Hoofdorp, Netherlands

PET/MRI to Stage Prostate Cancer Patients

This is a prospective monocentric open study (Phase II study). The study will include 50 consecutive PCa patients who will be recruited in the first 36 months of the study. All clinical and pathological variables available at the time of PET/MRI will be recorded for each patient and all patients will take a blood sample before the first PET/MRI study. All patients will undergo 68Ga-PSMA and 68Ga-RM2 PET/MRI studies at San Raffaele Hospital in two different days (> 48 hours between the two studies) and within one month from each other. Then, patients will undergo surgical intervention (prostatectomy and pelvic/retroperitoneal lymphadenectomy) and the surgically removed prostate will be fixated and processed. Ex-vivo 3T-MRI study will be performed on the processed specimen (prostate gland) and afterwards, the prostate will be examined by a dedicated pathologist. Spatial coregistration of in vivo, ex-vivo and histopathological images will be performed so that the annotation (dominant tumor lesion) made by the pathologist will be translated onto in vivo PET/MR images and semi-quantitative and radiomic features will be extracted from PET and mp-MRI images

Novel Targets for the Development of Monoclonal Antibodies for Immunotherapy)

Dietary Intervention to Improve Fertility in Women With Endometriosis Undergoing IVF

Women who agree to participate in the study will be randomized into two groups: one group will receive standard IVF protocols, and the other will undergo a 12-week anti-inflammatory diet followed by the standard IVF protocol. In both groups, participants' dietary habits will be monitored throughout the study period to detect any variations. The primary outcome will be to compare the rate of inadequate ovarian response to hormonal stimulation (defined as the retrieval of ≤3 oocytes according to the Poseidon 2016 criteria) in infertile women with endometriosis.

Functional Capacity in Anderson-Fabry Disease Patients

Biological Markers and Advanced Imaging for Prostate Cancer Progression in Active Surveillance

