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Purpose The purpose of this enquiry is to explore the symptom experience and the health-related quality of life (HRQL) of children who have survived a brain tumour. Design An emergent, mixed-method study design was used with three phases of inquiry. 1) A systematic review was undertaken of previous research on the HRQL outcomes and symptom experience of children who have survived a brain tumour. 2) A quantitative study of the relationship between symptom experience and HRQL in 50 children who have survived a pediatric brain tumour was completed. This study was followed by a qualitative study of 12 children that used an interpretive descriptive methodology to understand the perceived relationship between symptom experience, coping and quality of life. 3) The results of phases 1 and 2 were translated into an evidence-informed clinical practice framework. Results 1) Pediatric brain tumour survivors had poorer HRQL outcomes than other cancer survivors or healthy peers. Only two previous studies had explored the relationship between symptoms and HRQL. 2) Pediatric brain tumour survivors experience many symptoms following the completion of treatment. The most distressing symptoms were pain, headaches, fatigue and sleep problems. Survivors of pediatric brain tumours described multiple symptoms that affect their life; yet overall they described their quality of life as good. Survivors used a variety of coping strategies to help mitigate the negative effects of these symptoms. 3) The results of the above studies informed the development of a clinical practice framework (the Queen’s-Macartney Multidisciplinary Action Plan for Oncology Survivors - Q-MapS), that requires further testing. It is intended to optimize clinical practice, to encourage education and to stimulate further research. Conclusions Child survivors of brain tumours experience various symptoms that can affect their HRQL. Nurses play a pivotal role in the systematic assessment and management of the multidimensional symptom experience of children following treatment for a brain tumour. Q-MapS can empower patients and their families by increasing their awareness of potential or actual problems related to their symptom experience and HRQL. More research is needed to better understand the relationship between symptoms and HRQL in children surviving brain tumours. / Thesis (Ph.D, Nursing) -- Queen's University, 2013-05-01 21:12:57.809

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Introduction The adjuvant treatment of colorectal cancer (CRC) has seen little improvement in terms of mortality of the disease in the last 40 years. There has been a resurgence in research into the use of monoclonal antibodies in the treatment of CRC. Carcinoembryonic antigen (CEA) is a useful target in cancer immunotherapy. The distribution of CEA in CRC differs from that in normal colorectal tissue. In normal colorectal tissue CEA is found only on the luminal surface of the cell which is inaccessible to intravenous antibody, whereas in CRC, CEA is found on all borders of the cell membrane and so becomes accessible to intravenous antibody. However, anti-CEA antibodies are prone to sequestration by circulating CEA. The anti-CEA antibody, PR1A3, binds only membrane-bound CEA and thus is able to overcome this problem. The aim of my research was to assess whether PR1A3 is suitable to be considered as a therapeutic agent in the treatment of CRC and what its mechanism of action might be. Methods The level of expression of CEA on a panel of cell lines was determined under different conditions using a solid-phase ELISA and FACS analysis. Humanized PR1A3 (hPR1A3) was assessed in a variety of in vitro cytotoxicity assays with colorectal cell lines expressing varying levels of CEA, using peripheral blood mononuclear cells and purified natural killer cells as sources of effector cells. The mechanism of action of PR1A3 was investigated by modifying the Fc fragment of the antibody and using antibodies to block the FcIIIA receptor on the effector cells. PR1A3 was also investigated in combination with a humanised A33 antibody. Results A panel of colorectal cell lines was found to have a range of CEA expression which could be upregulated in certain cell lines by growing the cell line beyond confluence and by treatment with the chemotherapeutic agent, 5-fluorouracil. The in vitro assays demonstrated hPR1A3 antibody-dependent and CEA-specific killing of tumour cell lines by human PBMC. The effect increased with increasing concentration of antibody and was lost by using the parent murine IgG1 PR1A3. Using 50&mu;g/ml hPR1A3, tumour cell lysis was increased by more than 3-fold above spontaneous killing (p < 0.001) in a high CEA-expressing cell line. Both antibody-dependent and antibody-independent (spontaneous) killing was blocked by using whole antibody to the Fc-&gamma;IIIA receptor, although the spontaneous killing was restored when a F(ab')2 was used instead of whole antibody. hPR1A3 and the A33 antibody showed potential synergy when used in combination against a high-CEA and a moderate-A33 expressing cell line. Conclusion The monoclonal antibody hPR1A3 causes CEA-specific lysis of human colorectal cancer-derived cell lines in the presence of human PBMCs. This lysis is dependent on the dose of the antibody, requires a compatible Fc-receptor and is inhibited by blockade of the FcγIIIA receptor. These findings show that hPR1A3 can kill tumour cells by antibody-mediated cellular cytotoxicity (ADCC) and implicate NK cells as a major contributor to this effect. The results support the development of hPR1A3 for therapy of colorectal cancer.

