Ústi Nad Labem, Czech Republic

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.

Supplemental High Flow Oxygen to Reduce Infections in Obese Gynecological Cancer Patients

This study aims to investigate the prophylactic value of postoperative oxygen administration against the development of wound infections in obese gynecological oncology patients undergoing laparotomy for the treatment of endometrial or ovarian cancer. At the same time, the factors that lead to an increase in this risk will be outlined.

Transcutaneous Vagus Nerve Stimulation on Fibromyalgia- Double-blind, Sham-controlled Randomized Clinical Trial

Fibromyalgia is a multidimensional disease, as many factors contribute to its development (biological, genetic, psychosocial). As a result, it demands a multifaceted approach, from patient education to pharmacological treatment etc. Regarding the pharmacotherapy, that should be aimed at a mechanism-oriented fashion. [7] Consistent with this approach, centrally acting medications can be effective in fibromyalgia, particularly antidepressants and anticonvulsants, which increase the presence of pain-inhibitory neurotransmitters by facilitating descending pathways and decreasing dorsal horn sensitization, or decreasing systemic hyperexcitability. Clinical trials have failed to conclusively provide overall benefits of specific therapies to treat fibromyalgia. Therefore, current pharmacological treatments for patients suffering from this syndrome are mainly directed to palliate some symptoms, with relevant clinical benefits experienced only by a minority of individuals. In those treated with pharmacotherapy, a 50% reduction in pain intensity is generally achieved only by 10% to 25%. However, some treatments seem to significantly improve the quality of life of certain FM patients. Only a few drugs have been approved for use in the treatment of FM by the US Food and Drug Administration (FDA), whereas no drug has been approved for this indication by the European Medicines Agency. Thus patients with FM frequently need to be treated on an off-label basis. Currently, only 25% to 40% pain reduction is granted by drugs and meaningful relief occurs in only 40% to 60%, in part due to dose-limiting adverse effects and incomplete drug efficacy. These limitations in clinical practice have led some to hypothesize that a combination of different analgesic drugs acting through different mechanisms may provide superior outcomes compared to monotherapy. Moreover, drugs should be started at low doses and cautiously titrated because severalpatients, either do not tolerate or benefit from drug therapy. Because sleep disturbance, pain and psychological distress are the most amenable to drug therapy, drugs should be chosen to manage the individual's predominant symptoms. Currently, several drugs are frequently used alone or in combination to manage FM symptoms. However, the US FDA indicated for FM only three: two selective serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran as well as an anticonvulsant, pregabalin. Although clinical evidence demonstrating the efficacy or effectiveness of opioids analgesics is scanty, these molecules are widely used for the treatment of FM. However, the long-term use of opioids in FM has been discouraged by several medical guidelines. As a result, there comes a need of a new treatment of fibromyalgia syndrome, which will be effective, safe, easily applied, with almost no side effects and low cost. Non-invasive neuromodulation techniques are gaining more and more the interest of the scientific society as regards a variety of medical conditions, such as chronic pain, epilepsy, rheumatoid arthritis. Transcutaneous Vagus Nerve Stimulation (tVNS) is one of these new techniques. The parasympathetic vagus nerve (10th cranial nerve) innervates multiple internal organs and integrates sensory, motor, and autonomic information by four vagal nuclei. The primary central relay of vagal afferents is the nucleus of the solitary tract in the brainstem, and several branches of this nucleus, project to different brain areas. The myelinated A- and B-fibers of the vagal nerve send somatosensory, motor, and autonomic signals, and the complex system of vagal projections is involved in inflammatory, immune, nociceptive, and emotional processes. A relevant role of the vagal nerve in pain processing is the transmission of peripheral inflammation signals to the central nervous system. Neuromodulatory activity has been identified in areas related to the sensory and emotional processing of pain, such as the insular cortex and the Anterior Cingulate Cortex (ACC), after vagal stimulation, which reveals that the central system of pain processing receives vagal afferences. In 1988 the first human implant of a vagal stimulating device was performed. In 1997, the US Food and Drug Administration (FDA) approved the use of Vagal Nerve Stimulation (VNS) as anadjunctive treatment for medically refractory epilepsy. Vagus nerve stimulation is a FDA-approved treatment for different pathologies. The regulation of the autonomic and immune systems and a specific effect on chemical mediators of inflammation are relevant physiological mechanisms of the VNS. At the present research study, we will use the 2016 revision to 2010/2011 ACR fibromyalgia diagnostic criteria. The treatment of fibromyalgia is based on a biopsychosocial approach and includes pharmacological and non-pharmacοlogical approaches, according to the EULAR recommendations. However, patients are still reporting high pain scores and increased interference with quality of life. Considering that the vagus nerve controls pain signals towards the central nervous system and growing evidence of autonomic dysfunction in fibromyalgia in terms of sympathetic hyperactivity, it can be argued that rebalancing the sympathetic- parasympathetic activity via vagal stimulation might reduce the intensity of pain and stabilize the autonomic symptoms of this disease. In addition, an immune system alteration seems to mediate the interaction between the autonomic nervous system and the chronic inflammatory state in fibromyalgia, apparently by the influence of inflammatory cytokines and chemokines. Stimulation of the auricular and cervical branches of the vagus nerve might reduce such inflammatory overactivity via efferent modulation of the activity of the inflammatory processes and hereby reduce pain symptoms. The potential of non-invasive stimulation of the auricular and cervical branches of the vagus nerve in repeated sessions to improve fibromyalgia symptoms has not been evaluated in randomized, sham-controlled clinical studies. Transcutaneous stimulation of the auricular and cervical branches of the vagus nerve (tVNS), are both non-invasive, low-intensity electric stimulation procedures. According to literature, the effectiveness of these non-invasive methods might not differ significantly from the invasive vagus nerve stimulation, while non-invasiveness provides an advantageous safety profile. Since fibromyalgia involves a dysregulation of the autonomic and immune systems, non-invasive tVNS is expected to improve the symptoms of fibromyalgia, including chronic, musculoskeletal, and generalized pain, through modulation of the vegetative and immune systems. The purpose of the proposed double blind placebo controlled randomized clinical trial is to investigate the effect of tVNS in Chronic Pain compared to medication and the future establishment of the given technique in the clinic. The research interest of the scientific community is growing more and more in recent years. However, research in thisfield is still in its infancy stages. At the same time the holistic treatment of chronic pain, including its neurobiological, psychosocial, cognitive and behavioral components, may become a valuable aid-giver in the best completion of the research project. Research question and Aim The hypothesis of our study is to evaluate, if the addition of transcutaneous stimulation of the auricular branch of the vagus nerves in patients suffering with fibromyalgia can lead to better pain control and quality of life. To investigate this, we will offer a 2 week treatment (14 sessions) in a double-sham controlled study. This study is designed to determine whether the standard pharmacological treatment paired with 14 sessions of tVNS can improve pain symptomatology in fibromyalgia and the whole range of FM symptoms, such as depression, anxiety, fatigue etc. by using appropriate scales as Numerical Rating Scale (NRS), Fibromyalgia Impact Questionnaire (FIQ), Brief Pain Inventory (BPI), Depression and Anxiety Stress Scale (DASS), Materials and Methods (binding+sham) Participants Our population will be comprised of fibromyalgia patients that are originally diagnosed or referred to Aretaieion Pain Clinic. For the diagnosis (or confirmation of diagnosis) we will be using the ACR (American College of Rheumatology) 2016 revised criteria. The present single center double blind sham-controlled randomized clinical trial will be conducted at the Pain Clinic of Aretaieion University Hospital, National and Kapodistrian University of Athens. Recruitment Methods Investigators may contact (or be contacted by) a potential subject by telephone or email or direct contact to discuss participation in this research protocol. The investigator will provide the subject with all the information contained in the written consent form and at the same time she will answer any questions regarding the research and give the subject sample, time to consider participation in the study, which may require a follow-up phone conversation or an in-person appointment at the Pain Clinic for a brief study enrollment screening visit.

