Clinical Research Directory

The Role of Transcutaneous Vagus Nerve Stimulation in Treatment of Acute Brain Injury

Acute brain injury is a major global health problem associated with high mortality and morbidity, limited therapeutic options, prolonged hospital stays, and long-term disability that significantly impairs quality of life and increases healthcare costs. Noninvasive transcutaneous VNS developed as a safer approach for treating cerebral edema, epileptic seizures, and blood-brain barrier disruption, for facilitating the recovery of motoric and cognitive functions, and for immunomodulation. Transcutaneous VNS improves cerebral perfusion pressure and tissue oxygenation, supports reperfusion of the penumbral zone, and reduces neuronal hyperexcitability, thereby suppressing seizures.It may exert anti-inflammatory effects by reducing microglial cytokine and chemokine production. Additionally, vagal stimulation promotes acetylcholine-mediated suppression of pro-inflammatory cytokines, including TNF, IL-1β, IL-6, and IL-18. Another anti-inflammatory mechanism involves ghrelin, a peptide hormone whose serum levels increase under vagal stimulation. Elevated ghrelin reduces TNF-α and other pro-inflammatory cytokines and may limit intracerebral hemorrhage by inhibiting the NLRP3 inflammasome and activating the Nrf2/ARE signaling pathway. Biomarkers such as S100 protein and neuron-specific enolase (NSE) are valuable indicators of brain tissue damage and clinical outcomes; tVNS may reduce their levels and support non-invasive monitoring of disease progression. The technique is considered safe in patients . To date, tVNS has not been evaluated in clinical trials in Croatia, nor reported in case studies or cohort analyses. Study outcomes will be correlated with patients' clinical status, duration and course of hospitalization, complication rates, and overall treatment outcomes.

Ivarmacitinib Combined With Camrelizumab and Apatinib for Unresectable Advanced Hepatocellular Carcinoma With Acquired Resistance to Immune Checkpoint Therapy: A Single-Arm Exploratory Clinical Study

Background： Hepatocellular carcinoma (HCC) stands as a formidable global health challenge. It ranks as the sixth most common malignant solid tumor worldwide and the third leading cause of cancer-related mortality. The disease is characterized by its insidious onset, rapid progression, and high recurrence rates, contributing to a dismal 5-year survival rate of approximately 18%. A critical factor in this poor prognosis is that nearly 57% of patients are diagnosed at an advanced stage, where curative surgical resection is no longer feasible. For these patients with unresectable advanced HCC (uHCC), effective systemic therapies are paramount to extend survival and improve quality of life. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, has revolutionized the treatment landscape for numerous advanced cancers, including uHCC. These agents work by blocking the inhibitory signals that tumor cells exploit to evade immune surveillance, thereby reactivating cytotoxic T cells to attack the cancer. However, the clinical benefit of ICI-based therapies is not universal. A substantial proportion of patients-estimated between 15% to 40%-derive limited or no benefit. Primary resistance is defined as a lack of initial response, while acquired resistance refers to disease progression after an initial period of clinical benefit. There is no established, evidence-based standard of therapy for uHCC patients who progress following first-line ICI combination therapy, highlighting an urgent need for novel therapeutic approaches. The mechanisms underlying acquired resistance to ICIs are multifaceted and intricately linked to dynamic remodeling of the tumor immune microenvironment (TME). Several key pathways contribute: 1. Loss of Tumor Immunogenicity: Immune editing during treatment can select for tumor cell clones with low neoantigen expression, making them less visible to the immune system. 2. Immune Suppressive Cell Infiltration: The TME in resistant tumors often exhibits an accumulation of immunosuppressive cell populations, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). These cells create a profoundly inhibitory milieu that dampens anti-tumor T cell function. 3. T Cell Exhaustion: Persistent antigen exposure leads to a state of CD8⁺ T cell exhaustion, rendering them dysfunctional. These interconnected mechanisms collectively foster an immunosuppressive TME that allows tumors to evade ongoing immune attack, underscoring the need for combination strategies that can reshape the TME and re-sensitize tumors to immunotherapy. The JAK-STAT pathway serves as a critical signaling hub for numerous cytokines and growth factors, playing a pivotal dual role in immunity and inflammation. In the context of HCC and ICI resistance, its activation is particularly relevant: 1. Pathway Activation in HCC: The JAK/STAT pathway is ubiquitously activated in both primary and recurrent HCC tumors and contributes to the proliferation and survival of tumor-initiating cells. 2. Driver of an Immunosuppressive TME: Hyperactivation of this pathway, often via cytokines like IL-6, promotes the recruitment and activation of immunosuppressive MDSCs and M2-polarized TAMs. It also contributes to T cell exhaustion. 3. Preclinical and Clinical Proof-of-Concept: In preclinical models, JAK/STAT inhibition has been shown to reduce MDSC infiltration and restore T cell function. Most compellingly, recent clinical studies in other cancer types published in high-impact journals like Science (2024) have demonstrated that adding a JAK inhibitor to PD-1 blockade can re-sensitize tumors and yield significant clinical responses in patients who had developed resistance to immunotherapy alone Purpose: This single-arm, exploratory clinical study aims to evaluate the efficacy and safety of Ivarmacitinib (a selective JAK1 inhibitor) combined with Camrelizumab (anti-PD-1) and Apatinib (anti-VEGFR2) in patients with advanced unresectable HCC who have progressed after first-line ICI-based combination therapy. Methods: This study plans to enroll 65 patients with advanced unresectable hepatocellular carcinoma (unresectable BCLC stage B or stage C) who have been clinically or pathologically diagnosed, have previously received at least 4 cycles of guideline-recommended first-line targeted therapy combined with PD-1/PD-L1 immunotherapy, achieved a partial response, but subsequently experienced disease progression confirmed by RECIST 1.1 criteria after at least 4 cycles (indicating acquired resistance). All enrolled patients will receive triple therapy consisting of Ivarmacitinib + Apatinib + Camrelizumab. Treatment will continue until disease progression, unacceptable toxicity, or for up to 2 years.

ESAN III - Energy Sensing in Depression

The purpose of this study is to assess the effects of carotenoids from natural carrot juice on the immune system. Therefore, the study aims to distinguish the effects of natural juices that are rich in phytonutrients such as carotenoids in healthy and depressive individuals, to explore their potential use in therapeutic settings. The consumption of natural fruit juices rich in polyphenols and carotenoids serves as a model for a vegetarian diet, due to the increased micronutrient density derived from plant-based foods. The results obtained may provide preliminary explanatory models for the beneficial effects of a vegetarian diet. It is hypothesized that the consumption of a natural carotenoid-rich juice alters the expression of regulatory T cells-specific immune cells that contribute to immunomodulation. Furthermore, beneficial changes in the gut microbiome, metabolome, and nutritional status are expected. This study was registered retrospectively (after recruitment had started) on ClinicalTrials.gov.