Projects

Surgical resection of lung metastases is a widely accepted procedure but due to local and distant recurrences reported 5-year survival rates are only 30 to 40%. Reoperations are feasible but often patients become inoperable due to insufficient pulmonary reserve and for this reason new treatment modalities are being investigated. The maximal dose of intravenous chemotherapy is limited due to systemic side-effects, mainly haematological. As is the case with isolated limb and liver perfusion, isolated lung perfusion has the advantage of selectively delivering an agent into the lung while diverting the venous effluent. Phase I and phase II studies have shown that isolated lung perfusion is feasible and may decrease local recurrence rate. However, it remains an invasive technique and less invasive alternative methods are being investigated. Pulmonary artery infusion is such a technique by injecting a cytostatic drug directly in the pulmonary artery without control of the venous effluent. This offers the advantage of high drug exposure in lung parenchyma with some controlled systemic exposure. In this way, isolated lung perfusion is combined with classical intravenous chemotherapy, which may offer an additional advantage to control distant systemic spread. Pulmonary artery infusion is mostly performed with a balloon catheter inflated in the pulmonary artery, so-called blood flow occlusion. The pulmonary circulation is temporarily arrested to allow a better uptake of the injected drug in the lung parenchyma. This represents a minimally invasive, endovascular technique, which can be repeated several times and which can also be applied in patients who cannot tolerate one-lung ventilation or initially, have inoperable lung metastases or even primary lung cancer. In the present research proposal, a minimally invasive and percutaneous method and device of use will be developed and tested in vitro to occlude and infuse/perfuse a lung locoregionally in large animals and patients. Devices and method are tested in vitro. Results are discussed in a design review whereby the parties concerned will jointly decide whether or not the objectives have been met which will conclude the investigation under this application. Regarding subsequent investigations, pulmonary infusion will be evaluated in a pig model of blood flow occlusion with injection of gemcitabine as this drug was found to be most promising in the experimental rodent setting. Pharmacokinetics will be determined specifically looking at lung and systemic concentrations. Afterwards, a phase I trial will be performed in patients with inoperable lung metastases or primary lung cancer. When the dose-limiting toxicity and maximum tolerated dose have been determined, a phase II trial may be designed similar to what as has been performed for isolated lung perfusion. By combining both worlds of high locoregional and distant exposure of chemotherapeutic drugs, we hope to improve the overall and disease-free survival rate of our patients with lung metastases or primary lung cancer.

Traumatic Axonal Injury (TAI) is now considered to be a frequent and important injury in all severities of traumatic brain injury (TBI). The global aim of TAI-MRI is to develop a novel classification for TAI using data from multimodal MRI and to determine its clinical value for the characterization of injury severity and prediction of outcome. This project, involving 4 partners, will use MRI datasets obtained early after injury (including clinical and advanced MRI) from two local studies (The Trondheim and Cambridge TBI studies: ~580 patients) and the EU-funded multicenter CENTER-TBI study (~800 patients). TAI-MRI will thus be the largest MRI study worldwide. These datasets comprise a comprehensive collection of acute phase variables reflecting the severity of injury with the possibility to adjust for confounding variables and outcome measures at multiple time points during the first year. Several training sets will be used for model selection. Automated methods involving deep learning techniques will be developed and used for lesion mapping in combination with manual assessments. Methods for computer aided diagnosis (CAD) will be refined and validated, and analyses will determine which aspects of CAD based evaluation could replace expert clinical evaluation by radiologists. Finally, this novel MRI classification system will be validated in the large CENTER-TBI dataset. An improved MRI-based classification system of TAI will provide both a better assessment of injury severity in the acute phase and better outcome prediction. Recent advances in CAD provide a unique opportunity to develop a classification with great clinical applicability. Hence, we will provide a timely new tool for neuroradiologists, clinicians and researchers to facilitate TBI diagnosis, thus improving the treatment and rehabilitation of TBI patients. Finally, TAI-MRI will bring the field forward by increasing our understanding of the pathophysiology of TBI, and how reduced consciousness can be linked to injury type and location and outcome.