GWAS to Identify Predictive Genetic Factors for the Success of Dietary Intervention in the Treatment of IBS Symptoms

Irritable bowel syndrome (IBS) is a very common chronic gastrointestinal disorder. Several factors seem to contribute to its development, such as psychological stress, intestinal dysbiosis, infections, post-traumatic syndrome and genetic predisposition. Regarding the nutritional management of IBS, there are several approaches to alleviate symptoms, such as the low-fructose diet low in fermentable oligosaccharides, disaccharides, monosaccharides and FODMAP polyols (LFD), recommendations from the British Institute of Health and Care Excellence (NICE) and the recently proposed combination of the Mediterranean diet and LFD (MED-LFD) proposed by our Research Group. However, genetic background expressed in single nucleotide polymorphisms (SNPs) appears to influence the response to even dietary interventions. The aim of this GWAS is to identify SNPs that are associated with the negative or positive response to the diet. At the baseline, blood samples will be collected for DNA extraction. Genotyping will be based on Next Generation Sequencing (NGS) technology to detect genetic factors associated with the effectiveness of the intervention. Symptom severity will be measured by the IBS-SSS scale. Mental health status will be assessed with the HADS (Hospital Anxiety and Depression Scale) questionnaire. Patients will be recruited by the Department of Clinical Nutrition, Attikon University General Hospital, where the nutritional intervention will be carried out.