FDG-PET/CT vs. CT for Monitoring Metastatic Breast Cancer

Background Breast cancer is the most commonly diagnosed cancer in Europe and worldwide. With a continuously increasing incidence, it is estimated that by 2040, the breast cancer burden will increase to more than three million new cases per year worldwide, with more than one million breast cancer-related deaths per year (50% increase). The prognosis of breast cancer is steadily improving due to the early detection of primary cancer through screening programs and revolutionising treatment development. Despite this, approximately one-third of patients diagnosed with primary breast cancer will develop metastatic disease. In the metastatic setting, therapy improvements have made breast cancer a chronic disease with declining mortality rates, and several effective treatment lines are available for metastatic breast cancer patients today and in the future. This favourable situation requires accurate methods to assess response to treatment to achieve the most effective treatment planning. FDG-PET/CT is increasingly used in cancer staging. Several studies have shown improved sensitivity of FDG-PET/CT compared with conventional imaging for diagnosing metastatic breast cancer in retrospective and smaller prospective studies. We expect FDG-PET/CT to detect disease progression earlier than CT in patients treated for metastatic breast cancer, enabling earlier start of second-line therapies. This has the potential to increase the beneficial effect of second-line therapies at the individual level and result in a delayed need for third-line therapies, prolonged overall survival, and improved quality of life compared with patients monitored with conventional CT. Currently, no specific recommendations are provided for a diagnostic modality to monitor treatment response in patients with metastatic breast cancer. European clinical practice guidelines (ESMO) state that there is no evidence of any staging or monitoring approach for metastatic breast cancer patients that provides overall survival benefit over another approach. ESMO suggests that FDG-PET/CT might provide earlier guidance in the monitoring of bone-only or bone-predominant metastasis, but it is emphasised that prospective trials are needed to study the impact of this on treatment decisions and overall survival. This is the evidence that MONITOR-RCT will deliver. Study objectives The primary objective of the MONITOR-RCT is to demonstrate that in patients with metastatic breast cancer, response monitoring based on FDG-PET/CT is superior to response monitoring based on CT with respect to overall survival. The objective will be based on applying standardized response evaluation criteria, using an appropriate adaptation of the PERCIST criteria for FDG-PET/CT and the RECIST1.1 criteria for CT. Secondary objectives of the MONITOR-RCT are to demonstrate superiority with respect to the quality of life and exposure to oncologic treatment and to investigate the cost-effectiveness. Consequently, the primary endpoint of the study is overall survival. Secondary endpoints are quality of life, exposure to oncologic treatment, and cost-effectiveness. Study design The MONITOR-RCT study will be an international multicenter study. The design will be a parallel group comparative randomized trial comparing an experimental monitoring strategy based on FDG-PET/CT with a standard monitoring strategy based on CT. Eight hospital sites in Denmark, two in Italy, and one in Germany will participate in patient recruitment and the conduction of the study. Inclusion criteria Criteria for inclusion will be: Women and men aged ≥18 years Diagnosis of distant relapsed metastatic breast cancer (biopsy-verified) or de novo breast cancer. In patients with distant relapsed metastatic breast cancer, biopsy verification from a distant metastasis is required. In patients with de novo metastatic breast cancer, biopsy verification of primary tumor and diagnostic imaging with distant metastasis with a typical pattern of metastatic breast cancer is required. Considered eligible for first-line systemic treatment Considered eligible for continuous treatment monitoring by scans. Signed informed consent Participants must have the ability to read and understand the following languages based on their country of participation: in Denmark, patients must be able to read and understand Danish; in Italy, they must be able to read and understand Italian or English; and in Germany, they must be able to read and understand German or English. Exclusion criteria Criteria for exclusion will be: Pregnant or lactating women Ongoing oncological treatment for another cancer Exclusively brain metastasis Allergy to FDG Target population Participating patients should have newly diagnosed metastatic breast cancer and be considered eligible for initiating first-line medicinal treatment and subsequent regular response monitoring. This is the patient population for whom a benefit from FDG-PET/CT-based response monitoring is expected. They are very similar to the criteria defining the populations investigated in Vogsen et al. (2023) and Naghavi-Behzad et al. (2022). Quality of life questionnaires Quality of life questionnaires will be completed at home every three months during the first year and every six months later. Two questionnaires will be used: EQ-5D-5L FACT-B In addition, patients can report complaints related to the conduct of scans in a final open question at the end of the questionnaires. Interventions The intervention of interest is the use of FDG-PET/CT for response monitoring compared with CT for response monitoring. The use of CT as a monitoring modality represents the usual care in patients with metastatic breast cancer. FDG-PET/CT scans will be evaluated using the standardized response evaluation criteria for patients with metastatic breast