Neuroblastoma (NB) is the most common solid tumor of early infancy. Despite a significant improvement in the general survival rate for children with cancer, the prognosis of high-risk NB remains low, at about 30%, despite the use of intensive chemo-radiotherapy followed by differentiation therapy with retinoic acid (RA). Relapses in this category of NB are often due to the emergence of multi-drug and RA-resistant minimal residual cancer cells. The use of natural 13-cis RA, as a single chemo-preventive agent, has improved the survival rate to 50% for high-risk NB patients. However, the prevalence of RA-resistance is high in high-risk NB, and in solid cancers, in general. RA-resistance in cancer cells is mediated by a number of factors. Loss of RA-induced expression of the putative tumor suppressor gene, retinoic acid receptor-beta (RARβ), is one of the most common factors that have been reported in RAresistant phenotypes of a wide range of cancer cells. The transcriptional regulation of RAR(β) gene and other retinoid responsive-genes is believed to be regulated by the ligand-dependent transactivation of the homo- or heterodimer complexes of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, namely alpha (α), beta (β) and gamma (γ). It is believed that the anti-cancer activities of natural all-trans RA and 13-cis RA are mediated through activation of RAR-complexes. The loss of RA-induced RAR β expression can be caused by aberrant recruitment of chromatin structure modifying enzymes, histone deacetylases (HDACs), which have major roles in the global regulation of gene transcription. However, the mechanism of RA-resistance in NB cells is unclear. This thesis set out to identify the molecular mechanism of RA-resistance and to develop a new therapeutic approach to overcome RA-resistance in NB cells. The data in this thesis demonstrated that deregulation or over-expression of proto-oncogene MYCN caused a total RA-resistance in NB cells in vitro and in vivo, despite the strong induction of RARI3 expression. The data also indicated that the activation of RAR-dependent pathways by aRA or 13RA alone is not sufficient to overcome MYCN-mediated RA-resistance in NB cells. In the light of this observation, this thesis went on to examine whether combined targeting activation of RAR and RXR subtypes with receptor specific ligands could enhance the therapeutic efficacy of the retinoid signaling pathway. NB cells were treated with a panel of receptor-specific retinoids, namely aRA, l3RA, 9RA (RAR-specific), CD 417, CD 2314 (RARβ-specific), CD 666 (RARγ-specific), CD 336 (RARα-specific), CD 3640, CD 2872 (RXR-specific), as a single agent or in combination at a low concentration of 0.1 ??M. The results showed that combined targeting activation of RARα and RXR was not only the most effective combination, but also overcame MYCN-mediated RA-resistance in NB cells in vitro.Collectively, these data demonstrated the combined targeting activation of RAR and RXRs as a new approach to enhance the efficacy of retinoid therapy and overcome RA-resistance in the treatment of high-risk NB, and other cancers. The emerging therapeutic potential of HDAC inhibitors (HDACi) as front line anti-cancer agents, or adjuvants to other agents such as RA, has suggested a new approach in the treatment of cancer. However, the molecular mechanism of the remarkably specific anticancer actions of HDACi is still largely speculation. The data presented in this study was the first to demonstrate a novel sequential order and the dosage-dependent roles of basal p21Wafl expression and G2/M arrest as protective mechanisms against HDACi-induced apoptosis. In addition, this thesis also examined and compared the therapeutic efficacy of HDACi as a single agent and in combination with other anti-cancer agents such as RA, IFNα and chemotherapeutic agents. Evaluation of the therapeutic effects of combinations of aRA, IFN and HDACi showed that combination of HDACi and IFNα exhibited the strongest synergy against NB cells in vitro. Treatment of MYCN transgenic mice, which consistently develop abdominal NB tumors that closely mirror the human disease in both physiological and biological aspects, with hydroxamic acid-based HDACi, trichostatin A (TSA), alone reduced tumor growth by nearly 50%, compared to the solvent control and IFNα alone, which had no effect on NB tumor growth. The most exciting finding was that the combination of HDACi and IFNα synergistically reduced tumor mass and angiogenesis by over 80% without any apparent systemic side-effects. The therapeutic effect of treatment with HDACi correlated with the induction of acetylation of histone 4 protein (H4) in both tumor and organ tissues, indicating a wide therapeutic index for HDACi in vivo. Collectively, the data in this study have demonstrated basal p21 Wafl expression as a potential marker of sensitivity to HDACi-based therapy, and the therapeutic efficacy of a novel combination of HDACi with IFNα in vivo. These preclinical data have provided an evidence-based rationale for a clinical trial of the combination of HDACi and IFNα in the treatment of high risk NB.

