Wilms Tumour (WT) is one of the commonest tumours in children. Hepatic Sinusoidal Obstruction Syndrome (HSOS) is a documented complication following treatment of WT. The role of malnutrition in the development of HSOS has not been studied. Malnutrition reduces tolerance to chemotherapy and shows increased risk for toxicity. Purpose of study To determine the prevalence of HSOS in children with WT, as well as its predisposing factors and outcomes. Method A descriptive retrospective analysis of medical records of children treated for WT, who developed HSOS, at the Paediatric Haematology/Oncology Unit, Chris Hani Baragwanath Hospital. Results 82 patients were evaluated. 19 (23%) showed features compatible with HSOS. Younger age, irradiation and a right-sided WT predicted the development of HSOS but were not statistically significant. Serum albumin levels were lower in the affected group (P = 0.02). Apart from 2 deaths, outcomes were good, with patients showing full resolution of symptoms. Conclusion A higher prevalence of HSOS was shown than previously reported. Low serum albumin levels points to the role of malnutrition. Effort needs to be put into the various methods of identifying malnutrition. Long term follow-up is needed.

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Introdução: O tumor de Wilms (TW) é o tumor renal maligno mais comum na infância. O conhecimento de certas características clínicas e a realização de procedimentos cirúrgicos adequados podem ter impacto no prognóstico desta doença. Objetivo: Avaliar as características clínicas e cirúrgicas com importância prognóstica nos pacientes atendidos no Serviço de Oncologia Pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Pacientes e Métodos: Estudo de coorte histórica dos pacientes com Tumor de Wilms (TW) tratados no HCPA entre 1989 e 2005. Foram revisados prontuários de pacientes com diagnóstico de TW com coleta de informações de características demográficas e do tratamento clínico e cirúrgico. A sobrevida global (SG) em 5 anos foi analisada pelo método de Kaplan-Meier. Resultados: Foram incluídos no estudo 56 pacientes consecutivos, sendo 31 do sexo feminino. A média de idade dos pacientes foi de 4 anos (0,5 -17 anos), com mediana de 3,5 anos. Quanto ao estadiamento, 5,10,26,10 e 5 eram estádios I, II III, IV e V, respectivamente. Quarenta e três pacientes apresentaram como principal sintoma inicial massa abdominal palpável; 59% dos pacientes tinham tamanho tumoral ao diagnóstico >10 cm. Hematúria foi observada em 5 pacientes, dor abdominal em quatro pacientes, febre em 2 pacientes; hipertensão arterial em 1 paciente e aumento do volume testicular em 1 paciente. Foram realizadas 41 biópsias para diagnóstico histológico. Cinqüenta e dois pacientes foram submetidos à cirurgia de ressecção tumoral e 4 foram considerados irressecáveis. A média de tempo entre o início do primeiro ciclo de quimioterapia e a cirurgia foi de 15 semanas. Foram realizados 43 nefrectomias totais, 5 nefrectomias parciais e 4 nefrectomia total + parcial contralateral. Em 5 pacientes havia doença microscópica nas margens cirúrgicas.Linfonodos livres de doença foram encontrados em 32 pacientes, comprometidos em 9; não havia relato de realização de biópsia em 11. Durante o ato operatório, 38 pacientes foram submetidos à avaliação do rim contra-lateral através da palpação e em 13 relatos de cirurgia não foram encontradas descrições sobre a realização deste procedimento.Houve relato de ruptura tumoral em 1 paciente; em dez prontuários havia registro de ausência de ruptura tumoral e em 41 prontuários não havia qualquer menção quanto à presença ou ausência desta complicação. A histopatologia confirmou 45 casos de histologia favorável e os demais de histologia desfavorável. A SG foi de 69%, 71%, 79%, 50% e 40% para os estádios I, II, III, IV e V, respectivamente (P=0,21). A SG foi de 64% e 70% para pacientes com idade superior e inferior a 4 anos, respectivamente (P=0,6). A SG para pacientes que realizaram cirurgia após a 6ª semana foi de 65,2% enquanto os que realizaram antes da 6 semana foi de 73% (P=0,7). Conclusão: Os resultados apresentados permitem concluir que os pacientes estudados apresentam características demográficas gerais semelhantes aos da literatura.Considerando-se que em um número expressivo de pacientes observou-se falta de aderência a certas etapas do procedimento cirúrgico, incluindo ausência de biópsia de linfonodos e atrasos na realização da ressecção tumoral, os autores recomendam que o cirurgião pediátrico tenha uma participação mais efetiva na equipe multidisciplinar e na elaboração das rotinas do protocolo cirúrgico para pacientes com TW. / Introduction: Wilms´tumor (WT) is the most common malignant renal tumor in childhood. The knowledge