cancer (PREMIO criteria), whereas the CT scan will be evaluated using the RECIST 1.1 criteria. Both criteria aim at classifying the patient as having complete (metabolic) response (CR/CMR), partial (metabolic) response (PR/PMR), stable (metabolic) disease (SD/SMD), equivocal metabolic disease (EMD) or progressive (metabolic) disease (PD). The PREMIO set of response evaluation criteria is an adaptation of PERCIST (for monitoring patients with metastatic breast cancer. The PREMIO criteria are defined based on data from the MESTAR study, Vogsen et al. (2023), introducing the nadir scan for comparison in cases where the disease has regressed compared with the baseline scan. Clinical decision-making: For patients in the intervention group, clinical decision-making will be supported by FDG-PET/CT and PREMIO, while the conventional group will be supported by the CE-CT and RECIST 1.1. The decision-making will be in both groups following the current standard according to the local practice and following international guidelines. The decision-making may include a request for further imaging procedures. Parameters such as toxicity profile and the patient's general condition will also influence treatment decisions. Major components of patient management and the main reasons for treatment decisions will be registered throughout the study. Scan procedure and interpretation: All patients will have baseline scans performed before treatment and according to the randomization group. Treatment and follow-up scans will be approximated at regular intervals of 9-12 weeks or according to local guidelines. The choice of the diagnostic modality does not influence the monitoring intervals or time points. Contrast-enhanced CT of at least the thorax and abdomen will be performed using diagnostic scan quality. Pelvic CT may be added based on clinical need. The scan reports will be made by specialists in radiology with an assessment according to the RECIST 1.1 criteria. FDG-PET/CT will follow standard guidelines from the European Association of Nuclear Medicine. FDG-PET/CT scans will be conducted on EARL2 certified PET scanners, and the quantitative assessment, using the SULpeak value of the hottest metastatic lesion, will based on the EARL2 reconstruction. The CT performed along with the PET scan will be of diagnostic quality and will have contrast enhancement, if not contraindicated. The scans will be assessed by specialists in nuclear medicine according to the suggested PREMIO criteria. According to RECIST 1.1 and PREMIO, disease measurability will be evaluated at the baseline and during follow-up in each study group. In cases of no measurable disease according to the respective criteria applied, the patient's scans will be assessed qualitatively with a parallel response categorization. This categorization slightly differs from the one used in the case of measurable disease, but it still allows for the distinction of progressive disease from all other states. CT and FDG-PET/CT scans will be viewed based on the existing standard software. Viewing of FDG-PET/CT scans will be further supported by software developed as part of the establishment of the PREMIO criteria. Application of the criteria remains a task for radiologists or nuclear medicine specialists. Outcome variables The primary endpoint "Overall survival" will be addressed based on the primary outcome variable "Time from randomization until death". The secondary endpoint "Quality of life" will be addressed by two outcome variables. The first is the overall summary score of the FACT-B, the second the complaints related to the conduct of scans reported by the patients. The secondary endpoint "Exposure to oncologic treatment" will be addressed by the following outcome variables describing different aspects of oncological treatment: Experience of progression Start of a new treatment line because of progression Time to first progression Time from first to second progression Time from second to third progression Experiencing other diagnostic procedures Hospitalization The secondary endpoint "Cost-effectiveness" will be addressed based on relating the outcome variables "Overall survival" and "Quality of Life" to the outcome variable "Costs". These outcome variables correspond to the expected benefits described above. Sample size considerations Sample size considerations are based on using a direct comparison of the survival rates at 42 months. The statistical test finally used will be more powerful due to summarizing the information from all time points and adjustment for prognostic covariates. In the study of Naghavi-Behzad et al. (2022), the survival rate after 42 months was 34% in the CT group and 51% in the FDG-PET/CT group. Due to the introduction of new, more effective treatment lines in the last decade, we expect higher survival rates in this RCT. Sample size calculations are based on the assumption that true survival probabilities will be 39% and 56%, respectively. Under this assumption, we have to include overall 420 patients to reach a power of 87% (based on two-sided testing at the 5% level). According to the timeline of the study, the minimal (planned) follow-up time of the patients will be 36 months, and the maximal follow-up time will be 54 months. In the above calculations, a uniform distribution of the follow-up time was assumed. With respect to the primary outcome (survival), we do not expect drop outs, as we can rely also on national registries. Hence drop-outs are not accounted for in the sample size calculation. Significance level A significance level of 5% (two-sided) will be applied. Exposure to radiation The radiation dose is an issue of consideration. The average radiation dose per patient per scan procedure is estimated, in conventional diagnostic CT, to be 9 mSv and in conventional 18F-FDG-PET/CT to an additional 4 mSv, respectively.