Thesis (M.S.)--University of Michigan, 1986.

Thesis (M.S.)--University of Michigan, 1986.

Thesis (M.S.)--University of Michigan, 1991.

Thesis (M.S.)--University of Michigan, 1991.

Thesis (MNutr)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: Background: The role of antioxidants and adequate nutrition in the prevention and course of cancer treatment is globally recognised in nullifying the effects of free radicals and increasing the nutritional status of children during treatment. Objective: To investigate whether children with cancer meet their Dietary Reference Values and Safe Intakes for antioxidants, energy and protein. Design: Single centre prospective study. Setting: Children were recruited from the East of England Primary Treatment Centre using convenience sampling over 8 months. Forty-two children and adolescents diagnosed with a Solid tumour, Lymphoma or Leukaemia were eligible for data analysis (n=20 male; n=22 female). Method: Data was collected with an Estimated Food Record (EFR) in the 1st (EFR1) and 3rd month (EFR2) post-diagnosis. In the week following EFR completion, parents and/or children were contacted to complete four non-consecutive days of 24-hr food recalls. Data was categorised into diet alone, diet + food supplement (FS), tube feeding (tube) or diet + multi-vitamin-mineral supplementation (VMS). Malnutrition was determined by weight-for-age z-scores. Nutrient intake was compared to the Recommended Nutrient Intake (RNI), the Estimated Average Requirements (EAR) and the Lower Recommended Nutrient Intake (LRNI). Result: The sample consisted of 33% (n=14) diagnosed with Leukaemia, 24% (n=10) with Lymphoma and 43% (n=18) with Solid tumours. Sixty seven percent (n=28) underwent chemotherapy and 33% (n=14) a combination of therapies. Significant correlations were seen between the assessment tools in the diet alone category for both months for; vitamins A, C, E, selenium and protein and for EFR1 for zinc and energy. In both months greater numbers of children achieved ≥100% of requirements for diet + VMS (EFR 1; p<0.05; EFR2 p<0.05) than for other feeding modes. Vitamin C achieved the highest intakes compared to the RNI at 773% (EFR1) and 829% (EFR2). Intakes above 200% of the RNI were seen for vitamins A, C, E, selenium and zinc. No significant differences were seen between modes of feeding in either month for selenium or zinc. Vitamin A (EFR1≤ 100% diet alone p<0.05) and zinc (EFR1≤ 100% diet alone p=0.02) met the least of the LRNI in the 1st month compared to other antioxidants. No statistical significant difference was observed between the number of children attaining their EAR’s between the 3 modes of feeding in the 1st month and 3rd month. In the 1st month 27% (n=8) of participants consumed vitamin and/or mineral supplements, 18% in the 3rd month (n=4). In the 1st month 5% (n=2) of children were moderately malnourished and 10% (n=4) in 3rd month. Conversely in the 1st month 3% (n=1) were overweight and 3% (n=1) obese; the leukaemia group predominant. Conclusion: The research tools showed good correlation. Children using vitamin and/or mineral supplements mostly achieved their RNI’s compared to other feeding modes. Across feeding modes some children achieved antioxidant intakes above 200% RNI. LRNI’s on diet alone were not achieved for vitamin A and zinc. The study showed Leukaemics as having a higher prevalence of obesity. More research is required to determine the clinical implications