Fatebenefratelli Hospital

Pancreatic and periampullary cancers are among the most challenging malignancies. Centralization of care and multidisciplinary management have been associated with improved outcomes. In 2024,the Italian Ministry of Health established a national Steering Committee with the objective of defining a centralized model for the management of pancreatic and periampullary diseases and identifying the minimum requirements for referral centers across Italy. The Steering Committee met every four weeks through plenary and focused working groups. Using data from the National Agency for Regional Health Services and the National Outcome Program, all ICD-9 codes related to pancreatic, periampullary, and distal biliary diseases were analyzed. Criteria were developed according to international recommendations and structured into a Hub-and-Spoke network model. Pancreas Units(Hub centers) were defined as hospitals providing 24/7 multidisciplinary expertise, advanced diagnostic and interventional capabilities, and a minimum surgical volume of ≥ 30 pancreatic resections per year with 90-day mortality < 10% (target < 5% within 3 years). Spoke centers were required to adhere to standardized diagnostic–therapeutic pathways and participate in multidisciplinary team meetings, without performing pancreatic surgery. Based on catchment area analyses, one Hub center per 700,000–1,200,000 inhabitants was recommended. Additional requirements included structured multidisciplinary processes, standardized diagnostic pathways, and integration with national research and training networks. This national model provides a comprehensive framework for centralizing pancreatic and periampullary diseases care. By defining minimum standards, enhancing multidisciplinary coordination, and concentrating complex procedures in high-performance centers, this initiative aims to improve outcomes, reduce regional disparities, and create a sustainable national Pancreas Unit network.

Despite continuous improvements in neonatal resuscitation and stabilization in the last decades, thermal management immediately after birth remains an unresolved issue in preterm infants. To compare 2 strategies of thermal management (plastic wrapping with or without drying) for preventing heat loss at birth in very preterm infants. This multicenter, unblinded, randomized clinical trial was conducted among very preterm infants (birth weight <1500 g and/or gestational age ≤30 weeks 6 days) at 21 tertiary care hospitals in Italy from February 21, 2023, to July 18, 2024. Eligible neonates were randomly allocated to either drying before plastic wrapping in the delivery room (intervention arm) or plastic wrapping without drying (control arm). The primary outcome was the proportion of participants with normothermia (36.5-37.5 °C) at admission to the neonatal intensive care unit (NICU). The secondary outcomes included hypothermia (<36.5 °C), moderate to severe hypothermia (<36.0 °C), and hyperthermia (>37.5 °C) at NICU admission, temperature at 1 hour after NICU admission, intraventricular hemorrhage, respiratory distress syndrome, late-onset sepsis, bronchopulmonary dysplasia, and mortality before hospital discharge. Overall, 354 very preterm infants were randomized (180 [50.8%] female; mean [SD] gestational age, 28.6 [2.5] weeks); all received the allocated intervention and were included in the analysis. Normothermia at NICU admission was achieved in 81 of 177 dried infants (45.8%) and 82 of 177 undried infants (46.3%; risk ratio, 0.99; 95% CI, 0.79-1.24). The mean (SD) neonatal temperature at NICU admission was 36.4 °C (0.8 °C) in dried neonates and 36.5 °C (0.7 °C) in undried neonates (mean difference, -0.1 °C; 95% CI, -0.2 °C to 0.1 °C). In-hospital mortality included 26 of 177 dried neonates (14.7%) and 10 of 177 undried neonates (5.6%) (unadjusted risk ratio, 2.60; 95% CI, 1.29-5.23). The other secondary outcome measures were not different between the 2 arms. In this multicenter randomized clinical trial, drying before plastic wrapping provided no benefit to very preterm infants in maintaining normothermia at NICU admission. Most deaths could be expected due to the compromised profile of the neonates, with no pathophysiological explanation related to the trial interventions. Approximately half of the infants were outside the normal thermal range at NICU admission; hence, thermal management remains a challenge requiring further investigations. ClinicalTrials.gov Identifier: NCT05740072.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) relapse is the most frequent cause of allogeneic stem cell transplantation (allo-SCT) failure. The utility of post-relapse therapy is controversial due to the high incidence of toxicity and the low efficacy. This sub-analysis of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) AML/MDS relapse study focuses on 647 AML/MDS relapsing after allo-SCT performed between 2015 and 2021. Following the relapse, these patients were treated with either hypomethylating agents (HMAs)-based therapy (n = 308) or other treatments (n = 339), including intensive chemotherapy, FLT3-inhibitors, and second allo-SCT. HMAs-based therapies were more frequently used in older patients, transplanted not in CR following a reduced-intensity conditioning regimen. The overall response rate (ORR) with or without HMA-based salvage treatment was 33% and 40%, respectively (P = .006). The complete remission (CR) rate was 23% and 33% in the two groups, respectively (P < .001). The long-term OS and TRM of the two groups were superimposable. Independently from the type of salvage, an advantage in OS was observed when donor lymphocytes infusion (DLI) was included (P < .001). Relapse within 12 months after SCT, low disease burden at relapse, and the CR status at transplant confirmed their independent strong prognostic impact on both HMA and non-HMA-based group (HR 0.05, 0.44, and 0.49 and HR 0.19, 0.32, and 0.53, respectively). Despite the lower ORR observed with HMA-based therapy, the long-term OS was comparable to that observed with other therapies. The immune control of the disease relapse with DLI is of benefit, independently from the salvage therapy. .

