Clinical trials

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system that may cause a broad range of motor and non-motor symptoms. New or worsening neurological symptoms in people with MS are frequently interpreted as a possible relapse. However, relapse-like episodes are not always caused by new inflammatory disease activity and may instead reflect infection, fever, comorbidities, fluctuations of pre-existing symptoms, or an overlapping functional neurological disorder. Functional motor disorders (FMDs) are characterized by altered voluntary motor control and may present with weakness, tremor, gait disturbance, postural instability, abnormal movements, or impaired motor performance. These manifestations may resemble MS-related symptoms and may coexist with established structural neurological disease. In people with MS, functional motor symptoms may therefore be misclassified as relapse or disease progression, potentially leading to unnecessary investigations, corticosteroid treatment, inappropriate escalation of disease-modifying therapy, avoidable healthcare use, and delayed access to appropriate rehabilitation. Despite growing recognition of FMD-MS overlap, its prevalence, clinical characteristics, and optimal management remain insufficiently defined. This multicenter prospective study aims to improve the identification, characterization, and management of FMD-MS overlap in people with MS presenting with acute neurological symptom worsening. The study consists of two sequential and interconnected parts. Part A is an observational, cross-sectional diagnostic and prevalence study. A total of 192 adults with MS according to the 2017 revisions of the McDonald criteria and reporting new or worsening neurological symptoms within the previous 30 days will be enrolled at two tertiary MS centers in Italy. No study-assigned treatment will be administered during Part A. Participants will undergo a standardized multidimensional assessment including demographic and MS-related clinical information, neurological examination, evaluation of positive functional motor signs, disability and functional measures, gait and balance assessments, patient-reported outcome measures, and review of laboratory and magnetic resonance imaging findings obtained as part of routine clinical care when clinically indicated. The primary aim of Part A is to estimate the prevalence of FMD-MS overlap, also referred to in the protocol as functional pseudorelapse, among people with MS presenting with acute symptom worsening. Additional aims are to distinguish FMD-MS overlap from true MS relapse and other causes of symptom worsening and to identify demographic, clinical, functional, gait, balance, psychological, quality-of-life, and routine-care imaging characteristics associated with each diagnostic category. Part B is a pilot randomized, assessor-blinded, active-controlled rehabilitation study. Approximately 26 participants with confirmed FMD-MS overlap identified during Part A and meeting the additional rehabilitation eligibility criteria will enter Part B. These 26 participants are included within the overall cohort of 192 participants and are not an additional study population. Participants entering Part B will be randomized in a 1:1 ratio to either a targeted FMD-specific multidisciplinary rehabilitation programme or conventional MS rehabilitation. The experimental programme will include five consecutive days of in-person rehabilitation focused on education regarding functional symptom mechanisms, movement retraining using attentional-redirection strategies, and development of an individualized self-management plan. This will be followed by a 12-week home-based programme supported by weekly telemedicine sessions. The active comparator will consist of conventional MS rehabilitation addressing mobility, strength, gait, balance, endurance, fatigue management, and functional independence, without protocolized FMD-specific techniques. Part B aims to assess the feasibility, safety, and preliminary efficacy of the FMD-specific rehabilitation programme compared with conventional MS rehabilitation. Outcomes will be assessed at baseline, immediately after the five-day intervention, and at three months. The main efficacy outcome will be change in functional motor symptom severity, with additional evaluation of disability, functional performance, gait, balance, fatigue, pain, emotional functioning, quality of life, healthcare utilization, and costs. Overall, the study is expected to provide prospective evidence on the frequency and clinical profile of FMD-MS overlap and preliminary evidence on whether a mechanism-specific rehabilitation approach may improve outcomes in affected people with MS.

