Azienda Ospedaliera di Padova

Background and ObjectivesPatients with multiple sclerosis (MS) exhibit variability in disability progression and response to disease-modifying therapies (DMTs). Identifying those at greatest risk of disability worsening and most likely to benefit from high-efficacy DMTs remains challenging. We aimed to identify distinct disability worsening phenotypes, explore their mechanisms, and evaluate DMT impact across them.MethodsIn this multicenter cohort study, we analyzed clinical and MRI data from propensity-matched cohorts of treated and untreated patients with relapse-onset MS from the Italian MS Register. Inclusion criteria were as follows: ≥3 years of follow-up, ≤1 year between disease onset and first assessment, and complete clinical and baseline MRI data. Latent class mixture models were applied to Expanded Disability Status Scale (EDSS) scores from untreated patients to identify disability worsening phenotypes. We compared proportions of progression independent of relapse activity (PIRA) and relapse-associated worsening events across phenotypes. A random forest algorithm, trained (70%) and tested (30%) on baseline clinical and MRI features of untreated patients, was used to assign phenotypes to treated patients. Linear mixed-effects models estimated DMT impact on disability trajectories within each phenotype.ResultsWe analyzed data from 2,563 untreated (mean age 41.2 ± 10 years, 67% female) and 2,952 treated (mean age 40.8 ± 11.4 years, 66% female) patients with MS over a median follow-up of 10.1 (interquartile range: 7.0–13.0) years. Four phenotypes were identified in untreated patients: “minimal-worsening” (15%), “late-worsening” (70%), “early-worsening” (3%), and “rapid-worsening” (12%). In all phenotypes, PIRA represented the main disability accrual mechanism. “Early-worsening” and “rapid-worsening” phenotypes exhibited more brain and spinal cord T2-hyperintense and gadolinium-enhancing lesions at baseline. The classification algorithm assigned phenotypes to patients receiving DMTs with 71% accuracy: “minimal-worsening” (18%), “late-worsening” (61%), “early-worsening” (13%), and “rapid-worsening” (8%). DMT exposure significantly reduced disability accrual in all phenotypes, with high-efficacy DMTs (β = −0.16, standard error (SE) = 0.06, p < 0.001) and early escalation (β = −0.18, SE = 0.06, p < 0.001) proving especially beneficial for the “rapid-worsening” phenotype.DiscussionWe identified 4 clinically relevant disability worsening phenotypes in relapse-onset MS, primarily driven by PIRA, with greater CNS involvement linked to early and rapid progression. Despite reliance on EDSS alone, these phenotypes may inform personalized treatment and response assessment.

Background: Cardiac implantable electronic devices (CIEDs) are vital for managing arrhythmias but carry a notable risk of infection, which increases patient morbidity, mortality, and healthcare burden. This review examines current evidence on risk factors and preventive strategies for CIEDI. Methods: A structured search was performed in PubMed, Embase, and the Cochrane Library using terms such as “CIED,” “infection,” “pacemaker,” “ICD,” “infection prevention,” “biofilm,” “antibiotic prophylaxis,” and “antibiotic-eluting envelope.” Study selection followed PRISMA guidelines. Results: For well-established topics, recommendations are based on high-quality evidence from the literature. In areas with limited CIED-specific data, evidence from related surgical fields was considered, and expert consensus was used to guide recommendations. Conclusions: This review offers practical guidance for clinicians on CIED infection prevention, addressing gaps not previously covered in existing guidelines.