Interactive Mirroring Games wIth sOcial Robot (IOGIOCO) and Robotic System Adapted Into a Clinical Scale (RISCALE)

Background: The importance of early intervention in Autism Spectrum Disorders (ASD) has been widely demonstrated, and developmental trajectories in ASD highlight the importance of nonverbal communication, such as intransitive gesture production, as a possible positive prognostic factor for language development. The use of technological tools in the therapy of individuals with ASD has also become increasingly important due to their increased engagement and responsiveness to technological objects, such as robots. We developed a training protocol using the humanoid robot NAO, called IOGIOCO (Interactive mirroring Games wIth sOCial rObot), based on the use of intransitive gestures embedded in naturalistic dialogues, stimulating a triadic interaction between child, robot and therapist. The training is divided into six levels; the first 2 levels were called "familiarization levels," and the other 4 were "training levels". The technological setup includes different complexity levels, from mirroring tasks to building spontaneous interactions. We previously tested the protocol on 10 preschool children with ASD (aged 2-6 years) in a pilot study founding promising results (Annunziata et al,2024). We therefore developed a Randomized Controlled Trial to test the efficacy of this intervention. The primary objective of the RISCALE study is to evaluate the effectiveness of NAO training in improving socio-communicative skills and acquiring communicative gestures using the ECSP-I scale as the primary outcome measure. A second objective stems from the technological experience acquired in these two years on the development of methods for the quantitative recording of social interaction (child-operator, child-NAO gaze contact, joint attention...). 2 scenarios have been identified in the scale that can be achieved both with the human operator and through the action of NAO: - the response to the adult's gesture of indication; - the differential response - Joint Attention and/or Behavior Regulation - to the activation of a mechanical toy). The two scenarios will be videotaped with Kinect equipment and measurable data will be acquired for quantitative analysis. The procedure will be validated on a sample of typically developing children (about 20); adapted and validated the instrument on the sample of typically developing children, then the administration and then the validation of the setup obtained on subjects with Autism Spectrum Disorder will take place. The aim is to evaluate whether and how the modes of visual exploration and joint attention change and/or differ pre- and post-training, and the differences that may be evident in the modes of interaction between child and operator and between child and robot. In time, therefore, the following will be provided: 1. to set, adapt and subsequently validate the video recording setting with the identification of the quantitative parameters detectable through technological tools (ECSP-I_rob) on a sample of typically developing children aged between 18 and 24 months 2. to set, adapt and subsequently validate the video recording setting with the measurement of the quantitative parameters detectable through technological tools (ECSP-I_rob) on a sample of children with Autism Spectrum Disorder under the age of 72 months 3. start training with NAO on a group of children with ASD aged 24-72 months with pre- and post-treatment ECSP-I administration. Objectives 1. To evaluate the effectiveness of the robot-based intervention on social-communicative skills and in the acquisition of intransitive gestures used for communicative purposes using the ECSP-I and the MacArthur questionnaire as an outcome measure. The rationale remains the one already detailed in the previous phase, namely that ASD children tend to have greater difficulty in paying attention to the variability and multiplicity of signals characterizing human social interaction (e.g. mimicry, gestures...), an aspect that could lead to a possible lower interest in interaction with an individual than in a technological object towards which they would seem more attentive, responsive and quick in response 2. identify and describe measurable parameters of "social" interaction within the rehabilitation session with NAO and operator and verify their evolution and differences at the beginning and end of treatment and between the different social partners. Translationality The present study will allow to verify the feasibility and usability of the experimental evaluation protocol based on the use of the social robot NAO. If its validity is demonstrated, this method could help to make habilitative interventions in children with ASD more motivating and effective, favoring the generalization of the skills acquired in the context of daily life. Methodology Study design Multicenter Experimental Randomized Open-Label Controlled Study Type of study Low-risk experimental study Case studies Phase 1: 20 typically developing children aged 18-24 months for ECSP-I_rob data acquisition (videotaped ECSP-I administration) Phase 2: 10 ASD children - videotaped ECSP-I administration Phase 3: 20 children diagnosed with ASD aged between 24 and 72 months, already in charge for rehabilitation treatment, who will subsequently be divided into two groups for treatment. Sample Recruitment The 20 typically developing children will be recruited for adaptation and validation of the ECSP-I scale to the NAO interaction system on a voluntary basis at the