Medulloblastoma (MB) is the commonest intracranial childhood malignancy and despite recent advances, current therapeutic approaches are still associated with high morbidity and mortality. A novel molecular classification has recently been proposed for these tumours – WNT Group (best prognosis), SHH Group (intermediate prognosis), Group 3 (worst prognosis) and Group 4 (intermediate prognosis). BMI1, a transcriptional repressor of the Polycomb group genes, is overexpressed in MB, most significantly in those of Group 4 MBs. Bone Morphogenetic Proteins (BMPs) are morphogens belonging to TGF-β superfamily of growth factors, and are known to inhibit MB cell proliferation and induce apoptosis in vitro, and to inhibit tumour growth in vivo. Our team have recently demonstrated that Bmi1 regulates cell adhesion properties during cerebellar development through repression of the BMP pathway. The aim of this project is to assess whether BMI1 overexpression may contribute to MB pathogenesis through repression of the BMP pathway. Here we demonstrate that BMI1 knock down derepresses BMP pathway, and using a novel xenograft model of human MB of Group 4, we show that BMI1 controls tumour volume and intraparenchymal invasion. In in vitro assays on MB cell lines we show that cell adhesion and motility is controlled by BMI1 in a BMP dependent manner and that deregulation of extracellular matrix proteins are key mediators of this effect. Furthermore, we demonstrate that BMP treatment to BMI1 overexpressing MB cells reduces cell proliferation and invasion, suggesting BMI1 as a possible biomarker for those tumours that could benefit from treatment with BMP agonist small molecules.

<p>This study was carried out to determine the phenotype of special dog mammary gland tumours that were grown in nude mice. 26 tumours were examined by the immunohistochemical ABC-Elite protocol. The tumour tissues were labelled with following anti-human antibodies:</p><p>- AE1/AE3 (pankeratin antibody) labelled epithelial and myoepithelial cells</p><p>- CD 31 labelled endothelial cells</p><p>- desmin labelled cross-striated and smooth muscle cells</p><p>- myosin labelled cross striated muscle cells</p><p>- neurofilament (NF) labelled nerve cells</p><p>- osteopontin labelled preosteoblasts, osteoblasts and osteocytes</p><p>- p63 labelled nuclei of the myoepithelial cells</p><p>- smooth muscle actin (SMA) labelled the cytoplasm of myoepithelial cells</p><p>- type I collagen labelled the extracellular matrix in connective tissue and bone</p><p>- type II collagen labelled the extracellular matrix in cartilage</p><p>- vimentin labelled fibroblasts, fibrocytes, lipocytes, smooth muscle cells, endothelial cells, nerve cells, macrophages and myoepithelial cells</p><p>The tumours were also submitted to a double immunolabelling study using p63 and SMA.</p><p>The study could not give a final conclusion about the origin the tumours. There was still need for more research to answer that question. However, the immunohistochemical technique was analysed in detail, in order to obtain perfect labelings.</p><p>Initially, all the antibodies were tested on normal dog tissue, to acquire the best working dilutions with the lowest background problems. In the tumours, good results were obtained with these dilutions for the antibodies p63, SMA, vimentin, desmin, NF, AE1/AE3 and CD 31. Except for type I collagen, type II collagen and osteopontin that gave too much unspecific labelling of the mouse connective tissue. Even, when using the Vector® M.O.M. blocking kit, the results were still very difficult to interpretate.</p><p>The antigen retrieval methods were evaluated for all the antibodies. The antibodies p63, SMA, vimentin, desmin, AE1/AE3, myosin, neurofilament and CD 31 needed the antigen retrieval treatment. The antibodies type I collagen and type II collagen needed the treatment with the enzyme pepsin, while osteopontin did not need any pretreatment at all.</p><p>The double immunolabelling with p63 and SMA gave excellent results. Different combinations were tried out with different substrates, namely Vector® Nova RED, Vector® DAB and Vector® SG. Vector® methyl green was used as counterstaining, but it interfered with the other substrates, and better results were obtained without this counterstaining.</p>

