No description available.

Brain tumours, even though rare, are one of the deadliest types of cancer. The five year survival rate for the most malignant type of brain tumours is below 5%. Modern medicine provides many options for treating brain cancer such as radiotherapy and chemotherapy. However, one of the most effective ways of fighting the disease is surgical resection. During such a procedure the tumour is partially or completely removed. Unfortunately, even after a complete resection some tumourous tissue is left behind and can grow back or metastasise to a different location in the brain. It has been shown, however, that more aggressive resections lead to longer life expectancy. This does not come without risks. Depending on tumour location, extensive resections can lead to transient or permanent post-operative neurological deficits. Therefore, when planning a procedure, the neurosurgeon needs to find balance between extending patients life and maintaining its quality. Recent developments in Magnetic Resonance Imaging (MRI) fueled by the field of human cognitive neuroscience have led to improved methods of non-invasive imaging of the brain function. Such methods allow the creation of functional brain maps of populations or individual subjects. Adapting this technique to the clinical environment enables the assessment of the risks and to plan surgical procedures. The following work aims at improving the use of functional MRI with a specific clinical goal in mind. The thesis begins with description of etiology, epidemiology and treatment options for brain tumours. This is followed by a description of MRI and related data processing methods, which leads to introduction of a new technique for thresholding statistical maps which improves upon existing solutions by adapting to the nature of the problem at hand. In contrast to methods used in cognitive neuroscience our approach is optimized to work on single subjects and maintain a balance between false positive and false negative errors. This balance is crucial for accurate assessment of the risk of a surgical procedure. Using this method a test-retest reliability study was performed to assess five different behavioural paradigms and scanning parameters. This experiment was performed on healthy controls and was aimed at selecting which paradigms produce reliable results and therefore can be used for presurgical planning. This allowed the creation of a battery of task that was applied to glioma patients. Functional maps created before the surgeries were compared with electrocortical stimulation performed during the surgeries. The final contribution of this work focuses on technical aspects of performing neuroimaging data analysis. A novel data processing framework which provides means for rapid prototyping and easy translation and adaptation of already existing methods taken from cognitive neuroscience field is introduced. The framework enables fully automatic processing of patient data and therefore greatly reduced costs while maintaining quality control. A discussion of future directions and challenges in using functional MRI for presurgical planning concludes the thesis.

No description available.

Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. This thesis aims to compare the distribution of anticancer drugs in normal tissues and tumours, to examine whether drug distribution is modifiable and quantifiable in solid tumours, and to determine whether extracellular drug distribution can be improved by modifying intracellular drug distribution. The time-dependent spatial distribution of three anticancer drugs, doxorubicin, mitoxantrone and topotecan, were studied in normal tissues and tumours. Ten minutes after drug administration, there was fairly uniform distribution in the heart, kidney and liver whereas drug distribution within tumours was limited to perivascular regions. Doxorubicin distribution in P-glycoprotein (PgP) over-expressing tumours was compared to that in wild-type tumours and changes in distribution were evaluated with the use of PgP inhibitors. There was better doxorubicin distribution in PgP-over-expressing tumours compared to wild-type tumours, and pretreatment of PgP-over-expressing tumours with PgP inhibitors decreased doxorubicin distribution. These data suggest that reduced uptake of drug into cells may enhance extracellular drug distribution, and the dual effects of PgP inhibitors (increased drug uptake in proximal cells, but poorer drug distribution) may explain, in part, why these agents have not provided clinical benefit. The effect of the proton pump inhibitor pantoprozole on intracellular and extracellular drug distribution was determined. Pantoprazole increased endosomal pH in cells, leading to less sequestration of doxorubicin within them, and increased the toxicity of doxorubicin for cultured cells. In wild-type MCF7 tumours, pretreatment with pantoprazole enhanced doxorubicin distribution and tumour growth delay without apparent increase in toxicity. These studies have led to initiation of a phase I clinical trial of pantoprazole and doxorubicin for patients with solid tumours. The work completed in this thesis demonstrates that drug distribution can be modified and that these changes can be quantified, and may correlate with improved anti-tumour effects. Improving drug distribution through the use of proton pump inhibitors may be an effective strategy to improve chemotherapeutic efficacy.

Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. This thesis aims to compare the distribution of anticancer drugs in normal tissues and tumours, to examine whether drug distribution is modifiable and quantifiable in solid tumours, and to determine whether extracellular drug distribution can be improved by modifying intracellular drug distribution. The time-dependent spatial distribution of three anticancer drugs, doxorubicin, mitoxantrone and topotecan, were studied in normal tissues and tumours. Ten minutes after drug administration, there was fairly uniform distribution in the heart, kidney and liver whereas drug distribution within tumours was limited to perivascular regions. Doxorubicin distribution in P-glycoprotein (PgP) over-expressing tumours was compared to that in wild-type tumours and changes in distribution were evaluated with the use of PgP inhibitors. There was better doxorubicin distribution in PgP-over-expressing tumours compared to wild-type tumours, and pretreatment of PgP-over-expressing tumours with PgP inhibitors decreased doxorubicin distribution. These data suggest that reduced uptake of drug into cells may enhance extracellular drug distribution, and the dual effects of PgP inhibitors (increased drug uptake in proximal cells, but poorer drug distribution) may explain, in part, why these agents have not provided clinical benefit. The effect of the proton pump inhibitor pantoprozole on intracellular and extracellular drug distribution was determined. Pantoprazole increased endosomal pH in cells, leading to less sequestration of doxorubicin within them, and increased the toxicity of doxorubicin for cultured cells. In wild-type MCF7 tumours, pretreatment with pantoprazole enhanced doxorubicin distribution and tumour growth delay without apparent increase in toxicity. These studies have led to initiation of a phase I clinical trial of pantoprazole and doxorubicin for patients with solid tumours. The work completed in this thesis demonstrates that drug distribution can be modified and that these changes can be quantified, and may correlate with improved anti-tumour effects. Improving drug distribution through the use of proton pump inhibitors may be an effective strategy to improve chemotherapeutic efficacy.

In 1899, the German surgeon Max Wilms hypothesised that different cell types in a variety of childhood kidney cancers were all derived from the mesodermal layer during embryonic development. Nearly a century later, the WT1 gene was identified on the short arm of chromosome 11, and was thought to be inactive in ~20% of nephroblastomas (Wilms’ tumours). The expression of WT1 after birth appears to be restricted to a finite number of tissues, namely, the glomerular podocytes, mesothelium and ~1% of bone marrow cells. Emerging evidence suggests WT1 is required not only for development, but also for tissue homeostasis, regeneration, repair and angiogenesis. Interestingly, WT1 has been implicated in the response to myocardial infarction and tumour angiogenesis, yet its precise role remains unclear. This thesis aims to address the hypothesis that activation of the WT1 gene in the vascular endothelium is essential for physiological and pathophysiological angiogenesis in the adult. In order to assess whether Wt1 was expressed in quiescent endothelial cells (ECs) immunofluorescence was used to analyse a variety of tissues in the adult mouse. Whilst Wt1 was detected in renal podocytes, no endothelial Wt1 expression was discovered in the lung, heart, kidney, spleen and gastrocnemius muscle. In contrast, tissues known to undergo physiological angiogenesis (endometrium and breast) did exhibit Wt1 expression in the vascular endothelium. Moreover, tubular EC outgrowths generated by aortic rings embedded in collagen ex vivo were positive for Wt1. The role of Wt1 in ischaemic angiogenesis was assessed using models of hind-limb and coronary ischaemia in the mouse. Wt1 was detected in ECs and non-vascular cells following ischaemic injury by a combination of immunofluorescence and qualitative real-time polymerase chain reaction (qRT-PCR). Using a time course analysis of these experimental models the chronology of this relationship was demonstrated, alongside the association with key angiogenic factors, such as Vegf. Given the findings in ischaemic tissue the C3(1)/Tag transgenic mammary cancer model was used to test the hypothesis that Wt1 would be upregulated in the tumour vasculature. Endothelial Wt1 was up regulated in these tumours compared to healthy control tissue. This finding was mirrored in a sub-set of aggressive breast cancers, confirming that the results obtained in mice can be translated to humans. Quantitative PCR revealed no association between histopathological grade of the tumours, oestrogen receptor status, and WT1 expression. In order to delineate the cell types involved in vessel formation, Wt1+ cells were sorted using fluorescent activated cell sorting (FACS) from transgenic mice with a green fluorescent protein knocked into the Wt1 locus following sponge implantation. Distinct sub-populations of Wt1+ cells were identified, some of which expressed EC and pericyte markers. Moreover, these Wt1+ sub-populations changed in composition and number over time. These findings were confirmed by genetic fate mapping of Wt1+ cells in this model. Finally, a conditional knockout mouse was generated to allow the selective deletion of Wt1 from vascular ECs in the sponge model of angiogenesis. The results demonstrated that deletion of Wt1 from this cellular compartment led to a dramatic reduction in vessel formation supporting a potential role in regulating angiogenesis. These results support the hypothesis that expression of WT1 in the vascular endothelium contributes to the regulation of angiogenesis in tumours and ischaemic tissue, and provides evidence that selective deletion of the gene inhibits new vessel formation. This suggests that targeting WT1 may have a therapeutic benefit in cancer and could aid regeneration of ischaemic tissues following injury in conditions such as myocardial infarction and critical limb ischaemia.

No description available.