NEARLab of the Politecnico di Miano and will be evaluated by a properly trained TNPEE of Fondazione Don Gnocchi Children with ASD will be recruited from among the subjects who belong to the outpatient clinics or outpatient rehabilitation treatments at IRCCS Fondazione Don Gnocchi. The sample will be recruited sequentially among children in charge for rehabilitation treatment, who have a diagnosis of Autism Spectrum Disorder confirmed with the main gold-standard tools. Sample size The calculation of the sample size is based on the primary objective of the study, i.e. the evaluation with the ECSP-I scale of the treated group and the control group. Using the Mann-Whitney Test for independent samples to compare the two groups, with a standard deviation estimate of 0.56 and a study design with a 1:1 ratio between the treated group and the control group, it is calculated that a sample of 10 subjects from each group is required to highlight an expected difference of 0.8 points on the scale with a study power of 80% and a level of significance of 5%. Statistical analysis A sequential design will be adopted for the comparison between the two groups. The adoption of this design will allow to obtain a sample of 20 participants for pre- and post-training comparison and to offer the training provided for the experimental group (group A) also to the initially control group (group B) without substantial burdens for the standard therapy procedure; it will also allow to verify the change due exclusively to the passage of time and standard therapy (T0 and T1 comparison for group B) and to carry out a follow-up (T1 and T2 comparison for group A). We also expect greater adherence to the trial, as parents would be enticed to participate by inclusion in an additional pathway to standard therapy (and not simply participation as a control group). Given the expected number of participants, and the scores of the ECSP-I scale that are expressed in ordered categories (Optimal Levels), the comparison between the measurements provided for by the sequential design (T0, T1 and T2) will be carried out with non-parametric statistical tests: - Wilcoxon Exact Test, for longitudinal comparison of each group. - test for independent samples in the exact form test for independent samples in the exact form (Mann-Whitney Exact Test), for the comparison between the experimental group and the control group. - The 2 groups will also be compared through a multivariate analysis, conducted by applying the ANCOVA model adjusted for months of age and baseline scale values to correct for potential imbalances due to the low sample size. Procedures Phase 1: ADMINISTRATION OF ECSP-I SCALE on a typically developing sample The 20 typically developing children will be recruited for the adaptation and validation of the two scenes of the ECSP-I scale to the NAO interaction system on a voluntary basis at the NEARLab of the Politecnico di Miano and the scale will be administered by a properly trained TNPEE of Fondazione Don Gnocchi Phase 2: ADMINISTRATION OF THE ECSP-I SCALE and robot-adapted scenes to a sample of children with ASD The ECSP-I scale and scenes adapted to the social robot will be administered to a sample of children with Autism Spectrum Disorder in order to gain experience and collect data about the administration of this scale to a clinical sample of 10 children. The administration will be videotaped and encoded with the supervision of the developers. Phase 3: Recruitment and randomization of the sample of children with ASD. 20 children with Autism Spectrum Disorder will be recruited, subjected to T0 assessment. Phase 4: The sample will then be divided into two groups: - a group A and group B, which will carry out training with the social robot (see Appendix A for the training protocol) at 2 different times. Phase 5: All the recruited sample will be subjected, at different times, to rehabilitation training with NAO following the protocol in the Appendix. The training will last 12 weeks, with one session per week, lasting 20-30 minutes. Phase 6: Re-evaluation to T1 and T2 according to the treatment scheme (see Table 3). Evaluation tools - Griffiths Mental Development Scales III ed (GMDS-III) [30] - Adaptive Behavior Assessment System II ed (ABAS II) [31] - Autism Diagnostic Observation Shedule (ADOS 2) [32, 33] - Autism Diagnostic Interwiev Revised (ADI-R) [34] - McArthur-Bates Questionnaire, First Vocabulary of the Child (PVB) Gestures and Words: total number of gestures [35] - Early Social Communication Scale (ECSP-I) [27] - Adapted scenes of the ECSP-I with NAO Social Robot (ECSP-I_rob) (quantitative measurement of interaction data) Criticality The main critical issue concerns the recruitment of subjects and their availability during the study period and the continuity of the intervention. For this reason, an extended recruitment period has been hypothesized, which will cover a large part of the entire duration period of the study. Expected results - Verification of the sensitivity of the ECSP-I in grasping the improvement of socio-communicative skills, in particular in the use of gestures. - Improvement in the use of gestures learned during training, in terms of: - Correctly learned gestures used in the therapeutic setting in known scenarios; - Learned gestures correctly used in the therapeutic setting in new scenarios (first step of generalization); - Increase in the number of gestures used in daily life (second phase of generalization; Mc Arthur questionnaire); - Measurement of social interaction parameters detectable with technological tools.