of the clinical characteristics and the accomplishment of standard surgical procedures may have an impact in the prognosis of this disease. Objectives: To assess the clinical and surgical features with prognostic significance in WT patients treated at the Pediatric Oncology Unit of Hospital de Clínicas de Porto Alegre (HCPA). Patients and Methods: Medical records of newly diagnosed WT patients treated from 1989 to 2005 were reviewed. We collected data on demographics, clinical characteristics and whether certain recommended surgical standard procedures were carried out. The five year survival (OS) was analyzed by the method of Kaplan-Meier. Results: Fifty-six consecutive patients were eligible; 31 were females; mean age at diagnosis was 4.0 years (0,5 -17), with median 3,5 years. There were 5, 10, 26, 10 and 5 stages I, II,I II, IV and V, respectively. Forty-three patients presented palpable abdominal mass as initial symptom; 59% of the patients had tumor size larger than 10 cm. Hematuria was presented in five patients, abdominal pain in four patients, fever in 2 patients, arterial hypertension in 1 patient and increased testicular volume in 1 patient. Forty-one biopsies were carried out for histophatological diagnosis. Fifty two patients were submitted to surgical tumor resection and 4 of them were considered inoperable. The mean time between the first chemotherapy cycle and surgery was 15 weeks. Total nephrectomy was carried out in 43 patients, partial nephrectomy in 5 and total nephrectomy + partial contralateral nephrectomy in 4. Microscopic residual disease was found in 5 patients. Linfonode biopsies were performed in 41 patients, with 9 of them being positive; in 11 cases there was no report whether the procedure was carried out or not. The surgeon in 38 patients performed palpation of the contralateral kidney and in 13 medical records there was no report whether this procedure was carried out. Tumor spillage was reported 1 patient, reported as absent in 10 patients; we were unable to find any mention about tumor rupture on the surgeon’s report for 41 patients. There were 45 cases of favorable histology and 7 of unfavorable histology. Five years OS was of 69%, 71%, 79%, 50% and 40% for the stages I, II, III, IV and V, respectively (P = 0,21). Five years OS was 64% and 70% for patients older and younger than 4 years, respectively (P = 0,6). Five years OS was 73% and 65,2% for patients submitted to surgery before and after the 6th week after diagnosis, respectively (p =0,31). Conclusion: The results of the present study indicate that patients in this study show demographic characters similar to the literature. Considering that surgeons did not performed standard recommended surgical procedure such as lymph nodes biopsy and carried out late surgical resection of the primary tumor in many patients, there is a need for a more effective participation of the surgeon in the multidisciplinary team and possibly in the designing protocols for the surgical management of patients with TW.

Introdução: O tumor de Wilms (TW) é o tumor renal maligno mais comum na infância. O conhecimento de certas características clínicas e a realização de procedimentos cirúrgicos adequados podem ter impacto no prognóstico desta doença. Objetivo: Avaliar as características clínicas e cirúrgicas com importância prognóstica nos pacientes atendidos no Serviço de Oncologia Pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Pacientes e Métodos: Estudo de coorte histórica dos pacientes com Tumor de Wilms (TW) tratados no HCPA entre 1989 e 2005. Foram revisados prontuários de pacientes com diagnóstico de TW com coleta de informações de características demográficas e do tratamento clínico e cirúrgico. A sobrevida global (SG) em 5 anos foi analisada pelo método de Kaplan-Meier. Resultados: Foram incluídos no estudo 56 pacientes consecutivos, sendo 31 do sexo feminino. A média de idade dos pacientes foi de 4 anos (0,5 -17 anos), com mediana de 3,5 anos. Quanto ao estadiamento, 5,10,26,10 e 5 eram estádios I, II III, IV e V, respectivamente. Quarenta e três pacientes apresentaram como principal sintoma inicial massa abdominal palpável; 59% dos pacientes tinham tamanho tumoral ao diagnóstico >10 cm. Hematúria foi observada em 5 pacientes, dor abdominal em quatro pacientes, febre em 2 pacientes; hipertensão arterial em 1 paciente e aumento do volume testicular em 1 paciente. Foram realizadas 41 biópsias para diagnóstico histológico. Cinqüenta e dois pacientes foram submetidos à cirurgia de ressecção tumoral e 4 foram considerados irressecáveis. A média de tempo entre o início do primeiro ciclo de quimioterapia e a cirurgia foi de 15 semanas. Foram realizados 43 nefrectomias totais, 5 nefrectomias parciais e 4 nefrectomia total + parcial contralateral. Em 5 pacientes havia doença microscópica nas margens cirúrgicas.Linfonodos livres de doença foram encontrados em 32 pacientes, comprometidos em 9; não havia relato de realização de biópsia em 11. Durante o ato operatório, 38 pacientes foram submetidos à avaliação do rim contra-lateral através da palpação e em 13 relatos de cirurgia não foram encontradas descrições sobre a realização deste procedimento.Houve relato de ruptura tumoral em 1 paciente; em dez prontuários havia registro de ausência de ruptura tumoral e em 41 prontuários não havia qualquer menção quanto à presença ou ausência desta complicação. A histopatologia confirmou 45 casos de histologia favorável e os demais de histologia desfavorável. A SG foi de 69%, 71%, 79%, 50% e 40% para os estádios I, II, III, IV e V, respectivamente (P=0,21). A SG foi de 64% e 70% para pacientes com idade superior e inferior a 4 anos, respectivamente (P=0,6). A SG para pacientes que realizaram cirurgia após a 6ª semana foi de 65,2% enquanto os que realizaram antes da 6 semana foi de 73% (P=0,7). Conclusão: Os resultados apresentados permitem concluir que os pacientes estudados apresentam características demográficas gerais semelhantes aos da literatura.Considerando-se que em um número expressivo de pacientes observou-se falta de aderência a certas etapas do procedimento cirúrgico, incluindo ausência de biópsia de linfonodos e atrasos na realização da ressecção tumoral, os autores recomendam que o cirurgião pediátrico tenha uma participação mais efetiva na equipe multidisciplinar e na elaboração das rotinas do protocolo cirúrgico para pacientes com TW. / Introduction: Wilms´tumor (WT) is the most common malignant renal tumor in childhood. The knowledge of the clinical characteristics and the accomplishment of standard surgical procedures may have an impact in the prognosis of this disease. Objectives: To assess the clinical and surgical features with prognostic significance in WT patients treated at the Pediatric Oncology Unit of Hospital de Clínicas de Porto Alegre (HCPA). Patients and Methods: Medical records of newly diagnosed WT patients treated from 1989 to 2005 were reviewed. We collected data on demographics, clinical characteristics and whether certain recommended surgical standard procedures were carried out. The five year survival (OS) was analyzed by the method of Kaplan-Meier. Results: Fifty-six consecutive patients were eligible; 31 were females; mean age at diagnosis was 4.0 years (0,5 -17), with median 3,5 years. There were 5, 10, 26, 10 and 5 stages I, II,I II, IV and V, respectively. Forty-three patients presented palpable abdominal mass as initial symptom; 59% of the patients had tumor size larger than 10 cm. Hematuria was presented in five patients, abdominal pain in four patients, fever in 2 patients, arterial hypertension in 1 patient and increased testicular volume in 1 patient. Forty-one biopsies were carried out for histophatological diagnosis. Fifty two patients were submitted to surgical tumor resection and 4 of them were considered inoperable. The mean time between the first chemotherapy cycle and surgery was 15 weeks. Total nephrectomy was carried out in 43 patients, partial nephrectomy in 5 and total nephrectomy + partial contralateral nephrectomy in 4. Microscopic residual disease was found in 5 patients. Linfonode biopsies were performed in 41 patients, with 9 of them being positive; in 11 cases there was no report whether the procedure was carried out or not. The surgeon in 38 patients performed palpation of the contralateral kidney and in 13 medical records there was no report whether this procedure was carried out. Tumor spillage was reported 1 patient, reported as absent in 10 patients; we were unable to find any mention about tumor rupture on the surgeon’s report for 41 patients. There were 45 cases of favorable histology and 7 of unfavorable histology. Five years OS was of 69%, 71%, 79%, 50% and 40% for the stages I, II, III, IV and V, respectively (P = 0,21). Five years OS was 64% and 70% for patients older and younger than 4 years, respectively (P = 0,6). Five years OS was 73% and 65,2% for patients submitted to surgery before and after the 6th week after diagnosis, respectively (p =0,31). Conclusion: The results of the present study indicate that patients in this study show demographic characters similar to the literature. Considering that surgeons did not performed standard recommended surgical procedure such as lymph nodes biopsy and carried out late surgical resection of the primary tumor in many patients, there is a need for a more effective participation of the surgeon in the multidisciplinary team and possibly in the designing protocols for the surgical management of patients with TW.