Siponimod, a selective sphingosine-1-phosphate receptor modulator was approved for patients with Secondary progressive Multiple Sclerosis (SPMS) with ongoing disease activity. However, its real-world positioning and management after discontinuation remain challenging. To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management. A retrospective, multicenter study on patients treated with siponimod across six Italian MS centers. Demographics, prior disease modifying therapy (DMTs), reasons for discontinuation, adverse events, and subsequent therapies were collected. Statistical analyses included propensity-adjusted Cox model. A total cohort of 188 patients (63.8% female, median age 52 years) was enrolled, out of them 76(40.4%) discontinued siponimod, with a median treatment duration of 26 months. The main reason for discontinuation was safety concerns (72.4%), particularly persistent lymphopenia (43.6%) and recurrent infections (27.3%). Disease activity accounted for 27.6% of discontinuations. No significant demographic or clinical predictors of discontinuation were identified. After discontinuation, 49 patients (64%) started a new DMT, most commonly ocrelizumab (n = 22) or cladribine (n = 15), while 25 (32.9%) received no further therapy. High discontinuation rates, mainly due to safety, and frequent post-treatment gaps highlight the need for improved, individualized management strategies for SPMS after siponimod.

The management of chronic lymphocytic leukemia (CLL) in older patients requires careful balancing of therapeutic efficacy with the risks of treatment intolerance. Frailty assessment is increasingly recognized as a critical determinant of clinical outcomes, but its specific role in guiding therapy with second-generation Bruton tyrosine kinase inhibitors remains poorly defined. We conducted a prospective, multicenter investigation of 326 consecutive CLL patients aged 65years or older who received zanubrutinib across 52 Italian centers, aiming to evaluate whether the Clinical Frailty Scale (CFS) could predict treatment discontinuation in real-world practice. The cohort was characterized by advanced age (median 78.1years, range 65.1-94.5), with over half of the patients presenting with Binet stage C disease. Two-thirds were treated in the frontline setting, while the remainder received zanubrutinib as salvage therapy. After a median follow-up of 8 months, 48 patients (14.7%) discontinued treatment, most commonly due to toxicity or disease progression. Receiver operating characteristic curve analysis identified a CFS of 3 as the optimal threshold for predicting discontinuation, with an area under the curve of 0.65 (95% CI 0.56-0.73, p<0.001). At 12months, the discontinuation rate was significantly higher among patients with a CFS >3 (29.2%) compared with those with a CFS ≤3 (8.8%) (p<0.001); among conventional prognostic variables, only relapsed/refractory disease demonstrated an independent association with TTD. These findings highlight the CFS as a simple yet powerful clinical tool that provides incremental prognostic information beyond standard disease-related factors. Incorporating frailty assessment into treatment planning may enhance patient selection and optimize therapeutic strategies for elderly CLL patients in daily practice.

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound (CEUS) has significantly improved the characterization of nodules first identified on conventional US. Yet, when CEUS is performed using sulfur hexafluoride (SonoVue)-the only contrast agent available in Western countries-assessment remains restricted to a single nodule per examination, and enhanced CT or MRI is still required for full characterization and staging. In clinical settings, such as hepatology, internal medicine, infectious diseases, and surgery, CEUS offers the advantage of immediate availability, enabling rapid characterization of suspicious nodules in cirrhotic livers and facilitating timely therapeutic decisions. Although the introduction of direct-acting antivirals (DAAs) has substantially reduced HCV-related HCC, HCC incidence is increasingly driven by metabolic dysfunction-associated steatohepatitis (MASH). Evidence on surveillance strategies for MASH patients remains limited, and current EASL guidelines recommend monitoring only patients with >F2 fibrosis. Additionally, the effectiveness of US in obese or diabetic/obese populations is under ongoing investigation; abbreviated non-contrast MRI has been proposed as an alternative surveillance tool, but its adoption would entail significant economic implications for healthcare systems. HCC arising from MASH-sometimes even without cirrhosis-exhibits different sonographic and pathological features. Instead of small, hypoechoic nodules, typically seen in HCV-related cirrhosis, clinicians increasingly encounter larger or multiple lesions, often accompanied by macrovascular invasion, limiting access to curative treatments. Furthermore, typical CEUS LI-RADS patterns are less frequently observed. This review summarizes the evolving US findings in the era of MASH-related HCC and underscores the continued importance of US as the primary imaging tool in routine clinical practice.

Bloodstream infections (BSIs) are serious conditions caused by the presence of microorganisms in the blood. Although blood culture remains the diagnostic gold standard, it is time-consuming. Neutrophil activation plays a central role in the early immune response to infection and can be quantified using the Neutrophil-Reactive Intensity (NEUT-RI) parameter, derived from hematological analyzer using the fluorescence flow cytometry technology. The purpose of this study is to evaluate NEUT-RI as an early marker of BSI and compare its diagnostic performance with standard infection biomarkers. We conducted a retrospective study involving 120 inpatients with documented BSI. Each inpatient underwent blood testing for PCT (Procalcitonin), serum CRP (C-Reactive Protein), WBCs (White Blood Cells), neutrophil absolute count within 12h prior to blood culture sampling. NEUT-RI values were retrieved from the complete blood count. A control group of 52 inpatients with negative blood cultures was also analyzed. Median NEUT-RI was significantly higher in BSI patients than in controls (53.43 FI vs 48.65 FI; p < 0.001). ROC (Receiver Operating Characteristic) curve analysis showed an AUC (Area Under the Curve) of 0.785 for NEUT-RI, with 72.5% sensitivity and 76.9% specificity at a cut-off of 50.7 FI. Only Procalcitonin (AUC 0.882) outperformed NEUT-RI (p = 0.01). Our findings suggest that NEUT-RI increases in the early stages of bacteremia and may serve as a useful early indicator of bloodstream infection. NEUT-RI could be integrated into multi-parametric diagnostic algorithms to improve early detection of BSIs. Further studies are warranted to validate these preliminary results.

ABSTRACTAging is a key driver of cardiac dysfunction, promoting structural remodeling, metabolic alterations, and loss of cellular resilience. In aged hearts, extracellular matrix remodeling and collagen accumulation reduce ventricular compliance, impairing both diastolic function and stress adaptability. Cardiomyocytes exhibit diminished regenerative capacity and dysregulated stress responses, with mitochondrial dysfunction emerging as a central contributor to energy imbalance, oxidative stress, and fibrosis. Traditional single‐omics approaches are insufficient to capture the complexity of these interconnected changes. To address this, we employed an integrative multi‐omics strategy—combining spatial transcriptomics, proteomics, and metabo‐lipidomics with electron microscopy—to investigate cardiac aging in mice at three life stages: adult (12 months), middle‐aged (24 months), and elderly (30 months). Electron microscopy revealed enlarged, structurally compromised mitochondria. Spatial transcriptomics showed reduced expression of cardioprotective genes (MANF, CISH, and BNP) and increased expression of profibrotic markers like CTGF. Proteomics revealed widespread mitochondrial dysregulation and impaired ATP production. Metabolic and lipidomic profiling identified reduced antioxidant metabolites and accumulation of lipotoxic species, such as ceramides and diacylglycerols. This multiscale analysis highlights key molecular and metabolic alterations driving cardiac aging, identifying potential therapeutic targets to mitigate age‐related functional decline. Overall, our findings highlight the value of integrated, system‐level approaches for uncovering the complex mechanisms that drive organ aging. Although our study was conducted in mice, validation in human models will be crucial to establish the translational relevance of these results and to guide future research with potential impact across diverse biomedical fields.