Mesothelioma of the tunica vaginalis testis (MTVT) is an exceedingly rare tumor. We performed a registry-based study on MTVT patient management and survival in Italy. Cases were extracted from the dataset of the Italian National Mesothelioma Registry. A descriptive analysis of patient characteristics, including asbestos exposure, clinical presentation, diagnostic work-up and therapeutic management, was performed. Overall survival was evaluated. We calculated hazard ratios (HR) and 95% confidence intervals (CI) for selected variables by fitting univariate and multivariable Cox models. Overall, 104 patients with MTVT were included. Median age was 72 years (range 17-92). Epithelioid histotype was the most frequent. Previous asbestos exposure was identified in two thirds of cases. Data on diagnostic and therapeutic management were available for 74 patients (71%). The most frequent presentations were scrotal swelling/mass, hydrocele and inguinal pain. All patients underwent surgery, mostly with orchi-funicolectomy. Adjuvant therapy was administered to 15 patients (20%). Overall median survival was 26.2 months (95% CI 22.1-52.1); 3-, 5- and 10-year survival was 49%, 30% and 18%. Older age at diagnosis and presence of distant metastasis (HR 1.91, CI: 0.85-4.26) were negative prognostic factors. Adjuvant therapy was associated with higher mortality (HR 2.54, CI: 1.25-5.15), indicating a more advanced stage at diagnosis. Surgery remains the mainstay of treatment for MTVT; adjuvant therapy in our study did not improve outcome. Data from cancer registries are essential for rare cancers, but they should be integrated routinely with additional diagnostic and therapeutic information.

We report the case of a 61-year-old patient with relapsing–remitting multiple sclerosis (RRMS) who developed asymptomatic macular edema (ME) after initiation of ozanimod, a sphingosine-1-phosphate receptor (S1PR) modulator. The patient had a history of completely resolved central serous choroidopathy (CSC) in the right eye. Following a recent clinical worsening and a new brain lesion, ozanimod was started after appropriate screening, including ophthalmological evaluation. Three months into treatment, an OCT performed as part of routine monitoring revealed ME in the contralateral (left) eye, despite the absence of visual symptoms. Ozanimod was discontinued, and ME progressively resolved over the subsequent 2 months. This case underscores the importance of ophthalmological monitoring even in asymptomatic patients, especially those with known risk factors such as prior retinal pathology. ME is a rare but recognized adverse event associated with all approved -imod therapies for MS, including ozanimod. Although the exact pathophysiology remains unclear, involvement of the inner blood–retina barrier via S1PR1 internalization has been hypothesized. Given ozanimod’s long half-life and active metabolites, ME resolution may be delayed after drug withdrawal. This report highlights the relevance of interdisciplinary management and the utility of OCT in early detection of asymptomatic ocular adverse events during S1PR modulator therapy.

To date, ESR1 activating mutations acts as key player to clinically stratify estrogen receptor (ER)+/HER2-advanced breast cancer (BC) patients eligible to novel new generation oral Selective Estrogen Receptor Degraders (SERD) relapsing after first line aromatase inhibitors. Liquid biopsy represents the most useful biological source to detect ESR1 activating mutations in clinical setting, but the lack of standardized pre-analytical and analytical procedures drastically impacts on detection rate of ESR1 mutations in diagnostic specimens. Here, we sought to harmonize technical procedures comparing technical performance of diagnostically available testing strategies on a series of three reference specimens (sample A, B, C) harboring ESR1 p.D538G mutation at different mutant allele fraction (MAF) (5.0%, 1.0%, 0.5%) shared with n=10 Italian referral institutions. A total of 10μl of gDNA from each reference sample built to mimic clinically detectable ESR1 molecular alteration (5.0%, 1.0%, 0.5% VAF) was shipped by coordinator institution to each participating group to test p.D538G ESR1 alteration leveraging own routinely available testing strategy. Artificial reference sample was previously validated by the University of Naples Federico II before arranging the shipment. ESR1 exon 10 p.(D538G) hotspot mutation was successfully identified in 90.0% of samples A, B whereas 8 out of 10 (80.0%) participating institutions detected sample referenced alteration in sample C. No statistically significant variations were observed between dPCR and NGS based workflows in terms of detectability rate on standard reference samples. A single participating institution (ID#5) failed to detect p.(D538G) ESR1 alteration but supervised procedures by coordinator institution enabled to detect referenced mutation in engineered reference samples set adopting an orthogonal technology (dPCR). In addition, NGS and dPCR platforms displayed a similar technical performance in detecting ESR1 across samples A-C. NGS and dPCR systems may be considered valid technical solutions to target low frequency ESR1 alterations in diagnostic routine samples. Harmonized ring trials are key weapons to standardize analytical and post-analytical procedures optimizing clinical stratification of BC patients.