MUDr. SKALICKÝ, Tomáš Five year period of experimental and clinical experience with radiofrequency ablation of liver tumors is described. RFA considerably extends the survival of patients with non-resectable liver metastases. The method has minimal complications and both mortality and morbidity are low.

Yes / Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes. / ALF, JFA, and MJM declare funding from St Baldrick’s Foundation; grant reference number 358099.

Thesis (MA)--Stellenbosch University, 2015 / ENGLISH ABSTRACT : Worldwide there are various reports on the prevalence of depression in patients diagnosed with brain tumours. In South Africa, psychological research in relation to psychiatric symptoms among patients with brain tumours is lacking. The aims of this study were to determine the incidence of depression in patients diagnosed with brain tumours and to clarify our understanding of the relationship between depression and tumour localisation, histopathological type of tumour, and participant characteristics. The study sample consisted of 35 patients (11 males and 24 females) aged between 21 and 64 years with a solitary primary brain tumour. The patients were treated at the neurosurgery clinics located at Tygerberg Hospital in the Western Cape and Universitas Hospital in the Free State between mid-2010 and 2013. The major histological subgroup consisted of meningiomas (47%), glioblastomas (22%), astrocytomas (19%), gliomas (9%) and epidiomas (3%). The tumour distribution was as follows: 52% in the left hemisphere, 37% in the right hemisphere, and 11 % in the midline. The psychiatric symptoms of the patients were assessed before treatment by the Beck Depression Inventory and Mini International Neuropsychiatric Interview. In addition, the patients’ neuropsychological functions were evaluated by a short neuropsychological test battery (Mini Mental State Examination, Trail Making Test (Part A), Letter Number Sequencing subtest, Hopkins Verbal Learning Test – Revised, and Brief Visuospatial Memory Test – Revised). Results from the quantitative data, showed the prevalence of mild depression was 26% for men and 43% for women. Overall 37% of the total sample had depressive symptoms. No significant relationship was found between depression and tumour location or between the various neuropsychological characteristics and neurological symptoms and tumour location. The study showed that depression is a common symptom in patients diagnosed with brain tumours and therefore depression symptoms have to be recognised and treated by psycho-educating the patients and their families, pharmacotherapy, or psychotherapy as soon as possible. However, due to the relatively small sample size, the results are of limited generalisability. / AFRIKAANSE OPSOMMING : Wêreldwyd is daar verskeie verslae oor die voorkoms van depressie in pasiënte gediagnoseer met breingewasse. In Suid-Afrika is daar ’n tekort aan sielkundige navorsing met betrekking tot psigiatriese simptome by pasiënte. Die doel van hierdie studie was om die voorkoms van depressie te bepaal in pasiënte gediagnoseer met breingewasse en om duidelikheid te kry oor die verband tussen depressie en die ligging van breingewasse, histopatologiese tipe gewas en karakter eienskappe van die deelnemers. Die steekproef van die studie het bestaan uit 35 pasiënte (11 mans en 24 vroue) tussen die ouderdomme 21 en 64 jaar met ‘n soliede breingewas. Die pasiënte is behandel by die neurochirurgiese klinieke by Tygerberg Hospitaal in die Wes-Kaap en by Universitas Hospitaal in die Vrystaat vanaf middel 2010 tot 2013. Die mees algemene histologiese subgroep het bestaan uit meningiome (47%), glioblastomas (22%), astrocytomas (19%), gliomas (9%) en epidiomas (3%). Die verspreiding van die gewasse was soos volg: 52% in die linkerhemisfeer, 37% in die regterhemisfeer en 11% in die middel. Die psigiatriese simptome van die pasiënte is voor behandeling geëvalueer met behulp van die Beck Depression Inventory en die Mini International Neuropsychiatric Interview. Bykomend is die pasiënte se neurosielkundige funksies geëvalueer met behulp van ‘n neurosielkundige toetsbattery (Mini Mental State Examination, Trail Making Test (Part A), Letter Number Sequencing subtest, Hopkins Verbal Learning Test – Revised en Brief Visuospatial Memory Test – Revised). Die resultate van die kwantitatiewe data het getoon die voorkoms van matige depressie was 26% vir mans en 43% vir vroue. In geheel het 37% van die totale steekproef depressiewe simptome getoon. Daar was geen beduidende verhouding tussen depressie en die ligging van die gewas of tussen die verskeie neurosielkundige eienskappe en die ligging van die gewas nie. Die studie het getoon dat depressie ’n algemene simptoom is in pasiënte gediagnoseer met breingewasse en daarom moet depressiewe simptome herken en so gou as moontlik behandel word deur psigo-opvoeding van die pasiënte en hul familie, farmakoterapie of psigoterapie. As gevolg van die relatiewe klein steekproef grootte het die resultate ’n beperkte veralgemeenbaarheid.