IRIS UniSR (’Università Vita-Salute San Raffaele)
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Natural history outcome of moderate tricuspid regurgitation with preserved left-ventricular ejection fraction
No full textBackground: The long-term natural history of moderate tricuspid regurgitation (TR) patients with preserved left-ventricular ejection fraction (LVEF) and without severe left-sided valvular heart disease (VHD) remains ambiguous. We aimed to assess the outcomes of patients with moderate TR, preserved LVEF and without concomitant severe left-sided VHD. Methods: We evaluated patients diagnosed with moderate TR in our centers between 2012 and 2020. The primary outcome was all-cause death, the secondary outcome was the composite of all-cause death+heart failure (HF) hospitalization, also accounting for pulmonary artery systolic pressure (PASP) values and concomitant moderate left-sided VHD. Results: Among 1198 moderate TR patients, 53 % had New York Heart Association class ≥II and mean LVEF was 58 ± 5 %. After a median follow-up of 2.9 years, 3-year survival was 69 % (95 % confidence interval [CI]: 66 %-72 %), significantly worse than an age- and gender-matched population (p < 0.001), and 3-year survival free from the secondary composite outcome was 63 % (95 % CI: 60-67 %). At secondary analysis, increasing PASP values were associated with worse adjusted prognosis, and in patients with PASP <35 mmHg 3-year survival free from the primary and secondary outcome was 85 % (95 % CI: 80 %-89 %) and 80 % (95 % CI: 75 %-86 %), respectively. Finally, among patients with concomitant moderate left-sided VHD groups, the group with moderate aortic stenosis+moderate TR presented the worst adjusted prognosis, and patients with isolated moderate TR had a yearly mortality of 8.9 % (95 % CI: 6.0 %-11.0 %). Conclusions: Our cohort of moderate TR patients, despite having preserved LVEF and no concomitant severe left-sided VHD, presented significant risk of death and of HF hospitalization
Preoperative predictors of new-onset diabetes mellitus following distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors
No full textBackground: Nonfunctioning pancreatic neuroendocrine tumors are typically indolent neoplasms with a rising incidence. Distal pancreatectomy remains the standard treatment for localized tumors in the pancreatic body/tail. Given the favorable long-term prognosis, accurate assessment of postoperative morbidity, particularly postoperative new-onset diabetes mellitus, is critical. Aims of the study were to identify preoperative predictors of postoperative new-onset diabetes mellitus in patients who underwent distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors and to develop a predictive model for individualized risk assessment. Methods: Consecutive patients who underwent curative distal pancreatectomy for localized nonfunctioning pancreatic neuroendocrine tumors at San Raffaele Hospital between 2015 and 2022 were included. Exclusion criteria included pre-existing diabetes and follow-up <24 months. Clinical and radiological data were evaluated. Results: After a median follow-up of 58 months, 27 of 65 patients (41%) developed postoperative newonset diabetes mellitus. Postoperative new-onset diabetes mellitus was significantly associated with elevated body mass index (P = .016), pancreatic atrophy (P = .044), increased total (P =.014) and visceral fat area (P = .021), and a higher proportion of pancreatic parenchyma distal to the tumor (P = .046). On Cox regression, higher body mass index (hazard ratio: 1.187; P = .001), elevated hemoglobin A1c (hazard ratio: 1.169; P = .001), and distal higher proportion of pancreatic parenchyma (hazard ratio: 1.030; P = .018) were identified as significant risk factors of postoperative new-onset diabetes mellitus. A nomogram and online risk calculator (https://net-distal-pancreatectomy.shinyapps.io/postoperativediabetes-risk-calculator/) were developed to predict individual risk at 1, 3, and 5 years, with good discriminatory performance (area under the curve: 0.766; P < .001). Conclusion: Postoperative new-onset diabetes mellitus occurred in 41% of patients who underwent distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors. Elevated preoperative body mass index, hemoglobin A1c levels, and proportion of distal higher pancreatic parenchyma emerged as significant risk factors of postoperative new-onset diabetes mellitus. The developed nomogram and web-based calculator may support preoperative counseling and guide tailored prehabilitation or parenchyma-sparing strategies in high-risk patients. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies
Preoperative prediction of metastatic body-tail peripancreatic lymph nodes as a guide for surgical decision-making in pancreatic neck ductal adenocarcinoma
No full textThe oncologically appropriate surgery for neck pancreatic ductal adenocarcinoma (PDAC) remains challenging due to the absence of standardized criteria. This study aims to preoperatively identify patients with neck PDAC at high risk of metastatic body-tail peripancreatic lymph nodes (BT-PLNs). This retrospective cohort study included adult patients undergoing resection for neck PDAC at San Raffaele Hospital (Milan, Italy). Patients with metastatic BT-PLNs were identified from histopathological records. Age, preoperative tumor size, preoperative Ca19.9, radiological response to neoadjuvant chemotherapy (NAT), resectability at diagnosis, and tumor site (distance in millimeters from the superior mesenteric vein and the point where the Wirsung duct starts dilating [W-SMV] on preoperative CT scan) were evaluated as potential predictors of metastatic BT-PLNs. Predictors were selected using multiple logistic regression with stepwise backward selection and then included in a predictive model to identify patients at high risk of metastatic BT-PLNs (online calculator: www.pancreaticneck.altervista.org). A total of 143 patients were included (67 years [IQR 59–73], 60% female). Among patients undergoing total pancreatectomy (TP) or distal pancreatectomy (DP) (n = 81/143), W-SMV (p < 0.001), radiological response to NAT (p < 0.001) and age (p = 0.021) acted as predictors of metastatic BT-PLNs. Additionally, the protective effect of NAT on the risk of lymph node metastasis decreased with each year increase in age (p < 0.001). Neck PDAC at high risk of metastatic BT-PLNs could benefit from at least a DP. Preoperative prediction of metastatic BT-PLNs could minimize the risk of suboptimal treatment for neck PDAC
Unmasking malnutrition through soluble RAGE: A biomarker-guided insight from FRASNET
No full textBackground: Malnutrition is a prevalent geriatric syndrome, with multifactorial etiology and consequences for health and independence. Inflammation contributes to nutritional decline, yet conventional inflammatory markers often lack sensitivity for identifying malnutrition risk. The soluble receptor for advanced glycation end-products (sRAGE), a modulator of inflammatory responses, has emerged as a biomarker of disease risk and adverse outcomes in various conditions. Objectives: to evaluate the association between circulating sRAGE levels and nutritional status in community-dwelling older adults. Methods: This prospective observational study was conducted within the FRASNET cohort. Fifty-two community-dwelling older adults underwent multidimensional geriatric assessments during two time periods: 2017-2020 and 2023-2024. Serum sRAGE levels were measured at both timepoints. Nutritional status was assessed using the Mini Nutritional Assessment Short Form (MNA-SF). Associations between sRAGE and clinical parameters were evaluated through linear regression models adjusted for age and sex. The diagnostic performance of sRAGE in identifying malnutrition was assessed using ROC curve analysis. Results: Higher baseline sRAGE levels were significantly associated with lower BMI (β = -0.003, p = 0.036), reduced calf circumference (β = -0.002, p = 0.04), and poorer nutritional status as revealed by MNA-SF scores (β = -0.001, p = 0.03) at follow-up. Associations were more pronounced in women. ROC analysis indicated good diagnostic accuracy for identifying malnutrition risk, with an AUC of 0.85. The optimal sRAGE cut-off value for malnutrition risk was 1362.5 pg/ml. Conclusions: Higher sRAGE levels were prospectively associated with poorer nutritional outcomes in older adults, particularly in women. sRAGE may aid early identification of inflammation-related malnutrition risk
Major arrhythmias in non-dilated left ventricular cardiomyopathy: a novel prediction score
No full textBackground and aims: The prediction of the first major arrhythmic event (MAE) is still an unmet need in the recently defined scenario of non-dilated left ventricular cardiomyopathy (NDLVC). Methods: A cohort of 337 patients with NDLVC and no history of MAE was retrospectively identified at two large centres. Patient-tailored diagnostic workup included cardiac magnetic resonance (CMR), endomyocardial biopsy, and genetic testing. The primary endpoint was the occurrence of the first MAE, including sustained ventricular tachycardia (VT), ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy, by 60-month follow-up. A pool of 216 NDLVC patients from 11 European centres served as a validation cohort. Results: In the study cohort (mean