Azienda Ospedaliero-Universitaria Policlinico - Vittorio Emanuele

Psoriasis is a chronic inflammatory skin disease associated with significant physical and psychological burden. Tildrakizumab, an interleukin-23 p19 inhibitor, has demonstrated efficacy in treating moderate-to-severe plaque psoriasis both in clinical trials and real-world setting. However, limited data are available on the impact of the effective treatment of psoriasis on the psychological health of patients. The aim of this study was to assess changes in psychological well-being, as well as clinical and quality-of-life outcomes, in patients with moderate-to-severe plaque psoriasis treated with tildrakizumab in routine clinical practice in Italy. This was an interim analysis (IA) of a 52-week multicenter, prospective, observational study. Adults with moderate-to-severe plaque psoriasis initiating tildrakizumab were enrolled. Endpoints focused on well-being and psychological health and included changes, from baseline to week28, in Depression, Anxiety, and Stress Scale-21 (DASS-21) scores, Dermatology Life Quality Index (DLQI), European Social Survey (ESS) items, and World Health Organization-Five Well-Being Index (WHO-5). Effectiveness was also monitored via Psoriasis Area and Severity Index (PASI), and safety via treatment-emergent adverse event reporting. A total of 115 patients were included (mean age 52.5years, 60.8% male), 102 receiving ≥ 1 dose of tildrakizumab and completing DASS-21 evaluations at baseline and week28. At week28, improvements were observed in DASS-21 subscales [depression (-2.6, 95%CI -2.0 to -1.0), anxiety (-2.3, 95%CI -2.0 to -1.0), and stress (-3.4, 95%CI -4.0 to -2.0)], accompanied by marked PASI reduction (-13.7, 95%CI -12.8 to -10.1). DLQI, ESS, and WHO-5 scores also improved. Adverse events were generally mild or moderate, with no unexpected safety signals. In this real-world IA, tildrakizumab was observed to improve the psychological well-being of patients, reflected by a reduction in all items of the DASS-21 scale and, in parallel, confirmed its effectiveness in managing physical symptoms of psoriasis, establishing its role in the holistic management of psoriasis.

Identifying chronic myeloid leukaemia (CML) patients at risk of therapeutic switch remains debated. We analysed the cumulative risk of treatment change in the CML Italian network prospective cohort based on first-line tyrosine kinase inhibitors and patient characteristics. Sub-hazard ratios (sHRs) were estimated using Fine and Gray multivariable models. Among 1662 patients, initial treatment consisted of imatinib for 840 (50.5%), nilotinib for 490 (29.5%) and dasatinib for 332 (20.0%). Subsequently, 492 patients (29.6%) required second-line therapy, with 232 (47.1%) switching due to resistance and 176 (35.8%) due to intolerance. At 2 years, the risk of resistance was 18.3% for imatinib, 8.4% for dasatinib (sHR = 0.32; 95% confidence interval 0.21-0.49) and 6.8% for nilotinib (0.29; 0.19-0.42). The risk of switching increased in intermediate (1.95; 1.40-2.72) and high Eutos long term survival (ELTS) risk (3.19; 2.10-4.83) but was reduced with older age (0.97 per year; p < 0.0001). Intolerance at 2 years was 8.5% for imatinib, 12.4% for dasatinib (2.55; 1.73-3.75) and 5.2% for nilotinib (1.04; 0.65-1.65). Switching to a third-line therapy at 3 years was 8% for imatinib, 5% for dasatinib and 4% for nilotinib. The results showed that the time to first treatment switch for resistance is shorter for younger patients, for imatinib and for intermediate/high ELTS risks. The risk of switching for intolerance is higher for patients initially treated with dasatinib.