A Study of BMS-986504 in Participants With Pre-treated Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) With Homozygous MTAP Deletion

The Echodynamic Approach

The non-invasive echocardiographic assessment will be used to esimate via mathematic formulas all the direct and indirect paramethers obtained from the right side catheterization. Each value obtained from the model using echocardiographic paramethers will be compared to the invasive finding.

Infection Control Link Nurses Program to Improve Compliance With Standard Precautions, Hand Hygiene, and Prevent Healthcare-Associated Infections

In this cluster RCT, all medical-surgical wards and ICUs of the Center where the study will be conducted, will be selected. Subsequently, cluster randomization will divide those hospital units in two arms: (1) Intervention group - 1 ICLN per ward/ICU will be identified and formed; (2) Control group - wards and ICU that will continue standard IPC practice. Assessment, data collection, and intervention will be administered within the hospital facility. Since this hospital comprises in total 6 medical-surgical wards and 2 ICUs, each study group (i.e., Intervention group and Control group) will comprise 4 hospital units. Data will be collected in presence at baseline (T0 - before ICLNs' implementation) and after 12 months (T1). - Primary endpoint will be nurses' compliance with standard precautions, using a validated instrument ("Compliance with Standard Precaution Scale-Italian version; CSPS-It) - Secondary outcomes (i.e., healthcare professionals' hand hygiene compliance, healthcare professionals' alchol-based hand rub consumption and healthcare-associated infections incidence rate) will be evaluated for all healthcare professionals working in the promoting center. Signing of Informed Consent will only be required by nursing staff who fill-out the CSPS-It, whereas all other data collected (hand hygiene compliance, alchol-based hand rub consumption consumption and HAIs incidence) are part of usual intra-hospital surveillance practices and do not involve the collection of any personal data. For this reason, nurses working in the selected units will be asked to participate in the study, and they will be asked to sign an Informed Consent form and will be consecutively enrolled until the sample size is reached (i.e., 100 nurses). After cluster randomization is performed, recruitment of potential participants will begin. 4 ICLNs will be selected and every clinical nurse working full-time in the selected hospital units will be asked to participate in the present RCT. After signing the Informed Consent, baseline data collection will begin. At baseline (T0) socio-demographic data and job-related informations (e.g., time in years of clinical experience as a nurse, study degree) will be collected. Afterward, participants will be asked to fill out a validated instrument aiming to measure compliance with standard precautions (i.e., CSPS-it). Sample size is composed only by nurses because CSPS-It is validated only for registered nurses and nursing students. Concurrently, data regarding healthcare professionals' (i.e., doctors, nurses, support personnel, technicians) compliance with hand hygiene (HH), Alcohol-Based Hand Rub (ABHR) consumption, and Healthcare-Associated Infections (HAIs)' incidence rate will be collected. During the 12-month ICLNs implementation program, ICLNs will be continuously supported in their activities by hospital management and by their colleagues, and they will be asked to participate in monthly educational meetings covering core elements on HAIs prevention and control, standard and isolation precaution measures, and hand hygiene paired with flexible times useful for ICLNs to create debates, reflect on barriers, and analyze situations together. After 12 months (T1), the same data collection at baseline (T0) will be performed (i.e., CSPS-it, HH compliance, ABHR consumption, HAIs' incidence rate). Data collection will be carried out by research assistants trained to the present protocol, HH compliance direct observations will be performed by hospital personnel not involved in this RCT, data related to AHRB consumption and HAIs rate will be collected by trained personnel working in the hospital facility. To ensure privacy, data at baseline and follow-up will be collected, analyzed and presented exclusively in aggregate form (i.e., for the intervention group and control group).