Tears of the anterior cruciate ligament (ACL) of the knee are a frequent injury with increasing incidence. Surgical treatment of ACL injuries is superior to conservative treatment for the majority of patients to facilitate a return to the desired daily activities, including sports. Although ACL reconstruction using autograft tissue remains the gold standard for treating ACL injuries, there is a current surgical trend toward primary repair of the ACL. Successful surgery requires that the ACL graft or repair tissue transforms into ACL-like tissue. A common challenge in ACL surgery and rehabilitation is the lack of a noninvasive, sensitive outcome measure to evaluate the efficacy of surgical treatment. With the recent developments in MR technology, several advanced imaging techniques have now become available for use on clinical 3T scanners. In this project we will focus on the use of quantitative diffusion tensor imaging (DTI) to asses the normal, the injured and postoperative ACL. We will conduct a large-scale study to investigate the ability of DTI to monitor ACL healing both in patients with ACL reconstruction and primary repair of the ACL. It is our aim to document within-patient temporal changes using the DTI technique and to correlate DTI metrics with ACL structural properties. This will help in understanding the ACL healing process, and ultimately, in determining the appropriate timing for patients to return to sports.

In Belgium, samples for prenatal genetic diagnosis are analyzed by Chromosomal Microarray Analysis (CMA). The main challenge herein lies in the interpretation of copy number variants (CNVs) for which knowledge about postnatal outcome is limited. All Belgian genetic centers have agreed on prenatal CNV classification, but ambiguous situations still occur. The goal of our research is to 1) investigate genotype-phenotype correlations using clinical data of children with prenatally registered non-benign CNVs; 2) narrow down the prenatal genotype-phenotype correlation of frequently found known pathogenic CNVs and 3) focus on outcome in children with other than benign CNVs and renal/urogenital anomalies on ultrasound. To secure our goals, we have created a Belgian database for registration of prenatal CMA data. In the first year of my PhD, I developed the framework of this database, guided the genetic centers in importing their data and presented our first results at international conferences. Next, I will start postnatal data collection of children with other than benign CNVs, determine renal function at the age of 1 year in case of a renal/urogenital ultrasound anomaly, and assess neurologic and psychomotor development at the age of 2-3 years. By ameliorating genotype–phenotype knowledge of prenatally registered CNVs, we will develop a strong scientific base for clinical decision-making in prenatal diagnosis. This work is a collaboration of all Belgian academic genetic centers.

Sepsis, defined as a systemic inflammatory response of the body to an infection, is frequently encountered in hospitals and is a major cause for mortality. While sepsis can originate from almost every organ or tissue, the gastrointestinal tract seems to play a central role in the pathophysiology of sepsis. During sepsis, systemic inflammation can induce the production of pro and anti-inflammatory mediators, therefore gastrointestinal inflammation. Gastrointestinal inflammation, hypoperfusion and ischemia-reperfusion injury can eventually result in gastrointestinal barrier disruption, with failure of the barrier function and as a result increased permeability of pathogenic molecules and microbiota. On the other hand, intra and extra luminal, gastrointestinal inflammatory processes can lead to intestinal barrier failure as well. The gastrointestinal tract can, as a result, also be the source of sepsis. As the gastrointestinal barrier seems to play a central role, we hypothesized that future therapies should also focus on modulating this leaky barrier during sepsis. Identified potential targets for modulation are intestinal alkaline phosphatase and protease activity. This project therefore aims to investigate the role of intestinal barrier function, intestinal alkaline phosphatase (IAP) and protease activity in a translational model for sepsis. As our laboratory experiments occur in a well-controlled environment, we aim to collect human samples to cross-validate our laboratory set-up with the clinical setting of sepsis. To achieve these goals, this project consist of 2 stages. During the first stage of the project, the effect of exogenously administered IAP will be determined in a caecal ligation and puncture (CLP) mouse model for sepsis. For this, a CLP-procedure will be performed. In this procedure, 50% of the caecum is ligated after which it is punctured with a 21 G needle to induce a reproducible, polymicrobial abdominal sepsis. 1 IU/g IAP is administered twice a day for 2 consecutive days and mice are monitored clinically. On the second day, the abdomen is reopened, the distal ileum is ligated and 4kDa-FITC Dextran is injected directly to the lumen. Mice are kept sedated for one hour, after which they are sacrificed, blood is collected and abdominal tissue samples are collected. Blood is analyzed fluorospectrophotometrically to assess the migration of 4kDa FITC over the gastrointestinal barrier as a measure for intestinal permeability. Tissue samples are used to determine gene expression of cytokines and tight junction proteins, microscopy and to determine expression on the protein level. In collaboration with the department of Medical Microbiology, we will determine bacterial translocation as a result of the induced sepsis. For this, hemocultures and mesenteric lymph nodes will be cultured and identified with MALDI-TOF after enrichment. Similarly with the investigations for the effect of IAP, the effect of protease inhibitors (Nafamostat Mesylate, SPIx) will be determined in our CLP-model. In the second stage of this project, human samples of patients with intra-abdominal sepsis will be collected. These samples will be used to determine expression of inflammatory cytokines and tight junction proteins in healthy and septic intestinal tissue. Results of our murine model will next be matched with the clinical results to validate our experimental model. Results are statistically analyzed with t-tests, ANOVA and linear regression models when appropriate.

