Birmingham West Midlands, United Kingdom

The Dragon PLC Trial (DRAGON-PLC)

Primary liver cancer (PLC) is the third most common cause of cancer death worldwide. Surgical resection is the mainstay for a curative approach as contemporary chemotherapy and immune-based therapies only lead to a median survival of 10-14 months. A complete surgical resection increases the median survival to 42 months (range 32-52 months). However, PLC is mainly diagnosed at an advanced stage and >70% of PLC patients are ineligible for an immediate surgical approach. There are different reasons that make a patient ineligible for surgery, one important reason is the risk of liver failure after the surgery due to a small remnant liver. This study aims to improve the oncological, radiological and surgical strategy to allow more patients to undergo liver resection safely, to improve quality of life and to extend overall survival at acceptable costs. Adequate function of the future liver remnant (FLR) is a prerequisite for surgical resectability. This is necessary in order to avoid liver failure after surgery, a major cause of morbidity (38%) and mortality (27%). To mitigate this risk, regenerative strategies based on preoperative calculation of the FLR volume and function are essential. Patients with technically resectable disease but predicted insufficient FLR volume or function are referred to as primarily unresectable or potentially resectable (PU/PR). These patients can undergo strategies that capitalize on the regenerative capacity of the liver which aim to preoperatively increase the FLR volume and function in order to allow surgery. Many of the patients that are primarily unresectable due to an insufficient FLR can become ultimately and safely resectable after the induction of adequate FLR-hypertrophy by the current standard, portal vein embolisation (PVE). However, 25% of patients do not show sufficient FLR growth after PVE and are unable to safely undergo resection. A new approach has been developed to improve this. Combined portal and hepatic vein embolisation (PVE/HVE) has great promise in terms of increasing FLR growth, resection rate (RR), safety and potentially, overall survival. Establishing PVE/HVE as the new standard could result in increased survival and a better quality of life (QoL) for patients.

The Biomechanical Outcomes of Autologous Chondrocyte Implantation

Knee joint articular cartilage is a primary load-bearing surface that endures repetitive high impact loading during activities of daily living. Individuals of any age can injure the knee's articular cartilage. However, as cartilage has an innate limited capacity to regenerate, surgical interventions that adopt tissue engineering techniques are often necessary to repair cartilage and preserve the joint. Autologous chondrocyte implantation (ACI) is a surgical procedure that is offered to some patients with focal cartilage injuries of the knee. The first pilot study on the use of ACI in humans was published by Brittberg and colleagues in 1994. By 2010 35,000 ACI procedures had been performed worldwide. Patient-reported outcomes and survivorship of ACI have been well reported in current literature. However, objective biomechanical and functional outcomes of ACI patients are not well understood. This knowledge is essential for optimising treatment, because poor functional outcome is known to worsen quality of life. This is particularly true for patients of working age who wish to return to an active and independent lifestyle. The applicant recently conducted and published a systematic review on the functional outcome of ACI. The review identified only 19 eligible articles of 20 ACI cohorts. The data showed that the average range of motion (ROM) improved with clinical (>5˚) and statistical significance (p < 0.05) postoperatively: 130.5± 14.8˚ to 136.1±10.2º, however only 7 studies reported both pre- and post-operative RoM. Knee strength significantly improved within the first two postoperative years but remained poorer than control groups at final follow-up (n=11). The review also found no statistical differences between ACI and control groups in their ability to perform functional activities like the 6-minute walk and hop tests post-operatively (n = 8). Only two papers had published on the kinematics of gait post-operatively. Both papers reported the outcomes of the same cohort, stating that there were no significant differences in spatio-temporal parameters between ACI patients and controls post-operatively. However, kinematic differences were observed during two specific phases of the gait cycle. Differences were also reported in peak knee adduction and peak knee extension moments. The limited literature identified by this review highlighted the urgent need for research into the functional outcomes of joint preservation surgeries like ACI to optimise functional outcome.

