IRIS UniSR (’Università Vita-Salute San Raffaele)
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Vitamin D Deficiency and Type 2 Diabetes: The Dangerous Link Between Two Modern Pandemics
No full textPredicting survival in patients with severe heart failure: Risk score validation in the HELP-HF cohort
No full textAims: Accurate selection of patients with severe heart failure (HF) who might benefit from advanced therapies is crucial. The present study investigates the performance of the available risk scores aimed at predicting the risk of mortality in patients with severe HF. Methods and results: The risk of 1-year mortality was estimated in patients with severe HF enrolled in the HELP-HF cohort according to the MAGGIC, 3-CHF, ADHF/NT-proBNP, and GWTG-HF risk scores, the number of criteria of the 2018 HFA-ESC definition of advanced HF, I NEED HELP markers, domains fulfilled of the 2019 HFA-ESC definition of frailty, the frailty index, and the INTERMACS profile. In addition, we tested the performance of different machine learning (ML)-based models to predict 1-year mortality. At 1-year follow-up, 265 patients (23.1%) died. The prognostic accuracy, tested in the subgroup of patients with completeness of all data regarding the variables included in the scores (497/1149 patients), resulted moderate for MAGGIC, GWTG-HF, and ADHF/NT-proBNP scores (area under the curve [AUC] ≥0.70) and only poor for the other tools. All the scores lost accuracy in estimating the rate of 1-year mortality in patients at the highest risk. Support vector machine-based model had the best AUC among ML-based models, slightly outperforming most of the tested risk scores. Conclusion: Most of the scores used to predict the risk of mortality in HF performed poorly in real-world patients with severe HF and provided inaccurate estimate of the risk of 1-year mortality in patients at the highest risk. ML-based models did not significantly outperform the currently available risk scores and their use must be validated in large cohort of patients
Pancreatic neuroendocrine neoplasms (pNENs): Genetic and environmental biomarkers for risk of occurrence and prognosis
No full textPancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes
Prophylactic Drain Placement and Postoperative Invasive Procedures After Gastrectomy: The Abdominal Drain After Gastrectomy (ADIGE) Randomized Clinical Trial
No full textImportance: Evidence suggests that prophylactic abdominal drainage after gastrectomy for cancer may reduce postoperative morbidity and hospital stay but this evidence comes from small studies with a high risk of bias. Further research is needed to determine whether drains safely meet their primary purpose of identifying and managing postoperative intraperitoneal collections without the need for reoperation or additional percutaneous drainage. Objective: To determine whether avoiding routine abdominal drainage increased postoperative invasive procedures. Design, setting, and participants: The Abdominal Drain in Gastrectomy (ADIGE) Trial was a multicenter prospective randomized noninferiority trial. Enrollment spanned from December 2019 to January 2023. Follow-up evaluations were completed at 30 and 90 days. Eleven centers within the Italian Research Group for Gastric Cancer, encompassing both academic medical centers and community hospitals, were included. Patients with gastric cancer undergoing subtotal or total gastrectomy with curative intent were eligible, excluding those younger than 18 years, with serious comorbidities, or undergoing procedure types outside the scope of the study. Of 803 patients assessed for eligibility, 404 were randomized and 390 were included in final analyses. Interventions: Patients were randomized 1:1 into prophylactic drain or no drain arms. Main outcomes and measures: The primary end point was a modified intention-to-treat (mITT) analysis measuring reoperation or percutaneous drainage within 30 postoperative days. The null hypothesis was rejected when the 90% CI upper limit of the proportion difference did not exceed 3.56%. The calculated sample size to achieve 80% power with a 10% dropout rate was 404 patients (202 in each group). Surgeons and patients were blinded until gastrointestinal reconstruction. Results: Of the 404 patients randomized 226 (57.8%) were male; the median (IQR) age was 71 (62-78) years. Intraoperative identification of nonresectable disease occurred in 14 patients, leading to their exclusion from the study, leaving 390 patients. In the mITT analysis, 15 patients (7.7%) in the drain group needed reoperation or percutaneous drainage by postoperative day 30 vs 29 (15%) in the no drain group, favoring the drain group (difference, 7.2%; 90% CI, 2.1-12.4; P = .02). Of note, the difference in the primary composite end point was entirely due to a similar difference in reoperation (5.1% in the drain group vs 12.4% in the no drain group; P = .01). Drain-related complications occurred in 4 patients. Conclusions and relevance: The findings of this study indicate that refraining from