Rusa, Bulgaria

Long-term Safety of Nipple Sparing Mastectomy in Women With GPV in Breast Cancer

A Global Phase III Study of Rilvegostomig or Pembrolizumab Monotherapy for First-Line Treatment of PD-L1-high Metastatic Non-small Cell Lung Cancer

This is a Phase III, two-arm, randomized, double-blind, global, multicenter study assessing the efficacy and safety of rilvegostomig compared to pembrolizumab as a 1L treatment for patients with mNSCLC whose tumors express PD-L1.

The Triad of Nutrition, Intestinal Microbiota and Rheumatoid Arthritis (TASTY)

100 RA patients will be recruited at ULS Santa Maria in Lisbon, Portugal, and randomly assigned to either the intervention (MedDiet+) or the control group. The 12-week nutritional intervention will include a personalized dietary plan based on the MedDiet+ pattern, educational resources, food basket deliveries, and clinical culinary workshops, all developed and monitored weekly by registered dietitians. The control group will receive general recommendations for a healthy diet at baseline. The intervention's effects will be assessed by evaluating disease activity, functional status, quality of life, intestinal permeability, endotoxemia, inflammatory biomarkers, intestinal and oral microbiota, serum proteomics, and serum glycome profile characterisation.

Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulants

International Cardiac Amyloidosis Registry

Rationale: Patients with cardiac amyloidosis are in general underdiagnosed and undertreated. AL amyloidosis is a disease with a very poor prognosis if left untreated. For ATTR amyloidosis, recently, specific treatment has become available for patients fulfilling certain criteria with good results in clinical trials. The rationale behind this prospective registry is to collect real-world data on diagnostic process, management, progression of disease and outcome of patients with cardiac AL and ATTR amyloidosis who are treated following local standards and to obtain (echocardiographic) predictors of prognosis in these patients. Objective: The objective of the study is to evaluate the diagnostic process from onset symptoms to diagnosis, the outcome in a real-world cohort of amyloidosis patients and to find predictors (both clinical and echocardiographic) of outcome Study design: Prospective long-term observational study Study population: All patients >18 years old, prospectively diagnosed with cardiac AL or ATTR amyloidosis Intervention (if applicable): n/a Main study parameters/endpoints: The main study endpoints are death, heart failure hospitalization and cardiovascular events Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients who participate in the registry will undergo structured follow up according to the clinical care pathway for amyloidosis patients based on the recommendations in the most recent Position Statement from the European Society of Cardiology [1]. There will be no additional visits planned, therefore no additional burden is associated with participation in the registry. Patients agree that their anonymized data is shared with other centers within the amyloidosis consortium.

Improving Colorectal Cancer Early Screening in Portugal: Identification of Gut Microbiome Biomarkers in Stool (GUTBIOME-PT)

This study will analyse the gut microbiome in stool samples collected from individuals living in the Lisbon Metropolitan Area, Portugal. Using shotgun metagenomics, the investigators aim to identify microbiome biomarkers associated with the early detection of CRC and the progression of precancerous lesions (adenomas). The identified biomarkers will be tested to develop a non-invasive and highly sensitive screening tool for CRC and precancerous lesions. Primary Objective: To identify gut microbiome biomarkers in faecal DNA associated with CRC and/or high-risk adenomas. Secondary Objectives: i) Establish the correlation between FIT results, faecal microbiome testing and colonoscopy results. ii) Estimate the incidence of CRC in the Lisbon Metropolitan Area among individuals aged 40-74 years, stratified by sex and age group. iii) Analyse associations between clinical data (e.g., clinical history, lifestyle, and dietary habits), faecal microbiome profiles, FIT results, and colonoscopy outcomes, comparing individuals with CRC and/or high-risk adenomas against healthy individuals, for the total sample and by sex and age group; iv) Identify risk factors (e.g., clinical history, lifestyle, dietary habits) associated with CRC development, stratified by sex and age group. Study Design: This is an observational, prospective, longitudinal study involving individuals aged 40-74 years residing in the Lisbon Metropolitan Area who voluntarily enrol in the study. Participants meeting all inclusion criteria and no exclusion criteria (as detailed in the relevant section) will be included. Based on sample size calculations using the Neyman allocation formula and taking as a reference the distribution of the population living in the Lisbon Metropolitan Area (stratified by sex and age groups: 40-49, 50-59, 60-64, 65-69 and 70-74 years), along with assumptions of the overall FIT test prevalence and sensitivity, a total of 30.000 participants will be enrolled. At baseline, participants will provide a faecal sample within 2 to 10 days of enrolment. Demographic, clinical, and lifestyle data-including age, family history of CRC, personal medical history, smoking habits, physical activity levels, stress, and body mass index (BMI)-will be collected via self-administered questionnaires. Dietary habits and adherence to the Mediterranean diet will be assessed through telephone interviews. Participants will be followed for six years, with faecal samples collected every 2 years. Clinical and lifestyle data will also be updated every two years throughout the study period.