of these findings. / AFRIKAANSE OPSOMMING: Agtergrond: Die rol van anti-oksidante en voldoende voeding in die voorkoming en verloop van kanker behandeling word wêreldwyd erken vir vernietiging van die effek van vry radikale en die verbetering van voedingstatus van kinders tydens behandeling. Doelwit: Om ondersoek in te stel of kinders met kanker hul Dieet Verwysingswaardes en Veilige Innames vir anti-oksidante, energie en proteïen bereik. Ontwerp: Enkel sentrum prospektiewe studie. Omgewing: Kinders was gewerf deur middel van gerieflikheidsteekproefneming oor 8 maande vanaf die “East of England Primary Treatment Centre”. Twee-en-veertig kinders en adolessente gediagnoseer met 'n Soliede tumor, Limfoom of Leukemie het in aanmerking gekom vir dataanalise (n=20 manlik, n=22 vroulik). Metode: Data was ingesamel met ‘n Geskatte Voedsel Rekord (GVR) in die eerste (GVR1) en derde maand (GVR2) na diagnose. In die week na voltooiing van die GVR is ouers en/of kinders gekontak om vier onopeenvolgende dae van 24-uur herroepe te voltooi. Data was verdeel in dieet alleen, dieet + voedsel supplement (VS), buisvoeding (buis) of dieet + multi-vitamien-mineraal supplementasie (VMS). Wanvoeding was bepaal deur middel van gewig-vir-ouderdom z-tellings. Nutriënt inname was vergelyk met die Aanbevole Nutriënt Inname (ANI), die Geskatte Gemiddelde Behoeftes (GGB) en die Laer Aanbevole Nutriënt Inname (LANI). Resultate: Die steekproef het bestaan uit 33% (n=14) gediagnoseer met Leukemie, 24% (n=10) Limfoom en 43% (n=18) Soliede tumore. Sewe-en-sestig persent (n=28) het chemoterapie ontvang en 33% (n=14) ‘n kombinasie van terapieë. Betekenisvolle korrelasies was waargeneem tussen die assesseringsinstrumente in die dieet alleen kategorie vir beide maande vir vitamiene A, C, E, selenium en proteïen en vir GVR1 ook vir sink en energie. In beide maande het ‘n groter aantal kinders ≥100% van hul behoeftes bereik vr dieet+VMS (GVR1; p<0.05; GVR2 p<0.05) as vir ander modi van voeding. Vitamien C het die hoogste innames bereik vergeleke met die ANI teen 773% (GVR1) en 829% (GVR2). Innames bo 200% van die ANI was waargeneem vir vitamiene A, C, E, selenium en sink. Geen betekenisvolle verskille was waargeneem tussen modi van voeding in enige maand vir selenium en sink nie. Vitamien A (GVR1≤100% dieet alleen p<0.05) en sink (GVR1≤100% dieet alleen p=0.02) het die minste van die LANI bereik in die eerste maand vergeleke met ander anti-oksidante. Geen statisties beduidende verskil was waargeneem tussen die aantal kinders wat hul GGB’s bereik het tussen die 3 voedingswyses in die eerste en derde maande nie. In die eerste maand het 27% (n=8) van deelnemers vitamien en/of mineraal supplemente ingeneem, en 18% (n=4) in die derde maand. In die eerste maand was 5% (n=2) van kinders matig wangevoed en 10% (n=4) in die derde maand. In die eerste maand was 3% (n=1) van kinders oorgewig en 3% (n=1) vetsugtig, die leukemie groep spesifiek. Gevolgtrekking: Die navorsingsinstrumente het goeie korrelasie getoon. Kinders wat vitamien en/of mineraal supplemente gebruik het het meestal hul ANI’s bereik vergeleke met ander modi van voeding. Oor voeding modi het sommige kinders anti-oksidant innames bo 200% ANI bereik. LANI’s op dieet alleen was nie bereik vir Vitamien A en sink nie. Hierdie studie het aangetoon dat dié met Leukemia ‘n hoër prevalensie van oorgewig/vetsug getoon het. Meer navorsing is nodig om die kliniese implikasies van die bevindinge te bepaal.