Multi-omics Study in Citrin Deficiency

Citrin deficiency (CD) is an inherited autosomal recessive metabolic condition that is also a secondary urea cycle disorder caused by mutations in the SLC25A13 gene, which encodes for the mitochondrial transporter, citrin. Citrin is a key component of the mitochondrial malate-aspartate shuttle (MAS) and is responsible for moving Nicotinamide Adenine Dinucleotide (NADH) from the cytosol into the mitochondria via reducing equivalents such as malate, which drives mitochondrial respiration to produce energy in the form of adenosine triphosphate (ATP). The MAS is also critical in regulating Nicotinamide Adenine Dinucleotide (NAD+/NADH) redox balance to maintain cytosolic redox-dependent metabolic pathways such as glycolysis, gluconeogenesis, amino acid metabolism, and lipid metabolism. Citrin is also required to supply cytosolic aspartate, which is the substrate of one of the urea cycle enzymes, namely argininosuccinate synthetase 1, and thus important for the proper functioning of the urea cycle. The clinical presentations of citrin deficiency often vary widely between patients but can generally be distinguished by distinct clinical phenotypes, which are neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) that affects infants, the "failure to thrive and dyslipidemia" form of CD (FTTDCD) in childhood, the adaptation or silent period, and citrullinemia type II (CTLN2), which represents the most severe form of the condition. While only a small percentage of CD patients develop CTLN2, the prognosis for these patients is typically poor. It is notable that all CD patients above 1 year old (post-NICCD) naturally develop a characteristic food preference that favors a diet rich in protein and fat while being low in carbohydrates. Other clinical findings observed in some CD patients include fatty liver, fatigue, hypoglycemia, and failure to thrive. There is currently no effective cure for CD. Before the onset of CTLN2, patients are primarily managed by diet control with a low carbohydrate, high protein and high-fat diet, as well as medium chain triglyceride (MCT) supplementation. CTLN2 patients have been treated with sodium pyruvate, arginine, and MCT with limited success, with severe cases requiring liver transplantation as the only solution. There are currently no specific biomarkers that effectively track the disease progression, making it challenging to monitor how well patients are actually doing or to measure the effectiveness of therapies. Without proper management or timely medical interventions, patients may develop CTLN2. Given the urgent and unmet need for biomarkers specific to CD, the main goal of this study is to uncover disease-specific biomarkers by analyzing blood samples collected from CD patients using both targeted and untargeted metabolomics, proteomics, lipidomics, and transcriptomics. Targeted omics will involve the analysis of cellular pathways associated with the condition, such as the MAS pathway, glycolysis, protein metabolism, de novo lipogenesis, lipolysis, gluconeogenesis, NAD+ metabolism, ureagenesis, and the glutamine synthetase pathway. Identification of such biomarkers will allow a deeper understanding of the disease pathogenesis. Importantly, these biomarkers may enable better tracking of disease progression and may help to prevent the onset of CTLN2. Finally, these biomarkers will also greatly benefit the development of effective therapeutic options for CD in clinical trials by serving as measurable endpoints. Obtaining the necessary material from patients consists of a minimally invasive venous blood sampling taken during a regular outpatient visit and after the informed consent of the patients or caretakers.

A Study on Safety and Effectiveness of Long-term Treatment With Vamorolone in Boys With Duchenne Muscular Dystrophy

All subjects in this study have completed previous studies with vamorolone and continued to receive vamorolone under special programs: Compassionate Use Program [CUP], Named Patient Program [NPP] or Expanded Access Protocol [EAP]. All subjects will continue treatment with vamorolone under Guardian protocol instead. The primary objective of this study is to evaluate the safety of long-term treatment with vamorolone in boys with Duchenne Muscular Dystrophy regarding vertebral fractures. Secondary study objectives will evaluate the safety of long-term treatment with vamorolone on non-vertebral fractures, cataracts, delayed puberty, overall safety as well as ambulatory and non-ambulatory function.

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

Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

Anti-viral Action Against Type 1 Diabetes Autoimmunity

A Study of Maribavir in Adults With Post-transplant Cytomegalovirus (CMV) Infection

This study will include two main periods of retrospective data collection from medical charts: the pre-index period and the post-index period. The index date is defined as the date of initiation of maribavir dosing, as documented in the medical records. The pre-index period covers the time from the transplant date to the index event, while the post-index period starts at the index event and ends at the date of chart abstraction, death, or loss to follow-up, whichever comes first.

Impact of Tixel Treatment on Symptoms and Signs in Patients with Dry Eye Disease

A Phase 1b Trial to Evaluate the Safety of MB310 in Patients With Active, Mild-to-Moderate Ulcerative Colitis