Sphingosine Kinases in B-lineage Acute Lymphoblastic Leukaemia

The work presented in this thesis examines firstly, the effects of the sphingosine like immunomodulatory drug FTY720 on B-lineage acute lymphoblastic leukaemia (ALL) cells. Secondly, the research focuses on a related area, namely, the intra-cellular enzymes called sphingosine kinases (SphKs). FTY720 resulted in cytotoxic effects and the induction of autophagy, in vitro in ALL cells. However, disparate in vivo effects were seen in Ph+ and Ph- ALL with a reduction in disease burden seen only in the former, highlighting the importance of pharmacological testing in both in vitro and in vivo settings. Sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) are over-expressed in ALL with inhibition producing cytotoxic effects, autophagy and predominantly caspase-independent cell death. SphK1 and SphK2 gene deletion resulted in reduced leukaemia penetrance in a murine Ph+ ALL disease model and SphK2 inhibition reduced the growth of human ALL xenografts. SphK2 inhibition resulted in lower MYC gene and protein expression through reduced association of acetylated histone H3 with the MYC promoter. This establishes a completely novel insight into the interactions of SphK2 in ALL and signifies the importance of sphingolipid signalling in this aggressive malignancy

Evaluation of tongue squamous cell carcinoma resection margins using ex-vivo MR

Contains fulltext : 174271.pdf (publisher's version ) (Open Access)PURPOSE: Purpose of this feasibility study was (1) to evaluate whether application of ex-vivo 7T MR of the resected tongue specimen containing squamous cell carcinoma may provide information on the resection margin status and (2) to evaluate the research and developmental issues that have to be solved for this technique to have the beneficial impact on clinical outcome that we expect: better oncologic and functional outcomes, better quality of life, and lower costs. METHODS: We performed a non-blinded validation of ex-vivo 7T MR to detect the tongue squamous cell carcinoma and resection margin in 10 fresh tongue specimens using histopathology as gold standard. RESULTS: In six of seven specimens with a histopathologically determined invasion depth of the tumor of [Formula: see text] mm, the tumor could be recognized on MR, with a resection margin within a 2 mm range as compared to histopathology. In three specimens with an invasion depth of [Formula: see text] mm, the tumor was not visible on MR. Technical limitations mainly included scan time, image resolution, and the fact that we used a less available small-bore 7T MR machine. CONCLUSION: Ex-vivo 7T probably will have a low negative predictive value but a high positive predictive value, meaning that in tumors thicker than a few millimeters we expect to be able to predict whether the resection margin is too small. A randomized controlled trial needs to be performed to show our hypothesis: better oncologic and functional outcomes, better quality of life, and lower costs

Study protocol PROMETHEUS: prospective multicenter study to evaluate the correlation between safety margin and local recurrence after thermal ablation using image co-registration in patients with hepatocellular carcinoma

Purpose The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions = 10% for patients with a minimal ablation margin >= 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan-Meier estimates are used to assess local and overall recurrence, disease-free and overall survival.Discussion It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

MR imaging in local staging of prostate cancer.

Item does not contain fulltextClinical staging to differentiate between localized and advanced disease stage appear to be unreliable. Curative therapy can only be performed in patients with localized prostate cancer. Accurate staging is therefore especially important for proper disease management. Since 1984 magnetic resonance (MR) imaging has been applied for this purpose. However, the role of MR imaging of the prostate is debated extensively in the literature. Initially MR imaging was performed using a conventional body coil with subsequent limited anatomical detail due to insufficient spatial resolution. With the introduction of new MR sequences, new coils and other technical developments numerous studies have attempted to improve local staging. The diagnostic capability of MR imaging in preoperative staging of prostate cancer is currently being established. In this review the role of MR imaging in staging prostate cancer is discussed

Multiparametric MRI in the Detection of Clinically Significant Prostate Cancer

Prostate cancer is the most common cancer among men aged 50 years and older in developed countries and the third leading cause of cancer-related death in men. Multiparametric prostate MR imaging is currently the most accurate imaging modality to detect, localize, and stage prostate cancer. The role of multi-parametric MR imaging in the detection of clinically significant prostate cancer are discussed. In addition, insights are provided in imaging techniques, protocol, and interpretation

High-Resolution Diffusion-weighted Imaging Increases Prostate Cancer Visibility?

Contains fulltext : 172683.pdf (publisher's version ) (Open Access

Imaging of recurrent prostate cancer

Item does not contain fulltextApproximately 30\% of patients who underwent radical prostatectomy or radiation therapy will develop biochemical recurrent disease. Biochemical recurrent disease is defined as an increase in the serum value of prostate-specific antigen (PSA) after reaching the nadir. Prostate recurrence can present as PSA-only relapse, local recurrent disease, distant metastases, or a combination of local and distant recurrence. In this review, the role of magnetic resonance imaging in the work-up of recurrent prostate cancer is discussed

Clinical symptoms related to anal sphincter defects and atrophy on external phased-array MR imaging

Contains fulltext : 154780.pdf (publisher's version ) (Open Access)Defecatory complaints have a severe impact on quality of life. The additional value of pelvic floor MRI in patients with defecatory complaints is unclear. Our aim was to correlate the presence of defects and atrophy of the anal sphincter complex using pelvic floor MRI in women with mixed pelvic floor symptoms and to establish patient characteristics and self reported complaints predictive of pathology.This is a retrospective study among women with mixed pelvic floor symptoms who underwent external phased-array MRI and completed a questionnaire on bothersome defecatory complaints. Data on patient characteristics, including obstetrical history and questionnaire scores were correlated with the assessment of anal sphincter defects and atrophy on pelvic floor MRI.One hundred and fifty-eight women were included. A defect of the external anal sphincter (EAS) and internal anal sphincter (IAS) was found in 18 (11 \%) and 5 (3 \%) patients respectively. Atrophy of the EAS was present in 72 patients (46 \%), with more cases of mild (n = 52, 33 \%) than severe atrophy (n = 20, 13 \%). The variable "previous third or fourth degree tear" had a significant positive association with an IAS defect on MRI, with an OR of 9.533 (1.425-63.776). Patients with EAS atrophy had higher scores for fecal incontinence (indicating more bother) than patients without EAS atrophy. Higher age and BMI were true predictors of the presence of more severe EAS atrophy.Atrophy of the EAS was highly prevalent in this population and was associated with bothersome symptoms of fecal incontinence

MRI-guided and robotic-assisted prostate biopsy

Item does not contain fulltextIn this review, we summarized and critically discussed the most recent developments in the field of MRI-compatible robot-guided prostate interventions.Currently, systematic transrectal ultrasound-guided prostate biopsy for prostate cancer detection is the standard of care. Multiparametric MRI providing anatomic, functional and molecular information is the most promising imaging technique to detect and localize prostate cancer. A number of MRI-compatible robots, ranging from simple manipulators to a fully automated system, have been developed. The feasibility of these MRI-compatible robotic devices in closed-bore systems for prostatic interventions have been investigated. However, most studies focused on phantom experiments rather than on patients' studies. Thus far, only a small number of patients have undergone MRI- guided and robotic-assisted prostate biopsy. Although this potential technique shows promising results, there is little evidence for its clinical applicability.The combination of MRI-guided and robotic-assisted prostate biopsy is a promising technique for prostate cancer detection. However, only limited research is performed in patients, and therefore the current clinical value of this technique is highly speculative