In this study the researcher explored and described the utilization of Gestalt play therapy concepts and techniques in order to strengthen the sense of self of the pediatric hematology/oncology patient. Literature studies were compiled to examine the concepts of the pediatric hematology/oncology patient, sense of self and Gestalt play therapy. These literature studies provided the theoretical frame in which the study was executed. During the empirical study qualitative data was gathered by means of unstructured interviews within an instrumental case study. Eight therapy sessions were conducted with the participant in order to explore how Gestalt play therapy concepts and techniques could be utilized to strengthen the sense of self of the pediatric hematology/oncology patient. Following the analysis of the data the researcher was able to describe how the Gestalt play therapy concepts and techniques were utilized to strengthen the sense of self of the pediatric hematology/oncology patient. / Social Work / M. Diac. (Play Therapy)

Submitted in fulfilment of the requirement for the degree Masters of Nursing in the Faculty of Health and Wellness Sciences 2015 / Background: Oncology nursing continues to evolve in response to advances in cancer treatment. The role of the oncology nurse in the management of cancer in children is very significant as these children go through a lot of emotional trauma due to the disease. Aim and objectives: The aim of the study is to explore and examine the quality of nursing care given to children diagnosed with cancer in Ghana. Some of the objectives are to examine strategies nurses use in planning care; and to determine processes nurses use to evaluate care given. Methodology: A mixed-methods qualitative cross-sectional descriptive design was used. Population and samples: Komfo Anokye Teaching Hospital in Ghana is selected as the research site. The population consists of all nurses working in the hospital and parents/carers looking after children diagnosed with cancer. The samples was nurses working on paediatric wards/clinics, parents/carers, and key informants. Selection of sample groups was opportunistic. Methods of data collection: three sources were used to collect data, i.e. questionnaires for nursing working on paediatric wards/clinics, interviews with nurses and carers, and key informant interviews. Analysis: descriptive statistical analysis of data was undertaken and the three data sources were triangulated to determine similarities and differences of responses. Benefits of the study: The results of the study will be submitted to the hospital management and articles will be submitted to peer-reviewed nursing journals. Key words: paediatric oncology, nurses, oncology nurses, Kumasi, Ghana, Komfo Anokye teaching hospital.

published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

A realidade de ter um filho com câncer e hospitalizado, é uma situação penosa para toda família. Na maioria dos casos, é a mãe que acompanha o internamento, sendo sua participação reconhecida como fundamental no tratamento e recuperação do filho. Para tanto, é necessário uma compreensão de suas reais necessidades frente ao universo do câncer infantil. Este estudo vem focalizar, portanto, o sentido das vivências de mães-acompanhantes de filhos no tratamento do câncer. Trata-se de uma pesquisa qualitativa de base fenomenológica, na qual buscamos trabalhar com observações livres e narrativas de mães que estão vivenciando o acompanhamento ao tratamento de filhos com câncer. Dentre as singularidades dessas vivências, destacamos algumas expressões que são compartilhadas e narradas pelas mães: diante do diagnóstico de câncer, expressam sentimentos de incredulidade, revolta, desespero; na hospitalização, relatam sentir temor, desamparo; buscam incessantemente uma causa para o adoecimento dos filhos; explicitam gratidão pelo hospital; demonstram necessidade de obter informações sobre o câncer. Entendemos que as mães- acompanhantes, durante a internação, necessitam, sobretudo, de suporte emocional, atenção efetiva e sistêmica, para que, assim, possam contribuir ativamente no tratamento e restabelecimento dos filhos / To have a child with cancer and hospitalized is a painful situation to all family. In most cases, is the mother who stays whit the child in the hospital, being her involvement recognized as fundamental for medical treatment and his recovery. Thats why, its necessary an understanding about her real necessities faced with universe of infant cancer. Therefore this study focus on sense of the livings of mothers-being close of children in cancer treatment. This research is quality, with phenomenologic grounding, in which, we used like devices the free observations and mothers-being close talks. In among specialties about the livings of mothers-being close, we highlight some expressions that are shared and told by her: faced with diagnosis cancer, they express feelings of unbelievable, despair and disgust; during the going with her child, the mothers tell to feel fear, helpless; they seek desperately a cause for the sickness of their children; they express grateful to the hospital; they show necessity for obtain information about cancer. We understand the mothers-being close, during the going into the hospital, need, especially, emotion support, effective and systemic careful, so that, can contribute effectively in the treatment and recovery of their children