The REACT study is a prospective, single-center, single-cohort study designed to evaluate the feasibility of a 4-week intensive multimodal postoperative rehabilitation program in patients who develop severe complications after proximal pancreatic resection (pancreatoduodenectomy or total pancreatectomy). Postoperative complications after pancreatic surgery may result in substantial physiological and metabolic stress, leading to loss of muscle mass, malnutrition, reduced functional capacity, and delayed recovery. Although prehabilitation programs have been proposed to improve patients' functional capacity before surgery, evidence regarding structured multimodal rehabilitation after pancreatic surgery is currently lacking. Adult patients undergoing elective proximal pancreatic resection who develop a severe postoperative complication (Comprehensive Complication Index \>21) will be eligible for the study. Participants will undergo a 4-week multimodal rehabilitation program starting after hospital discharge and including individualized exercise training, nutritional therapy, and anxiety-reducing techniques. The program may be delivered either in a supervised hospital-based setting or through a home-based program according to patient preference and availability. The primary objective is to assess the feasibility of the rehabilitation program in terms of recruitment, adherence, completion of outcome assessments, completeness of data, and safety. Secondary objectives include evaluating postoperative functional recovery using PROMIS-29 Physical and Mental Health Summary Scores, the 6-minute walk test, and the Duke Activity Status Index. In patients with malignancy who are candidates for adjuvant treatment, return to intended oncologic treatment will also be evaluated. A total of 40 patients will be enrolled and followed for up to 90 days after surgery.

Age-related macular degeneration (AMD) is the major cause of legal blindness in developed countries. Intermediate AMD represents the most frequent stage. However, it often evolves towards complicated stages, namely neovascular AMD or geographic atrophy (GA). Despite the available treatments, the visual outcome is highly heterogeneous. The scientific interest is growing regarding the assessment of neuroretinal changes in AMD. Although AMD is mainly considered an outer retinal disease, recent evidence suggests a major involvement of retinal glia and neurons, i.e. an involvement of the inner retina. This damage may remarkably affect the morphological and functional AMD outcome, subverting retinal signal transmission cascade and more clearly explaining the outcome of the disease. The main goal of this study is to perform a multidisciplinary, multicenter, both prospective and retrospective evaluation of neuroretinal degeneration in different AMD stages in preclinical and clinical models.

One in five people in Italy has a mental disorder, with depression being the most common and schizophrenia the most severe. People with mental illness have a higher risk of cardio-metabolic and oncologic comorbidities. They also face disparities in accessing appropriate care, with a 20-year life expectancy reduction. IN-TIME will employ an innovative and highly interdisciplinary approach to characterize barriers to healthcare in people with mental illness for informing interventions and enhancing screening, diagnostic pathways and health outcomes. The project will provide: 1) population-based evidence and characterization of disparities in diagnosis and care for cancer and cardio-metabolic disorders; 2) a fine-grained identification of modifiable barriers, such as those relating to stigma and communication; 3) change promoting interventions, including a policy brief to orient clinical guidelines and best practice to reduce stigma, improve doctor-patient communication and optimize care.

The purpose of this study is to collect all radiological data which evaluated with clinical data may help assess malignancy and prognosis of pancreatic disease.This registry aims to collect retrospective data from 2014 and prospective data until 2027 with a maximum follow-up of 3 years per patient.

This study will compare the standard MRI protocol with an advanced MRI protocol for the assessment of ischemic heart disease. The goal is to evaluate whether the advanced protocol provides comparable or improved diagnostic performance relative to the standard approach.

Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. Coronary Computed Tomography angiography (CCTA) gained a pivotal clinical role for excellent sensitivity in rule-out CAD, but has limited specificity for a tendency to overestimate stenoses and for the lack of information about their hemodynamic impact. Fractional Flow Reserve derived from CT (FFR-CT) and stress CT perfusion (CTP) have been recently proposed to complement CCTA in the non-invasive assessment of myocardial ischemia, increasing the specificity and avoiding unnecessary catheterization. However, on energy-integrating (EID)-CT, FFR-CT has suboptimal performance, while CTP is affected by high radiation exposure. Both these approaches may benefit by the introduction of the new Photon Counting Detector (PCD)-CT technology, but data completely lacks. Aim of the study is to assess the performance of PCD-CT in the identification of significant CAD combining CCTA with FFR-CT and spectral CTP.

Single-center, cross-sectional observational study assessing the feasibility of advanced accelerated MRI sequences versus standard ones in terms of image quality, diagnostic reliability, and acquisition time.