Els tumors de cervell humans (HBTs) són uns dels càncers més agressius i intractables. El sistema actual de diagnosi i prognosi dels HBTs es basa en l'examinació histològica d'un tall de biòpsia, el qual es considera el sistema de referència ("gold¬standard"). A més de ser invasiva, aquesta tècnica no és prou acurada per a diferenciar els graus de malignitat de determinats HBTs i la correlació amb la resposta del pacient a la teràpia sol ser variable. En aquest context, les signatures gèniques obtingudes a partir de microarrays de DNA poden millorar els resultats del "gold-standard". En aquesta tesi, vaig recollir 333 biòpsies de varis tipus de HBTs. Com un 38% de les mostres tenien l'RNA degradat, vam avaluar si el tipus de HBTs, el contingut aparent de sang de la biòpsia i el medi de recollida de la biòpsia hi afectaven. Com no vam determinar cap relació, hipotetitzo que un temps variable d'isquèmia a temperatura normal del cos abans de l'extracció de la biòpsia podria induir la degradació de l'RNA. Això va ser avaluat en un tumor glial pre-clínic desenvolupat en ratolí. Es va detectar que 30 minuts de temps d'isquèmia afecta la integritat del RNA en tumors no necròtics, però no en els necròtics. Una part crucial de la tesi va ser la demostració com una "prova de principis" de l'habilitat de les signatures gèniques per a predir objectivament els HBTs. Això es va mostrar mitjançant una predicció perfecta de glioblastoma multiforme (Gbm) i meningioma meningotelial (Mm) utilitzant microarrays de cDNA i microchips d'Affymetrix. Els histopatòlegs poden discriminar perfectament aquests dos tipus de tumors, però aquest treball demostra una predicció perfecta utilitzant una fórmula matemàtica objectiva. Un cop es va demostrar això, em vaig sentir confiat per a predir diferents graus de malignitat i possibles subtipus moleculars de tumors glials. En aquest sentit, es va descriure una signatura gènica basada en l'expressió de 59 transcrits, la qual va distingir dos grups de glioblastomes. Finalment, una anàlisi inicial de les dades clíniques associades suggereix que la signatura gènica podria correlacionar amb glioblastomes primaris i secundaris. / Human brain tumours (HBTs) are among the most aggressive and intractable cancers. The current system for diagnosis and prognosis of HBTs is based on the histological examination of a biopsy slice, which is considered the 'gold standard'. Apart from being invasive, this technique is not accurate enough to differentiate malignancy grades of some HBTs and it provides a variable correlation with response to therapy of the patient. In this context, gene signatures from DNA microarray experiments can improve the results of the 'gold standard'. In this thesis, I collected 333 biopsies from various types of HBTs. As 38% of samples displayed degraded RNA, I evaluated whether the HBT type, the apparent blood content and the collection medium of the biopsy could play a role in this. As no relationship was found, I hypothesized that the variable ischaemia time at normal body temperature prior to removal of the biopsy may induce degradation of RNA. This was tested in a preclinical glial tumour model in mice. It was detected that 30 minutes ischaemia time affects the integrity of the RNA in non-necrotic tumours, but not in the necrotic ones. A crucial part of this thesis was the demonstration of proof-of-principle of the ability of gene signatures for objective prediction of HBTs. This was shown by perfect prediction of glioblastoma multiforme (Gbm) and meningothelial meningioma (Mm) using cDNA and Affymetrix microarrays. Histopathologists perfectly discriminates both tumour types, but this work demonstrated perfect prediction using a simple mathematical formula. Once this was demonstrated, I felt confident to predict different malignancy grades and possible molecular subtypes of glial tumours. In this respect, a gene signature based on the expression of 59 transcripts, which distinguished two groups of glioblastomas, was described. Finally, a crude initial analysis of associated clinical data suggests that this gene signature may correlate to primary and secondary glioblastomas.