IntroductionIn the phase 3 EVOKE-01 trial (NCT05089734), sacituzumab govitecan (SG) exhibited a numerical improvement in overall survival and tolerability compared with docetaxel in patients with metastatic NSCLC previously treated with platinum-based chemotherapy and programmed cell death protein (ligand) 1 inhibitors, although results were not statistically significant. This analysis evaluated health-related quality of life (HRQoL) data from EVOKE-01.MethodsPatients (N = 603) were randomized 1:1 to SG (n = 299) or docetaxel (n = 304) in 21-day cycles. HRQoL was assessed by the NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ), European Organization for Research and Treatment of Cancer Quality of Life questionnaire–Core 30 (QLQ-C30), and EuroQol 5 Dimension 3-level questionnaire. Least square mean changes from baseline at week 25, time to first meaningful deterioration or death, and time to confirmed deterioration were analyzed.ResultsSG exhibited significantly and meaningfully better effects than docetaxel on NSCLC-SAQ shortness of breath (SoB), fatigue, total score, and on QLQ-C30 role functioning, fatigue, and dyspnea. Time to first meaningful deterioration or death favored SG over docetaxel for NSCLC-SAQ SoB (hazard ratio [95% confidence interval ]: 0.75 [0.61–0.91]), fatigue (0.70 [0.57–0.86]), and total score (0.80 [0.66–0.97]); QLQ-C30 fatigue (0.80 [0.66–0.96]) and dyspnea (0.74 [0.60–0.90]); and EuroQol visual analog scale (0.79 [0.65–0.96]). The time to confirmed deterioration favored SG over docetaxel for NSCLC-SAQ SoB (0.59 [0.44–0.77]) and fatigue (0.70 [0.52–0.95]), and QLQ-C30 fatigue (0.75 [0.59–0.95]).ConclusionsThese exploratory results suggest that SG may benefit HRQoL over docetaxel, supporting SG as an active therapeutic agent for metastatic NSCLC post platinum-based and programmed cell death protein (ligand) 1 inhibitor therapy.

WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins). Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)-assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR). Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance (P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%). Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.

Background: Neonatal seizures are critical neurological events with long-term implications for brain development. Standard antiseizure medications, such as phenobarbital, often yield suboptimal seizure control and may be associated with neurotoxicity. This narrative review explores the role of vitamin B6 as a precision therapy in neonatal seizure syndromes, particularly in pyridoxine-responsive conditions. Methods: We conducted a narrative review of the biochemical functions of vitamin B6, focusing on its active form, pyridoxal 5′-phosphate (PLP), and its role as a coenzyme in neurotransmitter synthesis. We examined the genetic and metabolic disorders linked to vitamin B6 deficiency, such as mutations in pyridox(am)ine 5’-phosphate oxidase (PNPO), Aldehyde Dehydrogenase 7 Family Member A1 (ALDH7A1), alkaline locus phosphatase (ALPL), and cystathionine β-synthase (CBS), and discussed the clinical rationale for empirical administration in acute neonatal seizure settings. Results: Vitamin B6 is essential for the synthesis of gamma-aminobutyric acid (GABA), dopamine, and serotonin, with PLP-dependent enzymes such as glutamic acid decarboxylase and aromatic L-amino acid decarboxylase playing central roles. Deficiencies in PLP due to genetic mutations or metabolic disruptions can result in treatment-resistant neonatal seizures. Early supplementation, especially in suspected vitamin B6-dependent epilepsies, may provide both diagnostic clarity and seizure control, potentially reducing exposure to conventional antiseizure medications. Conclusions: Vitamin B6-responsive epilepsies highlight the clinical value of mechanism-based, individualized treatment approaches in neonatology. Incorporating genetic and metabolic screening into seizure management may improve outcomes and aligns with the principles of precision medicine.

Efforts to enhance risk stratification in patients with coronary artery disease have driven the pursuit of early detection of rupture-prone plaques-before destabilization and the onset of life-threatening thrombosis-giving rise to the concept of the vulnerable plaque (VP). Invasive diagnostic modalities closely mirror histology and provide instrumental information on VP hallmarks and their prognostic significance. However, limited positive predictive value and invasive nature restrict their use for systematic screening. Noninvasive techniques offer broader application potential, but their specificity and resolution remain inferior to those of invasive techniques. A deeper understanding of the complex interplay between traditional ischemic risk factors, anatomic settings, rheological effects and systemic influences contributing to plaque evolution and rupture has refined our approach to identifying and managing VPs. Systemic therapies have been shown to counteract plaque progression and stabilize VPs by thickening the fibrous cap, decreasing atheroma and necrotic core volumes, and reducing inflammation. In parallel, the hypothesis of sealing and passivating VPs by intravascular imaging-guided preventive stenting is gaining support after the promising results of clinical trials and substantial advances in contemporary device performance and biocompatibility. Upcoming evidence will be instrumental in defining the net benefit of novel diagnostic tools and therapeutic strategies for VPs.