This is a prospective single-center observational study comparing single-port (SP) and multi-port (MP) robot-assisted surgery in adult patients undergoing robot-assisted radical prostatectomy (RARP) or robot-assisted partial nephrectomy (RAPN) for prostate or kidney cancer. Consecutive eligible patients will be managed according to routine clinical practice and assigned to SP or MP surgery based on predefined clinical and anatomical criteria, surgeon assessment, patient and tumor characteristics, platform availability, and surgical expertise. No randomization will be performed. The study aims to compare perioperative outcomes between the two surgical approaches, with length of hospital stay (LOS) as the primary endpoint. Secondary endpoints include intraoperative outcomes (operative time, estimated blood loss, and intraoperative complications), postoperative recovery, pain, postoperative complications, readmission rates, positive surgical margins, and hospital costs. Functional and patient-reported outcomes will also be evaluated, including urinary continence, sexual function, health-related quality of life, renal function after partial nephrectomy, decision regret, and cosmetic satisfaction.

The EUS-AI-R study is an observational, single-center, two-phase (retrospective-prospective) study designed to develop and validate artificial intelligence (AI) models for predicting chemotherapy response and oncological outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Patients who underwent endoscopic ultrasound (EUS) with tissue acquisition (EUS-FNA/FNB) for suspected pancreatic lesions at IRCCS San Raffaele Hospital between January 1st, 2019 and January 2026 will be retrospectively included. All patients have a histologically confirmed diagnosis of PDAC and a minimum follow-up of six months. These data derive from an IRB-approved institutional study (BIOPANCREAS; NCT06552078). Retrospective multimodal data, including EUS imaging (B-mode, elastography, contrast-enhanced EUS), clinical and laboratory variables, CT/MRI imaging, digital pathology, and molecular data when available, will be used to develop and internally validate multiple AI models. In the prospective phase, the best-performing AI model will be applied to an independent cohort of patients undergoing EUS at the same institution to evaluate feasibility, calibration, and real-world performance. No additional procedures beyond standard clinical practice will be performed.

The GENTLENESS study is a prospective, multicenter, observational registry designed to evaluate the endoscopic management of patients with suspected biliopancreatic and periampullary neoplastic diseases within the Pancreas Units network of the Lombardy Region. Patients undergoing endoscopic ultrasound (EUS) for suspected pancreatic or periampullary malignancies, including pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumors, cystic pancreatic neoplasms requiring endoscopic, surgical, or oncological management, and periampullary tumors of the distal bile duct, ampulla, or duodenum, will be prospectively enrolled according to standard clinical practice. The study aims to assess the diagnostic accuracy of EUS-guided tissue acquisition, procedural safety, the need for repeat sampling, and organizational performance indicators, including time to definitive cyto-histological diagnosis and time to initiation of disease-specific treatment. No additional procedures beyond routine clinical care will be performed as a result of study participation.

The purpose of establishing the biobank is to create a collection of biological material and clinical data, with a prospective and retrospective mold, in order to investigate the role of genetic predisposition in multifactorial bilio-pancreatic diseases, so that an evaluation of the possible association in the pathogenesis of exogenous factors with endogenous factors can be allowed. Multifactorial diseases are in fact an expression of genetic predisposition upon which one or more environmental stimuli act. Usually the aforementioned factors are not capable individually of triggering disease but, when simultaneously present, can cause the pathological phenotype. Therefore, it becomes important in the description of disease pathogenesis to identify as many risk factors for disease prevention and early diagnosis.

The aim of the TAILOR-EUS study (Iconographic Registry of Bilio-Pancreatic Endoscopic Ultrasound Procedures) is to establish a clinical registry comprising images and videos generated during endoscopic procedures conducted for the investigation of pancreatic diseases (PD). The study will compile historical, pathological, and imaging data from approximately 12,000 patients (2,000 retrospectively and 10,000 prospectively) who underwent endoscopic ultrasound procedures for inflammatory pancreatic conditions (e.g., acute, recurrent, chronic pancreatitis), autoimmune bilio-pancreatic diseases (e.g., autoimmune pancreatitis), neoplastic bilio-pancreatic conditions, and screenings for individuals at high risk of developing such diseases at the Bilio-Pancreatic Endoscopy and Endoscopic Ultrasound Unit of the IRCCS San Raffaele Hospital between 2000 and 2027. Participants have undergone or will undergo the standard diagnostic pathway appropriate for their conditions as part of routine clinical practice. All instrumental examinations and endoscopic ultrasound procedures are integral to the standard diagnostic and therapeutic approach for pancreatic diseases.