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

The objective of our research is to determine whether the process of eNOS uncoupling can also be demonstrated in lung tissue after ischemia and reperfusion injury (IRI). In the first part of the project, experimental techniques were developed in order to detect free radical production during IRI using electron paramagnetic resonance. A murine model of pulmonary IRI was also developed. We are currently working on the effect of eNOS itself, and eNOS uncoupling, on free radical generation during pulkmonary IRI. Our final aim is to develop therapeutic strategies to tackle pulmonary IRI in patients undergoing complex surgery such as cardiopulmonary bypass, lung transplantation and isolated lung perfusion.

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a formal service agreement between UA and on the other hand Troubleyn/Jan. UA provides Troubleyn/Jan research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a formal service agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

This project represents a formal research agreement between UA and on the other hand Sint-Augustinus Ziekenhuis. UA provides Sint-Augustinus Ziekenhuis research results mentioned in the title of the project under the conditions as stipulated in this contract.

Endothelin-1 is being increasingly recognized as an important molecule in the development and progression of cancer, but also in the occurrence of cancer pain. So far, all studies have used acute administration of ET-1, bearing little resemblance with the prolonged exposure observed in clinical conditions. It is therefore proposed to investigate the effects of chronic exposure to ET-1 on signs of spontaneous and evoked pain behaviour.

In this project we aim to characterize the biological properties of purinergic pathways in human inflammatory cells in the context of their contribution to the development and persistence of chronic human inflammatory airway diseases.

The study will investigate which progenitor cells are involved in liver regeneration, and if there is contributionof CD133 stem cells to the liver after resection in a predamaged liver by chemo & non-alcholic steatohepatitis in mice. Next, recruitment and eventual improvement of liver regeneration after infusion of CD133 cells will be studied. This study will give more insight in liver regeneration in pathologcial conditions which can be applied in the treatment of patients.

This project about RSI in musicians has two goals: 1. to constitute a centre of expertise related to musculoskeletal complaints in musicians and 2. related, clinical and biomechanical (kinematic and kinetic) research about the muscle coordination, fatigue and arthrokinematics of the motoric performance control of music scores and the causes of RSI in musicians. In a first phase, this research furthers with the study on violists/violinists, research which has been started last year on violists of the Koninklijk Conservatorium Antwerpen.

Due to its filtering capacity for the entire circulation, the lung is a common site for malignant disease. Among patients with metastic cancer, 20-30 % will have secondary spread to the lung according to necropsy series. The poor results of surgical resection of pulmanory metastases from osteogenic sarcomas, soft tissue sarcomas and colorectal adenocarcinomas are probably due to genetic drug resistance and the inability to achieve effective drug concentrations within the tumor mass. In this way, isolated lung perfusion can be a promising procedure for the treatment of tumors metastatic to the lungs which are surgically unresectable and unresponsive to conventional chemotherapy. It has the advantage of both selectively delivering an agent and diverting the venous effluent. This allows the drug to to be delivered in a higher dose without systemic complications.

The morphological, neurochemical and electrophysiological characteristics of the enteric neurons during the development of the zebrafish gut will be unravelled to define the neuronal types of the enteric nervous system. This knowledge is necessary to analyse the functional changes in the enteric nervous system of zebrafish mutants which are used in studies of gastrointestinal diseases.

Using different morphological (multiple immunofluorescence, confocal microscopy,¿) and molecular biological techniques (in situ hybridisation, Real-Time PCR,¿), the distribution of P2 purinoceptors, playing a key role in transducing mechanosensory signals, in the murine gastrointestinal tract is studied during normal physiological conditions and during gastrointestinal inflammation (i.e. intestinal schistosomiasis).

In vitro research of the influence of an implantation of a radial head prosthesis on the 3D arthrokinematic behaviour of the elbow by means of an electromagnetic tracking device and measurement of the 3D coordinates of anatomical landmarks. Evaluation of the variables length of the prosthesis and diameter of the radial head. Implication of the finite helical axis parameters in the 'minimal constraint' conditions in the redesign of a 'floating' radial head prosthesis.