Introdução: O tumor de Wilms (TW) é o tumor renal maligno mais comum na infância. O conhecimento de certas características clínicas e a realização de procedimentos cirúrgicos adequados podem ter impacto no prognóstico desta doença. Objetivo: Avaliar as características clínicas e cirúrgicas com importância prognóstica nos pacientes atendidos no Serviço de Oncologia Pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Pacientes e Métodos: Estudo de coorte histórica dos pacientes com Tumor de Wilms (TW) tratados no HCPA entre 1989 e 2005. Foram revisados prontuários de pacientes com diagnóstico de TW com coleta de informações de características demográficas e do tratamento clínico e cirúrgico. A sobrevida global (SG) em 5 anos foi analisada pelo método de Kaplan-Meier. Resultados: Foram incluídos no estudo 56 pacientes consecutivos, sendo 31 do sexo feminino. A média de idade dos pacientes foi de 4 anos (0,5 -17 anos), com mediana de 3,5 anos. Quanto ao estadiamento, 5,10,26,10 e 5 eram estádios I, II III, IV e V, respectivamente. Quarenta e três pacientes apresentaram como principal sintoma inicial massa abdominal palpável; 59% dos pacientes tinham tamanho tumoral ao diagnóstico >10 cm. Hematúria foi observada em 5 pacientes, dor abdominal em quatro pacientes, febre em 2 pacientes; hipertensão arterial em 1 paciente e aumento do volume testicular em 1 paciente. Foram realizadas 41 biópsias para diagnóstico histológico. Cinqüenta e dois pacientes foram submetidos à cirurgia de ressecção tumoral e 4 foram considerados irressecáveis. A média de tempo entre o início do primeiro ciclo de quimioterapia e a cirurgia foi de 15 semanas. Foram realizados 43 nefrectomias totais, 5 nefrectomias parciais e 4 nefrectomia total + parcial contralateral. Em 5 pacientes havia doença microscópica nas margens cirúrgicas.Linfonodos livres de doença foram encontrados em 32 pacientes, comprometidos em 9; não havia relato de realização de biópsia em 11. Durante o ato operatório, 38 pacientes foram submetidos à avaliação do rim contra-lateral através da palpação e em 13 relatos de cirurgia não foram encontradas descrições sobre a realização deste procedimento.Houve relato de ruptura tumoral em 1 paciente; em dez prontuários havia registro de ausência de ruptura tumoral e em 41 prontuários não havia qualquer menção quanto à presença ou ausência desta complicação. A histopatologia confirmou 45 casos de histologia favorável e os demais de histologia desfavorável. A SG foi de 69%, 71%, 79%, 50% e 40% para os estádios I, II, III, IV e V, respectivamente (P=0,21). A SG foi de 64% e 70% para pacientes com idade superior e inferior a 4 anos, respectivamente (P=0,6). A SG para pacientes que realizaram cirurgia após a 6ª semana foi de 65,2% enquanto os que realizaram antes da 6 semana foi de 73% (P=0,7). Conclusão: Os resultados apresentados permitem concluir que os pacientes estudados apresentam características demográficas gerais semelhantes aos da literatura.Considerando-se que em um número expressivo de pacientes observou-se falta de aderência a certas etapas do procedimento cirúrgico, incluindo ausência de biópsia de linfonodos e atrasos na realização da ressecção tumoral, os autores recomendam que o cirurgião pediátrico tenha uma participação mais efetiva na equipe multidisciplinar e na elaboração das rotinas do protocolo cirúrgico para pacientes com TW. / Introduction: Wilms´tumor (WT) is the most common malignant renal tumor in childhood. The knowledge of the clinical characteristics and the accomplishment of standard surgical procedures may have an impact in the prognosis of this disease. Objectives: To assess the clinical and surgical features with prognostic significance in WT patients treated at the Pediatric Oncology Unit of Hospital de Clínicas de Porto Alegre (HCPA). Patients and Methods: Medical records of newly diagnosed WT patients treated from 1989 to 2005 were reviewed. We collected data on demographics, clinical characteristics and whether certain recommended surgical standard procedures were carried out. The five year survival (OS) was analyzed by the method of Kaplan-Meier. Results: Fifty-six consecutive patients were eligible; 31 were females; mean age at diagnosis was 4.0 years (0,5 -17), with median 3,5 years. There were 5, 10, 26, 10 and 5 stages I, II,I II, IV and V, respectively. Forty-three patients presented palpable abdominal mass as initial symptom; 59% of the patients had tumor size larger than 10 cm. Hematuria was presented in five patients, abdominal pain in four patients, fever in 2 patients, arterial hypertension in 1 patient and increased testicular volume in 1 patient. Forty-one biopsies were carried out for histophatological diagnosis. Fifty two patients were submitted to surgical tumor resection and 4 of them were considered inoperable. The mean time between the first chemotherapy cycle and surgery was 15 weeks. Total