A Phase 3, Placebo-Controlled Study to Investigate LP352 in Children and Adults With Dravet Syndrome (DS)

A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)

Evaluation of PreveCol's Efficiency As a Second Line Method for the Early Colorectal Cancer Detection

High - Flow Nasal Cannula Versus Conventional Nasal Cannula During Endobronchial Ultrasound Procedure

Introduction 1. EBUS - bronchoscopy From a physiological point of view bronchoscopy is an introduction of a foreign body into the airway. Response mechanisms include laryngospasm, bronchospasm, cough, increased secretion of bronchial mucus and reduced depth of breathing. Sympathetic response with increased heart rate and blood pressure is common even before the procedure, while the patient is being prepared on the examination table. The bronchoscope occupies 10 to 15% of the cross-sectional area in the major airways and increases air flow resistance. Suction applied during the procedure causes air stealing through the working channel of the bronchoscope which reduces end inspiratory and expiratory volumes leading to alveolar de-recruitment with increased intrapulmonary shunting consequently. EBUS bronchoscopy is associated with prolonged procedure time, increased airway contact, a thicker instrument, and multiple needle punctures through the tracheal and/or bronchial wall. All these factors cause additional stress to the patient and require additional local anesthesia and deeper level of sedation. 2. Sedation Although topical anesthesia of the upper airways, vocal cords, trachea, and bronchi enables a tolerable bronchoscopic procedure, a moderate level of sedation during bronchoscopy is currently the golden standard. Use of sedation facilitates the passage through the vocal cords, inhibits airway protective reflexes and increases patient safety (2,3). In combination with physiological responses to bronchoscopy which increase oxygen demand, sedatives used during bronchoscopy reduce respiratory drive and further compromise patients, especially those with chronic diseases. When it occurs, hypoxemia can induce periprocedural arrythmias and ischemia therefore should be generally avoided and, if encountered, must be reverted quickly (4). An oxygenation strategy with appropriate oxygen supplementation is therefore required during most bronchoscopic procedures. 3. Oxygen supplementation Low flow oxygen up to 6 liters per minute applied through a nasal catheter is the most often used method for oxygen supplementation during flexible bronchoscopy. Inspired oxygen fraction (FiO2) can reach up to 45% but cannot be reliably predicted and may not be enough in all cases. High flow nasal cannula (HFNC), a device first introduced in neonates and pediatric care, is currently used in a wide range of indications in adult respiratory and critical care medicine (5-7). It is a relatively new method in bronchoscopy with several notable theoretical advantages over low flow oxygen via conventional nasal cannula (CNC): - High flow up to 60 liters per minute ensures a more stable FiO2 and better matches the increased patient's inspiratory flow - High flow generates a small positive expiratory airway pressure (up to 5 cm H2O) which could stabilize the upper airways during sedation and have a beneficial effect in the lower airways - High flow reduces dead space in the upper airways and increases alveolar ventilation. CPAP and NIV can provide similar beneficial effects, but their use is challenging because they require a close-fitting facial mask which limits the use of a bronchoscope, aspiration of secretions from the upper airways, pharynx, or oral cavity and expectoration of sputum. 4. Previous studies on HFNC A recent meta-analysis which included six randomized controlled trials found that patients who underwent bronchoscopy with the use of HFNC experienced less hypoxemic events and desaturations, had fewer procedural interruptions and pneumothorax compared to patients supplemented with CNC (10). The three studies which evaluated HFNC during EBUS all showed that HFNC is more effective than CNC during the procedure and that HFNC can be considered an alternative to CNC. However, the studies had several important limitations such as a low number of patients included with a historical control (Takakuwa O et al), a large difference in FiO2 between trial groups (2L/min in the CNC vs. 100% FiO2 and 70L/min flow rate in the HFNC group) (Irfan et al) and lack of assessment of CO2 levels during the procedure (Ulcar et al). Nevertheless, conclusions suggested that HFNC is sufficiently safe and provides adequate oxygenation for most of bronchoscopy examinations including EBUS (8,9). 