Advanced PDAC patients undergo polychemotherapy, yet responses are highly variable. Transcriptome signatures are emerging as key predictors of treatment response. However, PDAC adapts across sites (primary vs. metastases) and evolves under treatment pressure (pre- vs. post-chemotherapy). Moreover, common environmental pollutants, like smoking and microplastics, contribute to carcinogenesis, yet their impact on PDAC evolution and treatment response remains unclear. To fill these gaps, the CLEAR project aims at investigating: 1. transcriptome patterns linked to treatment response; 2. effects of smoking and microplastic exposure on treatment outcomes; 3. PDAC evolution across organ sites and under chemotherapy. These studies will help uncover biomarkers and factors shaping disease progression, hence paving the ground for personalized therapies.

This prospective observational registry aims to systematically collect preoperative, intraoperative, and postoperative clinical data from patients undergoing surgery for benign gynecological conditions. The main goal is to evaluate clinical outcomes, surgical approaches, and complications in real-world clinical practice.

This prospective observational study aims to investigate pathogenic myelopoiesis in patients with pancreatic ductal adenocarcinoma (PDAC) and to characterize the systemic immune alterations associated with tumor-related inflammation. The study will enroll 50 patients with newly diagnosed, non-metastatic, treatment-naïve PDAC and 50 age-matched control patients with intraductal papillary mucinous neoplasm (IPMN) under surveillance and no evidence of pancreatic malignancy. Control patients will be matched to PDAC patients by age within a range of ±5 years whenever feasible. A single peripheral blood sample will be collected at baseline from all participants. In PDAC patients, blood collection will be performed before initiation of any anti-tumor treatment. Translational analyses will characterize circulating myeloid cells, progenitor cells, and hematopoietic stem and progenitor cell-related transcriptional programs using high-dimensional flow cytometry and single-cell transcriptomic analyses. The primary objective is to identify the molecular drivers of pathogenic myelopoiesis in PDAC by assessing quantitative and qualitative differences between PDAC patients and age-matched controls in circulating myeloid and progenitor cell populations and their transcriptional profiles. The study will specifically explore the hypothesis that IL-1β-associated tumor inflammation contributes to systemic reprogramming of hematopoietic progenitor compartments and promotes myeloid-biased hematopoiesis. PDAC patients will also be followed clinically for 12 months using data derived from routine clinical practice to explore associations between baseline pathogenic myelopoiesis-related profiles and subsequent clinical outcomes. No follow-up is required for control patients.

Adult patients with chronic lymphocytic leukemia (CLL), splenic marginal-zone lymphoma (SMZL) and hairy cell leukemia (HCL) followed at participating clinical sites will be enrolled and undergo sampling of additional amount of blood during the blood draws performed as part of standard clinical care. The project aims to develop and validate innovative patient-derived 3D bioprinted models that faithfully reproduce the key microenvironments of lymphoid tissues, enabling a more physiologically relevant study of mature B-cell malignancies.

This is a monocentric, retrospective and prospective study aimed to underline the potential of T-cell receptor (TCR)-mediated Ab recognition from the post transplant setting in acute myeloid leukemia (AML). The study is based on three key biological concepts: * the essential role of CD4+ T cells in leukemia immunosurveillance, * the impact of human leukocyte antigen (HLA) loss or downregulation on immune escape, * the ability of leukemic cells to remodel the tumor microenvironment and impair T-cell function. By addressing these mechanisms, the study aims to identify novel TCRs and generate next-generation engineered T-cell products with improved anti-leukemic activity. The study will be conducted using samples from healthy donors and patients with AML. The Retrospective part will involve samples collected per standard of care from patients already present in the institutional Hematologic Cancer Biobank, while prospective part will regard the use of samples collected during the study protocol from healthy donor and AML patients. Healthy donor peripheral blood samples will be used to isolate tumor-specific TCRs and generate engineered T cells, whereas bone marrow and peripheral blood samples from AML patients will be used to evaluate the anti-tumor activity of the engineered T cells.

Patients with chronic lymphocytic leukemia (CLL) followed at Strategic Research Program on CLL will be enrolled and undergo sampling of additional amount of blood at the time of standard blood tests. Leukemic B cells and peripheral blood mononuclear cells (PBMC).