nephrectomy was carried out in 43 patients, partial nephrectomy in 5 and total nephrectomy + partial contralateral nephrectomy in 4. Microscopic residual disease was found in 5 patients. Linfonode biopsies were performed in 41 patients, with 9 of them being positive; in 11 cases there was no report whether the procedure was carried out or not. The surgeon in 38 patients performed palpation of the contralateral kidney and in 13 medical records there was no report whether this procedure was carried out. Tumor spillage was reported 1 patient, reported as absent in 10 patients; we were unable to find any mention about tumor rupture on the surgeon’s report for 41 patients. There were 45 cases of favorable histology and 7 of unfavorable histology. Five years OS was of 69%, 71%, 79%, 50% and 40% for the stages I, II, III, IV and V, respectively (P = 0,21). Five years OS was 64% and 70% for patients older and younger than 4 years, respectively (P = 0,6). Five years OS was 73% and 65,2% for patients submitted to surgery before and after the 6th week after diagnosis, respectively (p =0,31). Conclusion: The results of the present study indicate that patients in this study show demographic characters similar to the literature. Considering that surgeons did not performed standard recommended surgical procedure such as lymph nodes biopsy and carried out late surgical resection of the primary tumor in many patients, there is a need for a more effective participation of the surgeon in the multidisciplinary team and possibly in the designing protocols for the surgical management of patients with TW.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Cardiovascular and heart diseases are the leading causes of death worldwide. In mammals, when heart damage occurs this organ is unable to regenerate itself. Understanding how to induce a regenerative process has been the focus of a great deal of attention recently. The understanding of heart development and the initial formation of several heart lineages could be used in finding a regenerative approach to heart damage that can mimic developmental processes. The Wilms’ tumour 1 gene (Wt1) is essential in the epicardium, the outer layer of cells around the heart, which during development has a multipotent potential and is the source of progenitors for several heart cell lineages such as: cells of the coronary vasculature, fibroblasts and cardiomyocytes. In my thesis I have focused on using an in-vitro (immortalized epicardial cells where Wt1 can be deleted by adding tamoxifen), and an in-vivo approach (genome wide expression analyses of Wt1 control and Wt1 knock-out epicardial enriched cells), to identify novel targets of Wt1 in the epicardium during development. I found that the chemokines Cxcl10 and Ccl5 are up-regulated in tamoxifen induced immortalized Wt1 knock-out epicardial cells and ex-vivo in heart explants when Wt1 is down-regulated. Ccl5 was found to be able to inhibit cardiomyocyte proliferation and Cxcl10 also inhibited epicardial cell migration, which could further explain ventricular thinning in Wt1 mutant mouse hearts. Wt1 is able to bind directly to the promoter of a chemokine and interferon response regulator gene, Irf7, which is also up-regulated in our in-vivo model. This could provide a mechanism by which Wt1 can inhibit chemokine expression during development, and could link Wt1 with immunological responses, which recently have been shown to play a role in the physiology and development of cells outside immunity, as well as being involved in physiological roles during damage and repair in adult tissues. I have also identified two Wt1-GFP populations (Wt1GFP++ and Wt1GFP+) in the ventricles of Wt1-GFP knock-in mice. The Wt1GFP++ population is enriched for epicardial cells, and a genome wide transcriptome analysis of these cells from E11.5 to E16.5 demonstrates they have a very dynamic regulation of a wide variety of genes, and also it indicates the existence of an early, transient and late Wt1GFP++ gene expression programs. The transcriptome analysis of Wt1GFP++ control and Wt1GFP++ Wt1 knock-out cells, from Gata5-Cre Wt1loxP/gfp mice at E13.5, reveals that Wt1 could regulate a number of previously un-described Wt1 targets related to the early Wt1GFP++ program, and gene ontology analyses indicate that many targets are related to cell to cell signalling and interaction, cell to extracellular matrix interaction, tissue development and morphogenesis. The Wt1GFP+ cell population is positive for a number of cardiomyocyte specific markers and has a low or negative expression of endothelial, epithelial and mesenchymal markers according to my transcriptome analysis. The findings I have described here shed light on the variety of targets of Wt1 and further reveal the function of Wt1 during epicardial development, which could be used in finding a regenerative approach to heart disease.