Genomic and Methylation Markers in SCLC and LCNEC for Chemo-Immunotherapy Resistance Prediction (STRATUS)

The STRATUS Trial (Study of Tumor Characteristics and Molecular Signatures in Neuroendocrine Tumors and SCLC) is an ambitious, prospective observational study designed to explore the molecular and genomic mechanisms underlying resistance to chemo-immunotherapy in patients diagnosed with extensive-stage small cell lung cancer (ES-SCLC) and metastatic large cell neuroendocrine carcinoma (LCNEC). These two aggressive forms of cancer represent a significant unmet clinical need, with high relapse rates and limited therapeutic options available following the development of treatment resistance. The study seeks to uncover actionable biomarkers, characterize resistance mechanisms, and improve our understanding of tumor evolution under selective pressures from standard therapies. By leveraging cutting-edge molecular techniques, such as next-generation sequencing (NGS), DNA methylation profiling, and liquid biopsies, STRATUS aims to set the foundation for personalized cancer treatment approaches in these difficult-to-treat malignancies. Background and Rationale The Challenge of Resistance in ES-SCLC and LCNEC Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are both high-grade neuroendocrine tumors characterized by rapid growth, early dissemination, and a poor prognosis. Approximately two-thirds of SCLC cases are diagnosed as extensive-stage disease (ES-SCLC), where the tumor has spread beyond the hemithorax and regional lymph nodes. Similarly, LCNEC, though rare, is frequently diagnosed at metastatic stages, with limited systemic treatment options available. Standard treatment for ES-SCLC includes platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs), such as atezolizumab or durvalumab. While initial response rates exceed 70%, resistance develops rapidly in most patients, leading to disease progression within months. For LCNEC, the therapeutic landscape is even more limited, with a lack of targeted therapies or predictive biomarkers guiding treatment. Need for Molecular Insights Resistance mechanisms in these cancers are thought to involve tumor heterogeneity, clonal evolution, epigenetic modifications, and immune evasion. However, the exact processes that drive resistance remain poorly characterized. Molecular profiling offers an opportunity to identify genomic and epigenetic alterations that correlate with treatment failure, allowing for the development of predictive biomarkers and targeted therapeutic strategies. Role of Liquid Biopsies Liquid biopsies, including the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), have emerged as powerful tools for non-invasive tumor monitoring. These biomarkers provide real-time insights into tumor dynamics, enabling the detection of resistance mechanisms, clonal evolution, and molecular relapse. Study Objectives Primary Objective To identify and characterize genomic, epigenetic, and methylation signatures associated with resistance to chemo-immunotherapy in ES-SCLC and LCNEC patients. Secondary Objectives To evaluate the relationship between circulating biomarkers (CTCs, ctDNA) and clinical outcomes, including progression-free survival (PFS) and overall survival (OS). To compare molecular profiles between long-term responders and patients who develop early resistance. To assess tumor-immune interactions and their role in resistance mechanisms, focusing on PD-L1 expression, T-cell exhaustion, and cytokine signaling pathways. Exploratory Objectives To investigate clonal evolution and emergent subpopulations associated with resistance using phylogenetic analyses. To explore spatial transcriptomic patterns within the tumor microenvironment. To evaluate the potential of novel biomarkers for guiding treatment decisions and monitoring disease progression. Study Design The STRATUS Trial is a multicenter, prospective observational study involving patients treated at the 3rd Department of Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, and other participating centers. The study includes detailed clinical, molecular, and imaging assessments over a three-year follow-up period. Inclusion Criteria Adults aged 18-85 years diagnosed with ES-SCLC or LCNEC. ECOG performance status of 0-2. Histological confirmation of diagnosis with available tumor tissue for molecular analysis. At least one measurable or evaluable lesion according to RECIST 1.1 criteria. Willingness to provide blood samples and participate in follow-up visits. Exclusion Criteria Inability to tolerate chemo-immunotherapy. Presence of another active malignancy or significant comorbidity. Patients with no measurable disease or inadequate follow-up potential. Data Collection and Sample Handling Baseline Assessments Before starting treatment, participants will undergo: Comprehensive clinical evaluations, including medical history, ECOG performance status, and comorbid conditions. Imaging studies (e.g., CT, PET) to assess tumor burden and metastatic sites. Blood sample collection for baseline ctDNA and CTC analysis. Tumor biopsies for genomic, transcriptomic, and methylation profiling. On-Treatment Monitoring Participants will attend follow-up visits every 9 weeks, during which: Blood samples will be collected to monitor ctDNA and CTC levels. Imaging studies will evaluate tumor response according to RECIST 1.1 criteria. Adverse events, clinical progression, and treatment modifications will be documented. Disease Progression Assessments For patients with progressive disease: Repeat biopsies of newly emerging lesions will be performed to identify resistance-associated changes. Blood samples will capture dynamic shifts in ctDNA and CTC profiles, enabling comparisons with baseline and on-treatment data. Laboratory Methods NGS-Based Genomic Analysis: Comprehensive sequencing will identify mutations, copy number alterations, and structural rearrangements. Epigenetic Profiling: DNA methylation arrays will uncover resistance-related epigenetic changes. Spatial Transcriptomics: High-resolution analysis of tumor microenvironment architecture and gene expression patterns. Statistical Analysis Sample Size A total of 111 patients will be enrolled, providing sufficient power to detect significant differences in molecular markers across subgroups. Primary Analysis Regression models will evaluate associations between molecular markers and treatment resistance. Descriptive statistics will summarize biomarker distributions and clinical outcomes. Secondary Analysis Kaplan-Meier survival curves will estimate PFS and OS. Cox proportional hazards models will assess the prognostic significance of identified biomarkers. Exploratory Analysis Machine learning models will predict resistance based on integrated multi-omic data. Clonal evolution will be modeled using phylogenetic techniques to trace tumor adaptation under therapeutic pressure. Ethical Considerations The study will comply with the Declaration of Helsinki and GDPR guidelines for data protection. Participants will provide written informed consent, and all data will be de-identified to ensure confidentiality. Significance and Anticipated Impact The STRATUS Trial is expected to: Identify actionable biomarkers for predicting and overcoming resistance. Advance the understanding of tumor evolution and immune evasion in SCLC and LCNEC. Guide the development of personalized treatment strategies, ultimately improving patient outcomes. Conclusion The STRATUS Trial represents a landmark effort to address the challenges of resistance in SCLC and LCNEC. By combining advanced molecular analyses with robust clinical monitoring, this study has the potential to transform the management of these aggressive cancers and pave the way for a new era of precision oncology.