prophylactic drain use after gastrectomy heightened the risk of postoperative invasive procedures, discouraging its avoidance. Future studies identifying high-risk groups could optimize prophylactic drainage decisions. Trial registration: ClinicalTrials.gov Identifier: NCT04227951.Importance: Evidence suggests that prophylactic abdominal drainage after gastrectomy for cancer may reduce postoperative morbidity and hospital stay but this evidence comes from small studies with a high risk of bias. Further research is needed to determine whether drains safely meet their primary purpose of identifying and managing postoperative intraperitoneal collections without the need for reoperation or additional percutaneous drainage. Objective: To determine whether avoiding routine abdominal drainage increased postoperative invasive procedures. Design, Setting, and Participants: The Abdominal Drain in Gastrectomy (ADIGE) Trial was a multicenter prospective randomized noninferiority trial. Enrollment spanned from December 2019 to January 2023. Follow-up evaluations were completed at 30 and 90 days. Eleven centers within the Italian Research Group for Gastric Cancer, encompassing both academic medical centers and community hospitals, were included. Patients with gastric cancer undergoing subtotal or total gastrectomy with curative intent were eligible, excluding those younger than 18 years, with serious comorbidities, or undergoing procedure types outside the scope of the study. Of 803 patients assessed for eligibility, 404 were randomized and 390 were included in final analyses. Interventions: Patients were randomized 1:1 into prophylactic drain or no drain arms. Main Outcomes and Measures: The primary end point was a modified intention-to-treat (mITT) analysis measuring reoperation or percutaneous drainage within 30 postoperative days. The null hypothesis was rejected when the 90% CI upper limit of the proportion difference did not exceed 3.56%. The calculated sample size to achieve 80% power with a 10% dropout rate was 404 patients (202 in each group). Surgeons and patients were blinded until gastrointestinal reconstruction. Results: Of the 404 patients randomized 226 (57.8%) were male; the median (IQR) age was 71 (62-78) years. Intraoperative identification of nonresectable disease occurred in 14 patients, leading to their exclusion from the study, leaving 390 patients. In the mITT analysis, 15 patients (7.7%) in the drain group needed reoperation or percutaneous drainage by postoperative day 30 vs 29 (15%) in the no drain group, favoring the drain group (difference, 7.2%; 90% CI, 2.1-12.4; P =.02). Of note, the difference in the primary composite end point was entirely due to a similar difference in reoperation (5.1% in the drain group vs 12.4% in the no drain group; P =.01). Drain-related complications occurred in 4 patients. Conclusions and Relevance: The findings of this study indicate that refraining from prophylactic drain use after gastrectomy heightened the risk of postoperative invasive procedures, discouraging its avoidance. Future studies identifying high-risk groups could optimize prophylactic drainage decisions. Trial Registration: ClinicalTrials.gov Identifier: NCT04227951
Determinants of response and molecular dynamics in HER2+ER+ breast cancers from the NA-PHER2 trial receiving HER2-targeted and endocrine therapies
Get PDFImproved outcomes in HER2+ female breast cancer have resulted from chemotherapy and anti-HER2 therapies. However, HER2+ER+ cancers exhibit lower response rates. The phase 2 NA-PHER2 trial (NCT02530424) investigated chemo-free preoperative HER2 blockade (trastuzumab + pertuzumab) and CDK4/6 inhibition (palbociclib) with or without endocrine therapy (fulvestrant) in HER2+ER+ breast cancer. Clinical endpoints (i.e. Ki67 dynamics and pathological complete response) were previously reported. Here we report on the biomarker analysis, secondary objective of the study. Through RNA sequencing and tumour infiltrating lymphocytes (TIL) assessment in serial biopsies, we identified biomarkers predictive of pCR or Day14 Ki67 response and unveiled treatment-induced molecular changes. High immune infiltration and low ER signalling correlated with pCR, while TP53 mutations associated with high Day14 Ki67. Stratification based on Ki67 at Day14 and at surgery defined three response groups (Ki67 HighHigh, LowHigh, LowLow), with divergent tumour and stroma expression dynamics. The HighHigh group showed dysfunctional immune infiltration and overexpression of therapeutic targets like PAK4 at baseline. The LowLow group exhibited a Luminal A phenotype by the end of treatment. This study expands our understanding of drivers and dynamics of HER2+ER+ tumour response, towards treatment tailoring
An Evaluation of the Diagnostic Accuracy of [68Ga]Ga-PSMA-11 vs. [18F]F-PSMA-1007 PET/CT for Lymph Node Staging in Patient Candidates for Radical Prostatectomy and Lymph Node Dissection: A Single Institutional Analysis
