 6 years of OCR treatment and serum levels of T CD4+, T CD8+, and natural killer lymphocytes were assessed. Infection occurrence, type, and outcomes were investigated. Multivariable Cox models examined the association of clinical and radiological baseline factors with the risk of confirmed disability worsening and the relationship of infections with clinical-laboratoristic risk factors. The final cohort retrieved 140 patients (80 relapsing remitting, 37 primary progressive, 23 secondary progressive) with a median (interquartile range) follow-up after treatment start of 4.62 (4.10–5.04) years. In the entire cohort, the mean annualized relapse rate decreased from 0.61 in the year before the start of OCR treatment to 0.02 in the second year, thereafter all patients in our cohort remained free of relapses and magnetic resonance imaging activity. The overall percentage of stable patients increased from the second to the fourth year, in parallel with a reduction in patients with confirmed disability worsening. A multifocal onset and the presence of at least two relapses before the start of OCR treatment were significant (p < 0.05) risk factors of confirmed disability worsening. During the follow-up, a reduction in the IgG serum level was observed, which further decreased, becoming stable after the third year. Immunoglobulin M levels slightly decreased over time, whereas IgA levels remained stable. No changes for T CD4+, natural killer cell absolute number, and a slight reduction in T CD8+ lymphocytes during follow-up were observed. Ocrelizumab did not determine a significant infection risk in the long term and no association was observed with Ig levels and severe infections. Ocrelizumab prevented disease activity over the long term and its effect on the immune system did not determine a significant infection risk in most patients.

The prevalence of cognitive impairment (CI) in Multiple Sclerosis is between 40 and 65

Introduction The transition from fingolimod (FIN) to siponimod (SIP) for Multiple Sclerosis (MS) treatment in the occurrence of Secondary Progressive Multiple Sclerosis (SPMS) diagnosis has increasingly attracted considerable interest in the recent literature. Methods We evaluated the efficacy and safety of a direct switch from FIN to SIP in nine MS patients who had switched directly from FIN to SIP due to SPMS diagnosis at the Multiple Sclerosis Center of the University Hospital Policlinico of Bari. Results and Conclusion Real-world results from our cohort demonstrated that the direct switch from FIN to SIP in patients transitioning in SP course is associated with clinical and disability progression stability, with a favorable safety profile.

Cancer therapies have revolutionized patient survival rates, yet they come with the risk of cardiotoxicity, necessitating effective monitoring and management. The existing guidelines offer a limited empirical basis for practical approaches in various clinical scenarios. This article explores the intricate relationship between cancer therapy and the cardiovascular system, highlighting the role of advanced multimodality imaging in monitoring patients before, during, and after cancer treatment. This review outlines the cardiovascular effects of different cancer therapy classes, offering a comprehensive understanding of their dose- and time-dependent impacts. This paper delves into diverse imaging modalities such as echocardiography, cardiac magnetic resonance imaging, cardiac computed tomography, and nuclear imaging, detailing their strengths and limitations in various conditions due to cancer treatment, such as cardiac dysfunction, myocarditis, coronary artery disease, Takotsubo cardiomyopathy, pulmonary hypertension, arterial hypertension, valvular heart diseases, and heart failure with preserved ejection fraction. Moreover, it underscores the significance of long-term follow-up for cancer survivors and discusses future directions.

According to the ESMO and ASCO clinical guidelines, the main role of liquid biopsy in EGFR+ advanced NSCLC patients is represented by T790M detection after erlotinib/gefitinib/afatinib progression. However, the general international expert consensus regards osimertinib as the preferred upfront treatment in this setting; therefore, this role has been scaled back in recent years. As of today, liquid biopsy has no ASCO or ESMO recommendation following first-line osimertinib; in the same vein, no targeted therapy has received ASCO or ESMO recommendation following post upfront Osimertinib progression. However, this standard could change in the near future. Therefore, adopting a clinical point of view, this paper aims to provide a comprehensive review on the previous, the current and the possible future role of liquid biopsy in the framework of the diagnostic–therapeutic algorithm of EGFR+ advanced NSCLC.

Background: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value. Methods: We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen’s kappa (Cohen’s k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan–Mayer estimator was used to estimate survival distribution according to the bulbar scale scores. Results: The raters showed a substantial to excellent agreement with Cohen’s k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906–0.936). The survival distribution was statistically different across the three bulbar scale scores (χ2(2) = 9.50, p < 0.01). Conclusions: Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS.

Lung cancer is the leading cause of cancer-related death worldwide. Since prognosis of early-stage non-small cell lung cancer (NSCLC) remains dismal for common relapses after curative surgery, considerable efforts are currently focused on bringing immunotherapy into neoadjuvant and adjuvant settings. Previously, perioperative chemotherapy showed only a modest but significative improvement in overall survival. The presence of broad tumor neoantigens load at primary tumor prior to surgery as well as the known immunosuppressive status following resection represent the main rationale for immunotherapy in early disease. Several trials have been conducted in recent years, leading to atezolizumab and nivolumab approval in the adjuvant and neoadjuvant setting, respectively, and perioperative immunotherapy in NSCLC remains a field of active clinical and preclinical investigation. Unanswered questions in perioperative therapy in NSCLC include the optimal sequence and timing of chemotherapy and immunotherapy, the potential of combination strategies, the role of predictive biomarkers for patient selection and the choice of useful endpoints in clinical investigation.