Digestive Enzyme Formulation Intervention in IBS Patients Who Previously Clinically Responded to Mediterranean LFD

IBS patients who participated in a two-arm clinical trial (ClinicalTrials.gov ID: NCT03997708) and responded to the Mediterranean Diet Adjusted Low FODMAP (MED-LFD) Diet will be considered eligible if their symptoms recurred one year after their initial response to the dietary intervention. Among them, patients without any or mild symptoms, defined as IBS severity scoring system (IBS-SSS) ≤ 175, will be excluded. Moreover, subjects who were randomized to the MED-LFD arm in the previous study, but could not adhere to the dietary intervention, will be included too. A jar containing the digestive enzymes in the form of powder will be provided to each patient at the start of the study. Patients will be instructed to use the powder formulation according to manufacturer instructions for 1 month. To assess compliance, the weight of each jar will be measured both at the initiation and the end of the study. Patients will also be asked on three different days (one day from the weekend), to estimate the average number of meals per day. Due to the limited sample size (54 patients who received the MED-LFD diet in the previous phase will be screened for eligibility), a control group will be omitted. To reduce the placebo effect, patients will be misinformed that half will take a placebo formulation, randomly. All patients will be thoroughly trained regarding the proper consumption of the powder (exact dose, timing, etc.), through personal training, videos, leaflets, and other type of training materials.

A Real-World Study to Gain Clinical Insights Into Faricimab (FaReal Study)

Emapalumab Treatment For Anticipated Clinical Benefit In Sepsis Driven By The Interferon-Gamma Endotype (The EMBRACE Trial)

The EMBRACE trial aims to generate proof-of-concept if treatment with emapalumab, a monoclonal antibody which blocks IFNγ signaling, may improve the outcome of patients with sepsis driven by the IDS endotype. In EMBRACE, two different dose regimens of emapalumab are administered in order to: a) investigate which dose regimen may provide most of efficacy in the decrease of SOFA score, a new endpoint for sepsis suggested already by others; b) investigate which dose regimen better attains the pharmacodynamic goal of emapalumab defined as the decrease of blood CXCL9; and c) compare the efficacy of the two dose regimens with placebo treated patients.

A Study of BMS-986482 Alone or as Combination Therapy in Participants With Advanced Solid Tumors

Volrustomig Priming Regimens Exploratory Phase II Platform Study

This is a platform, randomized, open-label, multicenter, global study. Enrolled participants with Stage IV non-squamous non-small cell lung cancer (NSQ NSCLC) who are treatment-naïve and have not received previous treatment for advanced or metastatic disease. These participants will be randomized in a 1:1 ratio to one of the two treatment arms: Arm 1A and Arm 1B. Both arms will test a volrustomig dosing in combination with chemotherapy.