The World Health Organization (WHO) ranks tuberculosis (TB) as one of the top 10 causes of deaths worldwide. Notably, tobacco smoking represents a significant promoting factor in TB progression, being associated with poorer treatment outcomes, delayed conversion to negative smear or culture, and higher dropout rates from treatment plans. Remarkably, high rates of smoking and TB frequently overlaps in the same countries, warranting the need for targeted public health interventions. Prioritising smoking cessation is essential for smokers with TB, as sustained abstinence has been associated with reduced mortality and a more successful cure. This review examines the intricate relationship between cigarette smoking, smoking cessation therapies and anti-TB drugs, focusing on the impact of tobacco smoking compounds on liver detoxifying systems, such as influence of polycyclic aromatic hydrocarbons (PAHs) on hepatic cytochrome P450 (CYP450) enzymes mostly, and on metabolism of antituberculous medications. Integrating smoking cessation and TB treatment programmes must also take into account potential drug-drug interactions between smoking cessation medications and anti-TB drugs, a critical area for patient safety and effective TB management. This review article aims to provide healthcare professionals with the knowledge to better support TB patients who smoke or are intending to quit, to ensure tailored and effective treatment strategies, while highlighting gaps in current research and advocating for further studies to fill these gaps.

Background and Objectives: Mitral valve transcatheter edge-to-edge repair (TEER) is a widely adopted therapeutic approach for managing significant mitral regurgitation (MR) in high-risk surgical candidates. While procedural safety and efficacy have been demonstrated, the impact of institutional expertise on outcomes remains unclear. We aimed at evaluating whether the institutional monthly volume of TEER influences short- and long-term clinical results. Materials and Methods: This analysis from the multicenter, prospective GIOTTO trial study evaluated the impact of institutional monthly volume on outcomes of TEER to remedy significant mitral regurgitation. Centers were stratified into tertiles based on monthly volumes (≤2.0 cases/month, 2.1-3.5 cases/month, >3.5 cases/month), and key clinical, echocardiographic, and procedural outcomes were analyzed. Statistical analysis was based on standard bivariate tests as well as unadjusted and multivariable adjusted Cox models. Results: A total of 2213 patients were included, stratified into tertiles based on institutional procedural volume: 645 (29.1%) patients in the first tertile, 947 (42.8%) patients in the second tertile, and 621 (28.1%) patients in the third tertile. Several baseline differences were found, with some features disfavoring less busy centers (e.g., functional class and surgical risk, both p < 0.05), and others suggesting a worse risk profile in those treated in busier institutions (e.g., frailty and history of prior mitral valve intervention, both p < 0.05). Procedural success rates were higher in busier centers (p < 0.001), and hospital stay was also shorter there (p < 0.001). Long-term follow-up (median 14 months) suggested worse outcomes in patients treated in less busy centers at unadjusted analysis (e.g., p = 0.018 for death, p = 0.015 for cardiac death, p = 0.014 for death or hospitalization for heart failure, p < 0.001 for cardiac death or hospitalization for heart failure), even if these associations proved no longer significant after multivariable adjustment, except for cardiac death or hospitalization for heart failure, which appeared significantly less common in the busiest centers (p < 0.05). Similar trends were observed when focusing on tertiles of overall center volume and when comparing for each center the first 50 cases with the following ones. Conclusions: High institutional monthly volume of TEER mitral valve repair appears to correlate with an improved procedural success rate and shorter hospitalizations. Similarly favorable results were found for long-term rates of cardiac death or hospitalization for heart failure. These findings inform on the importance of operator experience and center expertise in achieving state-of-the-art results with TEER, while confirming the usefulness of the proctoring approach when naïve centers begin a TEER program.