5. Study questions Our hypothesis is that HFNC provides better control over hypoxemia during EBUS-TBNA procedure than CNC. The primary outcome of the study is therefore proportion of patients with successfully controlled hypoxemia during EBUS TBNA in each arm. Secondary outcomes are incidence of complications in each arm (number of hypoxemic events, mean lowest oxygen saturation during procedure, average saturation, drop in saturation, pulse rate, blood pressure, incidence of arrhythmia), number of patients who experienced mild, moderate, or severe hypoxemia, number of patients who required escalation of the support and which support is effective, what are risk factors for desaturation. Methods 1. Study design and study population The study is designed as multicenter randomized controlled prospective trial. Study will enroll patients who need EBUS -TBNA procedure with sampling of mediastinal lymph nodes for diagnosis and/or staging. Patients will be recruited from four university hospitals in Slovenia, Croatia, Portugal and Greece. Study was approved by The National Medical Ethics Committee of the Republic of Slovenia and registered as 0120-294/2023/3. 2. Recruitment, consensus, and randomization Bronchoscopy coordinator will screen the scheduled patients and notify study investigator about eligible patients. Study investigator will explain the study to eligible patients and obtain informed consents. Inclusion and exclusion criteria will be checked on the day of examination from the data routinely obtained before procedure, including laboratory data. Patients will be randomized in bronchoscopy suite according to allocation group written in sequentially numbered, sealed and opaque envelopes. Envelopes will be prepared by independent statistician on the basis of block randomization with the block size of 4. 3. Bronchoscopy and sedation Topical anesthesia with lidocaine will be provided routinely before insertion of the bronchoscope. Patients will be sedated by bedside anesthesiologist by combination of midazolam, fentanyl and propofol. The depth of sedation will be assessed using Modified Observer's Assessment of Alertness / Sedation scale (MOAA/S). The level of sedation will be maintained between 1 and 2 throughout the procedure. Patients will be monitored by BIS monitor for further analysis and comparison. The standard group of patients will receive oxygen through double-prong nasal cannula with the oxygen flow set to 6 liters per minute, which corresponds to FiO2 45%. The HFNC group will receive mixture of oxygen and air at FiO2 45% with initial flow of 60 liters per minute pre-warmed to 37 degrees of Celsius. Nasal cannula will be chosen according to the patient's face size. Before procedure, patients from both groups will be tested with HFNC with the flow of 60 l/min if they are able tolerate it. EBUS bronchoscope will be inserted through the oral bite block by experienced bronchoscopist and the whole procedure will be conducted according to ERS recommendations. After systematical evaluation of mediastinal and hilar lymph nodes, EBUS TBNA's will be performed according to the individual procedure plan. Patients will be monitored by continuous pulse oximetry, periodical blood pressure measurements, ECG and BIS. 4. Hypoxemia escalation protocol, complications, and termination criteria Oxygen will be delivered to the patient according to the allocation group (6l/min O2 CNC or 45% FiO2 60 l/min HFNC). If desaturation occurs, defined as SpO2<90% for more than 10s the patients will be approached according to the escalation protocol (Figure 1): 1. jaw thrust maneuver 2. patients in CNC group will be switched to 45% FiO2 60 l/min HFNC 3. patients with 45% FiO2 60 l/min HFNC will be switched to 100% FiO2 4. patients with HFNC failure will be switched to advanced respiratory support (balloon ventilation, laryngeal mask, intubation, reversal of sedation) In the case of moderate hypoxemia there will be temporal suspension of the bronchoscopy but in the case of severe hypoxemia the termination of the procedure will be considered if there is no immediate improvement after escalation of ventilatory support. Procedure will be terminated also in the case of other severe adverse events as are hemodynamic instability, myocardial ischemia, or pneumothorax. Resuscitation equipment will be prepared on dedicated medical cart inside the bronchoscopy suite. Any patient with adverse event will be monitored until complete recovery (Alderete score 9 or