No full textBackground/Objectives: This study evaluates and compares the diagnostic accuracy of [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 for lymph node staging in patients with prostate cancer (PCa) scheduled for robot-assisted radical prostatectomy (RARP) and lymphadenectomy (LND). Methods: We retrospectively reviewed prospectively collected data on patients referred to our hospital from October 2020 to January 2023. We included all patients who underwent [68Ga]Ga-PSMA-11 or [18F]F-PSMA-1007 PET/CT for primary staging and subsequently had RARP with concomitant LND. The maximum standard uptake value (SUVmax) for lymph nodes (LNs) and the SUV node-to-background ratio were reported. Two different cut-off values for the SUV node-to-background ratio (i.e., ≥2 vs. <2 and ≥15.5 vs. <15.5) were used to evaluate the diagnostic performance of both tracers. The first cut-off was empirically chosen, while the second was based on Liu’s method. Results: A total of 156 patients were included (median age: 67 years). Among them, 83 underwent [68Ga]Ga-PSMA-11 and 73 underwent [18F]F-PSMA-1007 PET/CT. Suspicious lymph nodes were identified in 21 patients (13.5%). Pathological nodal involvement (pN1) was confirmed in 25 cases (16%). Of the 21 patients with suspicious pathological lymph nodes on PSMA PET/CT, 9 (42.9%) had positive nodes on the final pathology report. With an SUV node-to-background ratio cut-off of ≥2, [68Ga]Ga-PSMA-11 showed 37.5% sensitivity (SE) and 98.5% specificity(SP), while [18F]F-PSMA-1007 demonstrated 33.3% SE and 100% SP. Using the ≥15.5 cut-off, SE and SP were 31.3% and 100% for [68Ga]Ga-PSMA-11 and 11.1% and 100% for [18F]F-PSMA-1007, respectively. Conclusions: [18F]F-PSMA-1007 PET/CT showed, even if not statistically significantly, slightly lower SE and higher SP for nodal staging compared to [68Ga]Ga-PSMA-11 PET/CT, irrespective of the SUV ratio used
Eligibility for the medical therapy among men with non-obstructive azoospermia—Findings from a multi-centric cross-sectional study
No full textBackground: Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for hormonal optimization therapy, according to specific pre-treatment criteria. Objectives: To investigate the characteristics of those men with NOA who would qualify for the medical therapy prior to any SR procedure in a large multi-centric cross-sectional study. Materials and methods: Complete data from 1644 NOA patients seeking medical help for primary infertility at three tertiary referral centers from USA, Brazil, and Italy were analyzed. Baseline serum hormone levels were collected for all patients. NOA was confirmed after two consecutive semen analyses. Genetic tests, including karyotype analysis and Y microdeletions, were performed on all patients. Patients with secondary hypogonadism (total testosterone (T) levels less than 300 ng/dL and luteinizing hormone (LH) levels less than 8 mIU/mL) were earmarked as potential candidates for receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG). Patients with a T to 17β-estradiol (E2) ratio < 10 were classified as eligible for aromatase inhibitors (AIs) therapy (e.g., anastrazole). A third sub-cohort was created by combining the criteria of the first two sub-cohorts. Descriptive statistics was used to detail overall characteristics and differences between the different sub-cohorts. Results: Among the 1,644 men, 28% (n = 460) had T < 300 ng/dL and LH < 8 mIU/mL, thereby being potentially suitable for CC and/or hCG, while 37% (n = 607) had a T to E2 ratio < 10 thus potentially suitable for AIs. Lastly, 17.7% (n = 280) met the criteria for potential eligibility for both CC and/or hCG and AIs. Conclusions: Findings from this multicentric cross-sectional study reveal that about 30% of men with NOA were eligible for hormonal treatment with CC and/or hCG while 37% were found to be potential candidates for AIs, and 17% for both therapies. Therefore, these findings show that a only a small subset of NOA patients can benefit from medical therapy prior to considering any SR procedures.Background: Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for hormonal optimization therapy, according to specific pre-treatment criteria. Objectives: To investigate the characteristics of those men with NOA who would qualify for the medical therapy prior to any SR procedure in a large multi-centric cross-sectional study. Materials and methods: Complete data from 1644 NOA patients seeking medical help for primary infertility at three tertiary referral centers from USA, Brazil, and Italy were analyzed. Baseline serum hormone levels were collected for all patients. NOA was confirmed after two consecutive semen analyses. Genetic tests, including karyotype analysis and Y microdeletions, were performed on all patients. Patients with secondary hypogonadism (total testosterone (T) levels less than 300 ng/dL and luteinizing hormone (LH) levels less than 8 mIU/mL) were earmarked as potential candidates for receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG). Patients with a T to 17β-estradiol (E2) ratio < 10 were classified as eligible for aromatase inhibitors (AIs) therapy (e.g., anastrazole). A third sub-cohort was created by combining the criteria of the first two sub-cohorts. Descriptive statistics was used to detail overall characteristics and differences between the different sub-cohorts. Results: Among the 1,644 men, 28% (n = 460) had T < 300 ng/dL and LH < 8 mIU/mL, thereby being potentially suitable for CC and/or hCG, while 37% (n = 607) had a T to E2 ratio < 10 thus potentially suitable for AIs. Lastly, 17.7% (n = 280) met the criteria for potential eligibility for both CC and/or hCG and AIs. Conclusions: Findings from this multicentric cross-sectional study reveal that about 30% of men with NOA were eligible for hormonal treatment with CC and/or hCG while 37% were found to be potential candidates for AIs, and 17% for both therapies. Therefore, these findings show that a only a small subset of NOA patients can benefit from medical therapy prior to considering any SR procedures
Prognostic value of NT-proBNP in patients with primary mitral regurgitation undergoing transcatheter edge-to-edge repair
No full textAims The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing mitral valve transcatheter edge-to-edge repair (M-TEER) for primary mitral regurgitation (PMR) is unclear. This study assessed the association between NT-proBNP and outcomes and explored its additive value to the Mitral Regurgitation International Database (MIDA) score. Methods and results PRIME-MR, a retrospective, international, multicentre registry, includes 3083 consecutive PMR patients treated with M-TEER. This analysis focused on 1382 patients (median age 81 years, 47% female, 82% New York Heart Association [NYHA] functional class III/IV, median EuroSCORE II 4.1%) with available NT-proBNP levels and follow-up. The primary endpoint was death or heart failure hospitalization within 3 years. Median NT-proBNP level was 1991 pg/ml (T1: 578, T3: 6285), and 384 patients reached the primary endpoint (Kaplan-Meier estimate: 48.5%). Log-transformed NT-proBNP levels independently predicted the primary endpoint (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.07-1.28; p < 0.001) after adjusting for NYHA class, haemoglobin, creatinine, and atrial fibrillation. In 1041 patients with a modified MIDA score (median 9), the score was initially associated with the primary endpoint (HR 1.10, 95% CI 1.04-1.17; p = 0.002), but lost significance when adjusting for NT-proBNP levels, which remained independently predictive (adjusted HR 1.20, 95% CI 1.07-1.34; p = 0.002). Conclusions NT-proBNP, but not the MIDA score, was independently associated with death or heart failure hospitalizations within 3 years in M-TEER-treated PMR patients. Incorporating NT-proBNP levels into clinical assessment may improve risk stratification and potentially supports earlier intervention at lower NT-proBNP levels to optimize outcomes
Endoscopic Submucosal Dissection (ESD) for the Management of Fibrotic Non-Lifting Colorectal Lesions (NLCLs): Results from a Large Multicenter Retrospective Study
No full textBackground/Objectives: The management of non-lifting colorectal lesions (NLCLs), often resulting from previous unsuccessful treatments or biopsies, remains challenging due to submucosal fibrosis that prevents adequate lifting. Endoscopic submucosal dissection (ESD) is a viable option for achieving complete resection in such cases. However, when standard ESD is not feasible, conversion to hybrid ESD (H-ESD) has been proposed as a rescue strategy. This study aimed to assess ESD’s feasibility, effectiveness, and safety for NLCLs, including cases requiring conversion to H-ESD, when performed by experienced endoscopists in tertiary referral centers. Methods: In this multicenter retrospective study, data from patients with NLCLs treated by ESD/H-ESD between January 2009 and September 2022 were analyzed. The primary endpoint was the recurrence rate (RR). Secondary endpoints included the adverse event (AE) rate, technical success (TS) rate (en bloc resection regardless of technique), complete resection (CR), curative resection (cR) rates, and surgical intervention rate. Predictors of ESD technical success were identified. Results: In total, 178 patients with NLCLs were included (52 previously biopsied, 126 recurrent after previous resection). ESD was used in 111 (62.4%) and H-ESD in 67 (37.6%) cases. During a median follow-up of 373 days (IQR 540), the overall RR was 3.6%. The overall AE rate was 13.4%, and perforation was the most frequent (8.4%). All AEs were successfully managed endoscopically. The TS rate was 71.9%, significantly higher in previously biopsied lesions compared to recurrent ones (78.8% vs. 55.6%, p = 0.04). On multivariate analysis, rectal location (p < 0.001), F1 fibrosis (p = 0.026), and previously biopsied lesions (p = 0.006) predicted ESD TS without the need for conversion to H-ESD. Conclusions: ESD/H-ESD is feasible and safe for NLCLs when performed by experienced operators, with low RR amenable to endoscopic treatment. Previously biopsied lesions, rectal location, and low fibrosis predict ESD TS