This is a monocentric, no-profit, retrospective and prospective observational cohort study conducted at IRCCS Ospedale San Raffaele. The study does not entail any additional procedures or interventions for participants. Biological samples (including blood/serum and muscle biopsies) are obtained for a previously approved study (LAMA2\_GUP24002) and collected under the existing BancaINSpe informed consent. For the present study, analyses will be performed on biospecimens already stored or that will be stored at BancaINSpe, using portions of material already collected for the LAMA2\_GUP24002 protocol.

Telemedicine has developed rapidly during the COVID-19 pandemic and is now integrated into the clinical practice of many hospitals. Telemedicine offers many advantages, and even after the end of the pandemic, many patients still choose to undergo healthcare visits remotely. However, the rapid expansion of telemedicine may be associated with the risk of providing patients with unvalidated and uncontrolled telehealth solutions, potentially negatively impacting their health. In this study, the researchers aim to investigate the effectiveness of remote cognitive training in patients with mild-to-moderate Alzheimer's disease (AD) using tablets equipped with virtual reality-based cognitive exercises. The investigators also aim to evaluate the impact of online supervision of cognitive training by a neuropsychologist and to compare the costs and burden of home-based versus hospital-based cognitive training in patients with AD. This project will define the optimal modalities for cognitive telerehabilitation to ensure validated protocols for the continuity of care in AD.

Pediatric refractory Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, not responsive to current treatments. Since hematopoietic stem and progenitor cells (HSPCs) in the bone marrow display immunomodulatory functions and IL-10-producing regulatory cells regulate gut homeostasis, by combining state-of-the-art strategies for the ex-vivo manipulation and expansion of HSPCs and gene delivery systems to drive HLA-class II-restricted antigen presentation and expression of tolerogenic molecules, the investigators propose to dissect the antigen- (Ag-) presenting capacity of HSPCs and to exploit their tolerogenic potential to induce IL-10-mediated tolerance in the intestinal mucosa of IBD patients. The investigators hypothesize that HSPCs can be engineered using commensal-derived Ags w/wo IL-10 to drive the differentiation of Tr1 cells with the desired Ag-specificity to control intestinal inflammation in IBD. The results of this study will pave the way for defining innovative cell-based approaches for treating refractory pediatric IBD.

OCt.IN.N is a national, monocentric, prospective, observational cohort study evaluating the utility and applicability of Optical Coherence Tomography (OCT) in the diagnostic workup and longitudinal monitoring of neurological diseases. 840 patients with Central Nervous System neurological diseases (Multiple Sclerosis, Alzheimer's disease, Parkinson's disease, migraine/headache) and 210 age-matched healthy controls will undergo OCT examination at baseline and at 6, 12, 18, and 24 months of follow-up at IRCCS San Raffaele Hospital, Milan, Italy. OCT is a non-invasive, rapid, and reproducible technique that automatically measures the thickness of individual retinal layers. Retinal layer thicknesses and their longitudinal changes will be correlated with established clinical scales, neuroimaging, and biological markers used in routine neurological practice.

BLAD is a prospective, monocentric, observational epidemiological study with an additional procedure (annual blood draw) evaluating the diagnostic and prognostic performance of plasma biomarkers for Alzheimer's disease (AD) in a large cohort of patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital, Milan, Italy. 2000 patients will be enrolled and followed annually for 5 years. A validation sub-study (150 patients) will compare plasma biomarkers against CSF biomarkers as the gold standard. The study aims to establish plasma biomarkers as a less invasive and more cost-effective alternative to CSF analysis and amyloid-PET for the diagnosis and prognosis of AD.

This is a Retrospective and Prospective Observational Single-Center Study. The purpose is to collect all data to generate a registry of primary liver cancer (hepatocellular carcinoma and biliary tract carcinoma) of patients accessing to San Raffaele Hospital. An additional purpose is to identify novel biomarkers to better manage primary liver cancer patients, for whom additional biological samples will be collected. A total of 4000 patients will be enrolled; for the prospective cohort: from protocol approval to the achievement of the last planned patients in the prospective cohort (2000 patients). The retrospective cohort will start from the year 2000. Patients will be followed for 5 years of follow-up.