age 37 ± 15 years, 62% male), the mean left ventricular ejection fraction (LVEF) was 52 ± 8%, and 79% of patients had late gadolinium enhancement (LGE) at baseline CMR. By 60-month follow-up, 51 patients (15%) experienced a MAE. The primary endpoint was predicted by male sex [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.3-4.4, P = .007], baseline non-sustained VT (HR 3.1, 95% CI 1.7-5.6, P < .001), LVEF < 45% (HR 5.5, 95% CI 2.7-11.0, P < .001), septal (HR 2.0, 95% CI 1.0-4.0, P = .046) and ring-like pattern of LGE (HR 1.3, 95% CI .6-2.6, P = .54), pathogenic/likely pathogenic variants in guideline-defined high-risk genes (HR 4.6, 95% CI 2.3-9.1, P < .001), and biopsy/CMR-proven myocardial inflammation (HR 15.7, 95% CI 6.1-40.3, P < .001). The results were confirmed in the validation cohort (Uno's C-index 0.81, 95% CI .75-.88). A novel risk score was subsequently derived. Conclusions: In NDLVC, male sex, non-sustained VT, LVEF < 45%, septal and ring-like LGE, high-risk genotypes, and myocardial inflammation predicted the first episode of MAE by 60 months
Response to ‘Towards an individualized strategy in perioperative chemotherapy for pancreatic cancer’
No full textAn Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study
No full textBackground & aims: The incidence of early-onset colorectal cancer (EOCRC; diagnosed before age 50 years) continues to increase, now standing as the leading cause of cancer-related deaths in young men. Screening participation in young adults remains low, but a noninvasive test may help. Methods: Early Onset Colorectal Cancer Detection (ENCODER) was an international, multicentric cohort study involving 542 individuals from 4 countries (ie, United States, Italy, Spain, and Japan). A panel of 6 cell-free and exosome-based circulating biomarkers were identified through small RNA sequencing from a biomarker discovery cohort (n = 118). A machine learning model (Extreme Gradient Boosting) was then trained on reverse-transcription quantitative polymerase chain reaction results from a training cohort (n = 192) and tested in an external and independent cohort (n = 191). Finally, we investigated the temporal dynamics of biomarker levels before and after surgery (n = 41). Results: Our liquid biopsy was highly accurate in detecting EOCRC in 2 independent cohorts (area under the receiver-operating characteristic curve, 97.5% in training vs 95.6% in testing). In the independent testing cohort, patients with EOCRC could be readily distinguished from nondisease controls, even in the age range from 20 to 35 years (area under the receiver-operating characteristic curve, 98.5%). This liquid biopsy had a specificity of 87.5% (95% CI, 79.4%-92.7%) and an overall sensitivity of 91.6% (95% CI, 84.2%-95.7%); the sensitivity for screening-relevant EOCRC stages I-III was 97.3% (95% CI, 90.6%-99.3%) and the sensitivity for premalignant lesions with high-grade dysplasia was 61.5% (95% CI, 35.5%-82.3%). Finally, we observed a reduction in the liquid biopsy values after surgery, reaching negativity after 4 days. Conclusions: ENCODER represents the largest EOCRC study to date to develop, train, and externally test a liquid biopsy for the growing population at risk of EOCRC, offering a complementary screening strategy. Clinicaltrials: gov, Number: NCT06342401
Oscillatory networks supporting perceptual and attentional sampling: a multimethod approach to investigate the rhythmic nature of visual cognition
No full textHow does the brain transform a continuous and cluttered stream of sensory information into coherent percepts? Neural oscillations have long been proposed as a mechanism that coordinates cortical communication and organizes sensory processing in time. Although not new, this idea has gained renewed attention in recent years, driven by novel methods and neuroimaging evidence. In this thesis, I will explore how rhythmic brain activity shapes visual cognition, presenting a series of studies that employ psychophysics, electroencephalography (EEG), and transcranial alternating current stimulation (tACS). I will first show how individualized alpha-band tACS (~7–13 Hz) can reveal the temporal dynamics of perceptual sampling, and later present EEG evidence on how spatial grouping properties can overwrite the link between endogenous alpha rhythms and temporal integration-segregation processes. Following, temporal processing in perception will be investigated through the predictive coding framework, leveraging a motion extrapolation task and a novel task introduced to induce statistical learning in the context of temporal processing. While most of the presented evidence relates to the neurotypical population, I