more). Complications, relevant to the decisions and study outcomes are defined as (1): - Desaturation <90% for more than 10s - Moderate desaturation 75%<= SpO2 <90% less than 60s - Severe desaturation <75% or 75%<= SpO2 <90% more than 60s - Tachycardia >100 or +25% - Bradycardia <50 or -25% - Hypertension +25% - Hypotension <90mmHg or -25% 5. Data collection Demographic data of patients (age, gender, height, weight, BMI, STOP-BANG score, ASA score) and laboratory results (lung function testing) relevant for the study will be collected before the procedure. During and after the procedure, there will be continuous (SpO2, pulse rate, ECG) or periodical (blood pressure) monitoring of vital signs and depth of the sedation (BIS, MOAA/S). The starting point of the procedure T0 is defined as the time immediately prior sedatives are given to the patient. T1 is the time point, where bronchoscope is inserted and Tend is the end of the procedure, when bronchoscope is withdrawn. Venous blood for pCO2 analysis will be drawn at T0 (on the procedure table before sedation) and at Tend (withdrawal of the bronchoscope). Timing and duration of desaturation, the lowest SpO2 and all treatment escalations will be recorded as well as other possible complications. 6. Sample size The protocol is designed to show a superiority of HFNC over CNC. According to pulled data in recently published meta-analysis we expect a 12% desaturation rate in the HFNC group and a 34% desaturation rate in CNC group. The sample size should be 112 with a confidence level (alpha) of 95%, power (1-beta) of 80%. With expected drop out of 25% the final number of included participants is set to 150. A web-based application was used for sample size calculation (https://clincalc.com/stats/samplesize.aspx). 7. Statistical analysis Data will be collected in specially designed case report formulars (CRF) and analyzed by GraphPad Prism 9.5. software (Boston, MA). Categorical variables will be presented as percentages and analyzed by chi-square test. Numerical variables will be presented as mean and standard deviation or median and ranges. Distribution will be tested by the Kolmogorov - Smirnov test and further analysis performed by t-test or Mann Whitney test depending on normality of distribution. Two-sided p-value will be regarded as statistically significant if < 0,05. 8. Patient and public involvement Patients and public were not involved in the study design. References: 1. Mason KP, Green SM, Piacevoli Q; International Sedation Task Force. Adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the World SIVA International Sedation Task Force. Br J Anaesth. 2012 Jan;108(1):13-20. doi: 10.1093/bja/aer407. PMID: 22157446. 2. Sazak H, Tunç M, Alagöz A, Pehlivanoğ Lu P, Demirci NY, Alıcı İO, et al. Assessment of perianesthesic data in subjects undergoing endobronchial ultrasound-guided transbronchial needle aspiration. Respir Care. 2015;60(4):567-76. 3. Douglas N, Ng I, Nazeem F, Lee K, Mezzavia P, Krieser R, et al. A randomised controlled trial comparing high-flow nasal oxygen with standard management for conscious sedation during bronchoscopy. Anaesthesia. 2018;73(2):169-76. 4. Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013 Aug;68 Suppl 1:i1-44. 5. Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-Flow Nasal Cannulae in the Management of Apnea of Prematurity: A Comparison With Conventional Nasal Continuous Positive Airway Pressure. Pediatrics [Internet]. 2001 May 1;107(5):1081-3. Available from: https://doi.org/10.1542/peds.107.5.1081 6. Roca O, Riera J, Torres F, Masclans JR. High-Flow Oxygen Therapy in Acute Respiratory Failure. Respir Care [Internet]. 2010 Apr 1;55(4):408 LP - 413. Available from: http://rc.rcjournal.com/content/55/4/408.abstract 7. Nishimura M. High-Flow Nasal Cannula Oxygen Therapy Devices. Respir Care [Internet]. 2019 Jun 1;64(6):735 LP - 742. Available from: http://rc.rcjournal.com/content/64/6/735.abstract 8. Takakuwa O, Oguri T, Asano T, Fukuda S, Kanemitsu Y, Uemura T, et al. Prevention of hypoxemia during endobronchial ultrasound-guided transbronchial needle aspiration: Usefulness of high-flow nasal cannula. Respir Investig. 2018;56(5):418-23. 9. Irfan M, Ahmed M, Breen D. Assessment of High Flow Nasal Cannula Oxygenation in Endobronchial Ultrasound Bronchoscopy: A Randomized Controlled Trial. J Bronchol Interv Pulmonol. 2021;28(2):130-7. 10. Su C-L, Chiang L-L, Tam K-W, Chen T-T, Hu M-C (2021) High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta- analysis of randomized trials. PLoS ONE 16(12): e0260716. https://doi.org/10.1371/journal. pone.0260716