will also present evidence in relation to neurodevelopmental disorders, such as developmental dyslexia, and personality traits of autism and schizotypy, characterized by perceptual anomalies in temporal processing and predictive coding. Together, this multimethod approach will provide insights into the rhythmic mechanisms that support visual cognition across different interacting networks.Come vengono formati percetti unitari e coerenti a partire da un flusso continuo e disordinato di input sensoriale? L’idea per cui le oscillazioni neurali siano alla base della comunicazione neuronale e dell’organizzazione dell’informazione sensoriale non è nuova, ma ha suscitato un rinnovato interesse nell’ultimo decennio grazie a nuovi metodi e recenti evidenze di neuroimaging. In questa tesi, esplorerò come l’attività ritmica cerebrale influenzi il processamento visivo attraverso studi che combinano tecniche di psicofisica, elettroencefalografia (EEG) e stimolazione elettrica a corrente alternata (tACS). Innanzitutto, mostrerò come la tACS a frequenze alpha (~7–13 Hz) individualizzate riveli le dinamiche temporali del campionamento percettivo. A seguire, presenterò evidenze EEG che mostrano come le proprietà di raggruppamento spaziale possono sovrascrivere la relazione tra i ritmi endogeni alpha e i processi di integrazione-segregazione temporale. In aggiunta, esaminerò come il processamento temporale può essere studiato alla luce di meccanismi predittivi; nello specifico, verranno descritti un compito percettivo di estrapolazione del movimento e un compito che induce apprendimento statistico in un contesto di percezione temporale. Sebbene la maggior parte delle evidenze sperimentali facciano riferimento alla popolazione neurotipica, presenterò anche delle evidenze sperimentali in relazione a disturbi del neurosviluppo, nello specifico la dislessia evolutiva, e in relazioni a tratti di personalità associati ad autismo e schizotipia, caratterizzati da anomalie percettive nel processamento temporale e predittivo. Complessivamente, questo approccio multimodale offrirà nuove prospettive sui meccanismi ritmici che supportano la cognizione visiva, attraverso l’interazione di network cerebrali
Characterization of the safety profile of trastuzumab deruxtecan by dose: a pooled analysis across DESTINY studies
Full text linkBackground Trastuzumab deruxtecan (T-DXd), an approved human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate, may cause treatment-emergent adverse events (TEAEs), most commonly gastrointestinal and hematologic TEAEs. This pooled analysis evaluated TEAEs across 2 doses of T-DXd in patients with different cancers to support safe and effective real-world use.Patients and Methods Data were pooled from 9 phase I-III clinical trials (DS8201-A-J101; DESTINY-Breast01/02/03/04; DESTINY-Lung01/02; DESTINY-Gastric01/02) of T-DXd 5.4 or 6.4 mg/kg every 3 weeks in patients (N = 1678) with metastatic breast, gastric, or lung cancer with varying HER2 expression or HER2 mutation status. Nausea, vomiting, neutropenia, fatigue, and interstitial lung disease (ILD) were evaluated for time to onset and dose-related outcomes. Antiemetic analysis was limited before a 2020 protocol change recommending prophylaxis.Results Common TEAEs (in >= 20%) were fatigue, nausea, vomiting, neutropenia, anemia, and thrombocytopenia; mostly grade 1 or 2. TEAEs leading to dose reduction, drug interruption, and discontinuation with T-DXd were 22.6%, 42.8%, and 17.7% (5.4 mg/kg), and 29.7%, 47.6%, and 16.6% (6.4 mg/kg), respectively. Neutropenia, nausea, and fatigue occurred in 34.6%, 74.6%, and 56.5% of patients (5.4 mg/kg) and 49.3%, 65.5%, and 52.8% (6.4 mg/kg). Adjudicated drug-related ILD occurred in 12.0% and 10.9%, respectively.Conclusion Gastrointestinal and hematologic TEAEs were most common, with nausea, neutropenia, and fatigue most commonly reported. ILD/pneumonitis occurred in similar to 11%-12% of patients, with severe cases infrequent. Most TEAEs were low grade, though dose modifications highlight the need for proactive TEAE management, particularly in older patients and those with renal impairment
International Reference Values for Surgical Outcomes of Total Pancreatectomy
No full textImportance: Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective: To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants: This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures: TP. Main Outcomes and Measures: Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results: Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (<6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance: This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery