In Australia, up to 80% of individuals diagnosed with childhood cancer are now expected to survive for more than five years after their initial diagnosis. However, survivors of childhood cancer are at risk of developing late sequelae as a consequence of therapies received during childhood. The aim of this study was to determine the incidence of selected late sequelae in a cohort of Australian childhood cancer survivors and identify treatment and genetic factors that may modify the risk of late sequelae in survivors. Our study included 1150 individuals treated for childhood cancer at the Sydney Children??s Hospital between 1962 and 1999, who had remained in remission >3 years and were confirmed to be alive. Rates of mortality and second cancers among survivors were compared against population rates to determine standardised mortality and incidence ratios. Survivors completed a questionnaire on the incidence of adverse health conditions and provided a buccal specimen. Real time PCR was used to detect polymorphisms in genes involved in drug detoxification and transport. Rates of mortality and secondary cancers were found to be 7.5-fold (95%CI 5.4-10.1) and 4.9-fold (95%CI 2.9-8.0) higher among survivors of childhood cancer relative to the general population, respectively, with the highest risks observed for those survivors previously treated for Hodgkin??s disease. Over 60% of survivors reported at least one cardiopulmonary, endocrine or sensory-motor condition following diagnosis of childhood cancer; the most frequently observed conditions included growth hormone deficiency, hypothyroidism, and hypertension. Late sequelae were most frequently reported by females and survivors of brain tumours. Genetic investigations showed that an increased risk of growth hormone deficiency was associated with homozygosity for the GSTM1 null polymorphism, while no gene associations were observed to influence the risk of second cancers among survivors. Our study demonstrates that survivors of childhood cancer are at risk of developing a variety of health conditions as a result of anti-cancer therapies received during childhood. Determining risk factors for late sequelae based on therapy type, lifestyle and genetic predisposition will enable the optimisation of treatment protocols and promote the future well-being of childhood cancer survivors.

Introdução linfoma de Hodgkin (LH) é uma neoplasia que atinge tipicamente crianças e adultos jovens, com uma taxa de cura superior a 80%. Consequentemente, estes pacientes podem viver por décadas com efeitos tardios (ET) persistentes e emergentes da doença e do seu tratamento. Estes sobreviventes possuem risco aumentado para vários tipos de doenças, dentre elas, segunda neoplasia, doença cardíaca, pulmonar, disfunção endócrina e infertilidade. Objetivos Analisar epidemiologicamente os pacientes com diagnóstico de LH tratados com esquemas terapêuticos de primeira linha no Serviço de Oncologia Pediatria do Hospital de Clinicas de Porto Alegre (HCPA), visando os ET do tratamento empregado. Métodos e análise estatística estudo de coorte retrospectivo, realizado através da revisão dos prontuários médicos dos pacientes pediátricos com diagnóstico de LH tratados com esquemas de primeira linha no Serviço de Oncologia Pediátrica do HCPA, no período de 1995 a 2012. Características dos pacientes, resposta ao tratamento e efeitos tardios foram avaliados através de análise descritiva. As variáveis contínuas foram descritas por média e desvio padrão ou mediana e amplitude interquartílica. As variáveis categóricas foram descritas por frequências absolutas e relativas. O método de Kaplan-Meier foi utilizado para estimar a sobrevida global e a sobrevida livre de eventos. A comparação entre as curvas de sobrevida foi realizada pelo teste de log-rank. Para avaliar a associação entre as variáveis categóricas, os testes qui-quadrado de Pearson ou exato de Fisher foram aplicados. Para comparar as médias das doses dos esquemas quimioterápicos conforme efeitos tardios, o teste t-student foi aplicado. Resultados total de 51 pacientes, o tempo de seguimento foi de 6,9 anos (mediana), a idade ao diagnóstico variou entre 3 a 17 anos (media 9,53 anos DP=3,85); 41(80,3%) eram do sexo masculino. O tipo histológico predominante foi esclerose nodular (56,5%). A sobrevida global foi de 91,8% em 5 anos e 82,7% em 10 anos e a Sobrevida livre de eventos (SLE) em 5 e 10 anos foram 76,4% e 76,4%, respectivamente. Dezoito (35,3%) apresentaram ao menos um ET, sendo 1 (2%) alteração musculoesquelético, 1 (2%) segunda neoplasia, 6 (11,8%) infertilidade, 8 (15,7%) alteração pulmonar, 9 (17,6%) alteração da tireóide. Trinta (58,8%) dos pacientes receberam radioterapia e 13 (43,3%) apresentaram ET, sendo 9 (17,6%) alteração da tireoide, 8 (15,7%) alteração pulmonar, 6 (11,8%) infertilidade 1 (2%) alteração musculo-esquelética, 1 (2%) segunda neoplasia e nenhuma alteração cardíaca. Dezoito (36,7%) pacientes receberam radioterapia cervical e 12 (66,7%) desses apresentaram ET contra 6/31 (19,4%) dos que não fizeram (P= 0,003); 23 (46%) receberam radioterapia do mediastino e 13 (56,5%) desses pacientes desenvolveram ET e apenas 5/27 (18,5%) dos que não receberam desenvolveram ET (P=0,013). Dentre os esquemas terapêuticos mais utilizados nesta coorte, 26 (53,1%) receberam ciclofosfamida, vincristina, procarbazina, prednisona, doxorrubicina, bleomicina e vimblastina (COPP/ABV) e 10 (38,5 %) dos que receberam este esquema apresentaram ET em comparação com 6/23 (26,1%) dos que não utilizaram (P=0,537); 14 (28,6%) dos pacientes receberam bleomicina, etoposide, doxorrubicina, ciclofosfamida, vincristina, procarbazina e prednisona (BEACOPP) e 3/14 (21,4%) desses apresentaram ET ao passo que 13/35 (37,1%) dos que não utilizaram esse esquema apresentaram ET (P=0,336); 7 (14,3%) receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVD) e apenas 1 (14,3%) apresentou ET em comparação com 15/42 (35,7%) que não receberam (P=0,402); 4 (8,2%) dos pacientes receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVPC) e 1 (25%) contra 15/45 (33,3%) dos que não receberam este esquema apresentaram ET (P=1). Conclusão devido ao risco de ET e aos bons índices de sobrevida, a atenção especial para criação de regimes de tratamento com cada vez menor toxicidade tardia, assistência médica para pacientes pós-tratamento e preparação dos médicos e sistemas de saúde são de suma importância para assegurar a qualidade de vida desses sobreviventes. / Introduction Hodgkin linfoma (HL) is a malignancy which typically affects children and adolescents, with a cure rate higher than 80%. Consequently, these patients may live for decades with treatment-related late effects (LE), which are persistent and emergent. These survivors possess increased risk for various diseases, including second malignancies, cardiac and pulmonary disease, endocrine dysfunction and infertility. Objectives Perform an epidemiological analysis of patients diagnosed with, and treated for, HL with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the Federal University Hospital of Porto Alegre (HCPA), focusing on each treatment’s late effects. Methods and statistical analysis This is a retrospective cohort study, performed by revising medical charts of patients diagnosed with HL and treated with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the HCPA, from 1995 to 2012. Patient characteristics, response to therapy and late effects are reported via descriptive analysis. Continuous variables are reported via mean and standard deviation or median and interquartile ranges. Categorical variables are described by absolute and relative frequencies. The Kaplan-Meier method was used to estimate overall and event-free survival. The comparison between survival curves were performed with the log-rank test. To explore the association between categorical variables, the Pearson Chi-square test or Fisher’s exact test were employed. The relationship between late effects and mean chemotherapeutic dose was evaluated with the student’s T test. Results a total of 51 patients, of which 41 (80.3%) were males. Median follow-up time was of 6.9 years. Age at diagnosis varied between 3 and 17 years (mean 9.53; SD 3.85). The most common histological subtype was nodular sclerosis (56,5%). Overall survival (OS) was of 91.8% in 5 years and 82.7% in 10 years, and event-free survival (EFS) was 76.4% and 76.4% for 5 and 10 years, respectively. Eighteen (35.3%) patients presented at least one LE, being 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, 6 (11.8%) infertility, 8 (15.7%) pulmonary alterations, 9 (17.6%) thyroid alterations and none presented cardiac alterations. Thirty (58.8%) patients received radiotherapy and of these 13 (43.3%) presented LE, being 9 (17.6%) thyroid alterations, 8 (15.7%) pulmonary alterations, 6 (11.8%) infertility, 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, and none presented cardiac alterations. Eighteen (36.7%) patients received cervical radiotherapy, and of these 12 (66.7%) presented LE, against 6 (19.4%) of 31 patients who were not submitted to cervical radiotherapy and developed a LE (P=0.003). Twenty-three (46%) patients received mediastinal radiotherapy, and of these 13 (56.5%) presented LE, against 5 (18.5%) of 27 patients who did not receive this treatment and developed a LE (P=0,013). With regards to treatment, 26 (53.1%) patients received COPPABV and 10 (38.5%) of these presented LE, against 6 (26.1%) of 23 patients who did not receive COPPABV and presented LE (P=0.537). Fourteen (28.6%) patients received BEACOPP, and of these 3 (21.4%) presented LE, against 13 (37.1%) of the 35 patients who did not receive BEACOPP and presented LE (P=0.336). Seven (14.3%) patients received ABVD and only one (14.3%) presented LE in comparison to 15 (35.7%) of 42 patients who did not receive ABVD and presented LE (P=0.402); four (8.2%) patients received ABVPC and 1 (25%) presented LE, against 15 (33.3%) of 45 patients who did not receive ABVPC and presented LE (P=1). Conclusion Because of the high overall survival rates in children and adolescents diagnosed with, and treated for LH, special attention should be given to treatment regimens with reduced late effects burden. In order to guarantee the quality of life of LH survivors, adequate medical attention to patients should be provided post-treatment. Physicians and other health care professionals would also benefit from training sessions which focus on these issues.

Introdução linfoma de Hodgkin (LH) é uma neoplasia que atinge tipicamente crianças e adultos jovens, com uma taxa de cura superior a 80%. Consequentemente, estes pacientes podem viver por décadas com efeitos tardios (ET) persistentes e emergentes da doença e do seu tratamento. Estes sobreviventes possuem risco aumentado para vários tipos de doenças, dentre elas, segunda neoplasia, doença cardíaca, pulmonar, disfunção endócrina e infertilidade. Objetivos Analisar epidemiologicamente os pacientes com diagnóstico de LH tratados com esquemas terapêuticos de primeira linha no Serviço de Oncologia Pediatria do Hospital de Clinicas de Porto Alegre (HCPA), visando os ET do tratamento empregado. Métodos e análise estatística estudo de coorte retrospectivo, realizado através da revisão dos prontuários médicos dos pacientes pediátricos com diagnóstico de LH tratados com esquemas de primeira linha no Serviço de Oncologia Pediátrica do HCPA, no período de 1995 a 2012. Características dos pacientes, resposta ao tratamento e efeitos tardios foram avaliados através de análise descritiva. As variáveis contínuas foram descritas por média e desvio padrão ou mediana e amplitude interquartílica. As variáveis categóricas foram descritas por frequências absolutas e relativas. O método de Kaplan-Meier foi utilizado para estimar a sobrevida global e a sobrevida livre de eventos. A comparação entre as curvas de sobrevida foi realizada pelo teste de log-rank. Para avaliar a associação entre as variáveis categóricas, os testes qui-quadrado de Pearson ou exato de Fisher foram aplicados. Para comparar as médias das doses dos esquemas quimioterápicos conforme efeitos tardios, o teste t-student foi aplicado. Resultados total de 51 pacientes, o tempo de seguimento foi de 6,9 anos (mediana), a idade ao diagnóstico variou entre 3 a 17 anos (media 9,53 anos DP=3,85); 41(80,3%) eram do sexo masculino. O tipo histológico predominante foi esclerose nodular (56,5%). A sobrevida global foi de 91,8% em 5 anos e 82,7% em 10 anos e a Sobrevida livre de eventos (SLE) em 5 e 10 anos foram 76,4% e 76,4%, respectivamente. Dezoito (35,3%) apresentaram ao menos um ET, sendo 1 (2%) alteração musculoesquelético, 1 (2%) segunda neoplasia, 6 (11,8%) infertilidade, 8 (15,7%) alteração pulmonar, 9 (17,6%) alteração da tireóide. Trinta (58,8%) dos pacientes receberam radioterapia e 13 (43,3%) apresentaram ET, sendo 9 (17,6%) alteração da tireoide, 8 (15,7%) alteração pulmonar, 6 (11,8%) infertilidade 1 (2%) alteração musculo-esquelética, 1 (2%) segunda neoplasia e nenhuma alteração cardíaca. Dezoito (36,7%) pacientes receberam radioterapia cervical e 12 (66,7%) desses apresentaram ET contra 6/31 (19,4%) dos que não fizeram (P= 0,003); 23 (46%) receberam radioterapia do mediastino e 13 (56,5%) desses pacientes desenvolveram ET e apenas 5/27 (18,5%) dos que não receberam desenvolveram ET (P=0,013). Dentre os esquemas terapêuticos mais utilizados nesta coorte, 26 (53,1%) receberam ciclofosfamida, vincristina, procarbazina, prednisona, doxorrubicina, bleomicina e vimblastina (COPP/ABV) e 10 (38,5 %) dos que receberam este esquema apresentaram ET em comparação com 6/23 (26,1%) dos que não utilizaram (P=0,537); 14 (28,6%) dos pacientes receberam bleomicina, etoposide, doxorrubicina, ciclofosfamida, vincristina, procarbazina e prednisona (BEACOPP) e 3/14 (21,4%) desses apresentaram ET ao passo que 13/35 (37,1%) dos que não utilizaram esse esquema apresentaram ET (P=0,336); 7 (14,3%) receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVD) e apenas 1 (14,3%) apresentou ET em comparação com 15/42 (35,7%) que não receberam (P=0,402); 4 (8,2%) dos pacientes receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVPC) e 1 (25%) contra 15/45 (33,3%) dos que não receberam este esquema apresentaram ET (P=1). Conclusão devido ao risco de ET e aos bons índices de sobrevida, a atenção especial para criação de regimes de tratamento com cada vez menor toxicidade tardia, assistência médica para pacientes pós-tratamento e preparação dos médicos e sistemas de saúde são de suma importância para assegurar a qualidade de vida desses sobreviventes. / Introduction Hodgkin linfoma (HL) is a malignancy which typically affects children and adolescents, with a cure rate higher than 80%. Consequently, these patients may live for decades with treatment-related late effects (LE), which are persistent and emergent. These survivors possess increased risk for various diseases, including second malignancies, cardiac and pulmonary disease, endocrine dysfunction and infertility. Objectives Perform an epidemiological analysis of patients diagnosed with, and treated for, HL with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the Federal University Hospital of Porto Alegre (HCPA), focusing on each treatment’s late effects. Methods and statistical analysis This is a retrospective cohort study, performed by revising medical charts of patients diagnosed with HL and treated with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the HCPA, from 1995 to 2012. Patient characteristics, response to therapy and late effects are reported via descriptive analysis. Continuous variables are reported via mean and standard deviation or median and interquartile ranges. Categorical variables are described by absolute and relative frequencies. The Kaplan-Meier method was used to estimate overall and event-free survival. The comparison between survival curves were performed with the log-rank test. To explore the association between categorical variables, the Pearson Chi-square test or Fisher’s exact test were employed. The relationship between late effects and mean chemotherapeutic dose was evaluated with the student’s T test. Results a total of 51 patients, of which 41 (80.3%) were males. Median follow-up time was of 6.9 years. Age at diagnosis varied between 3 and 17 years (mean 9.53; SD 3.85). The most common histological subtype was nodular sclerosis (56,5%). Overall survival (OS) was of 91.8% in 5 years and 82.7% in 10 years, and event-free survival (EFS) was 76.4% and 76.4% for 5 and 10 years, respectively. Eighteen (35.3%) patients presented at least one LE, being 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, 6 (11.8%) infertility, 8 (15.7%) pulmonary alterations, 9 (17.6%) thyroid alterations and none presented cardiac alterations. Thirty (58.8%) patients received radiotherapy and of these 13 (43.3%) presented LE, being 9 (17.6%) thyroid alterations, 8 (15.7%) pulmonary alterations, 6 (11.8%) infertility, 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, and none presented cardiac alterations. Eighteen (36.7%) patients received cervical radiotherapy, and of these 12 (66.7%) presented LE, against 6 (19.4%) of 31 patients who were not submitted to cervical radiotherapy and developed a LE (P=0.003). Twenty-three (46%) patients received mediastinal radiotherapy, and of these 13 (56.5%) presented LE, against 5 (18.5%) of 27 patients who did not receive this treatment and developed a LE (P=0,013). With regards to treatment, 26 (53.1%) patients received COPPABV and 10 (38.5%) of these presented LE, against 6 (26.1%) of 23 patients who did not receive COPPABV and presented LE (P=0.537). Fourteen (28.6%) patients received BEACOPP, and of these 3 (21.4%) presented LE, against 13 (37.1%) of the 35 patients who did not receive BEACOPP and presented LE (P=0.336). Seven (14.3%) patients received ABVD and only one (14.3%) presented LE in comparison to 15 (35.7%) of 42 patients who did not receive ABVD and presented LE (P=0.402); four (8.2%) patients received ABVPC and 1 (25%) presented LE, against 15 (33.3%) of 45 patients who did not receive ABVPC and presented LE (P=1). Conclusion Because of the high overall survival rates in children and adolescents diagnosed with, and treated for LH, special attention should be given to treatment regimens with reduced late effects burden. In order to guarantee the quality of life of LH survivors, adequate medical attention to patients should be provided post-treatment. Physicians and other health care professionals would also benefit from training sessions which focus on these issues.

Introdução linfoma de Hodgkin (LH) é uma neoplasia que atinge tipicamente crianças e adultos jovens, com uma taxa de cura superior a 80%. Consequentemente, estes pacientes podem viver por décadas com efeitos tardios (ET) persistentes e emergentes da doença e do seu tratamento. Estes sobreviventes possuem risco aumentado para vários tipos de doenças, dentre elas, segunda neoplasia, doença cardíaca, pulmonar, disfunção endócrina e infertilidade. Objetivos Analisar epidemiologicamente os pacientes com diagnóstico de LH tratados com esquemas terapêuticos de primeira linha no Serviço de Oncologia Pediatria do Hospital de Clinicas de Porto Alegre (HCPA), visando os ET do tratamento empregado. Métodos e análise estatística estudo de coorte retrospectivo, realizado através da revisão dos prontuários médicos dos pacientes pediátricos com diagnóstico de LH tratados com esquemas de primeira linha no Serviço de Oncologia Pediátrica do HCPA, no período de 1995 a 2012. Características dos pacientes, resposta ao tratamento e efeitos tardios foram avaliados através de análise descritiva. As variáveis contínuas foram descritas por média e desvio padrão ou mediana e amplitude interquartílica. As variáveis categóricas foram descritas por frequências absolutas e relativas. O método de Kaplan-Meier foi utilizado para estimar a sobrevida global e a sobrevida livre de eventos. A comparação entre as curvas de sobrevida foi realizada pelo teste de log-rank. Para avaliar a associação entre as variáveis categóricas, os testes qui-quadrado de Pearson ou exato de Fisher foram aplicados. Para comparar as médias das doses dos esquemas quimioterápicos conforme efeitos tardios, o teste t-student foi aplicado. Resultados total de 51 pacientes, o tempo de seguimento foi de 6,9 anos (mediana), a idade ao diagnóstico variou entre 3 a 17 anos (media 9,53 anos DP=3,85); 41(80,3%) eram do sexo masculino. O tipo histológico predominante foi esclerose nodular (56,5%). A sobrevida global foi de 91,8% em 5 anos e 82,7% em 10 anos e a Sobrevida livre de eventos (SLE) em 5 e 10 anos foram 76,4% e 76,4%, respectivamente. Dezoito (35,3%) apresentaram ao menos um ET, sendo 1 (2%) alteração musculoesquelético, 1 (2%) segunda neoplasia, 6 (11,8%) infertilidade, 8 (15,7%) alteração pulmonar, 9 (17,6%) alteração da tireóide. Trinta (58,8%) dos pacientes receberam radioterapia e 13 (43,3%) apresentaram ET, sendo 9 (17,6%) alteração da tireoide, 8 (15,7%) alteração pulmonar, 6 (11,8%) infertilidade 1 (2%) alteração musculo-esquelética, 1 (2%) segunda neoplasia e nenhuma alteração cardíaca. Dezoito (36,7%) pacientes receberam radioterapia cervical e 12 (66,7%) desses apresentaram ET contra 6/31 (19,4%) dos que não fizeram (P= 0,003); 23 (46%) receberam radioterapia do mediastino e 13 (56,5%) desses pacientes desenvolveram ET e apenas 5/27 (18,5%) dos que não receberam desenvolveram ET (P=0,013). Dentre os esquemas terapêuticos mais utilizados nesta coorte, 26 (53,1%) receberam ciclofosfamida, vincristina, procarbazina, prednisona, doxorrubicina, bleomicina e vimblastina (COPP/ABV) e 10 (38,5 %) dos que receberam este esquema apresentaram ET em comparação com 6/23 (26,1%) dos que não utilizaram (P=0,537); 14 (28,6%) dos pacientes receberam bleomicina, etoposide, doxorrubicina, ciclofosfamida, vincristina, procarbazina e prednisona (BEACOPP) e 3/14 (21,4%) desses apresentaram ET ao passo que 13/35 (37,1%) dos que não utilizaram esse esquema apresentaram ET (P=0,336); 7 (14,3%) receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVD) e apenas 1 (14,3%) apresentou ET em comparação com 15/42 (35,7%) que não receberam (P=0,402); 4 (8,2%) dos pacientes receberam bleomicina, vimblastina, doxorrubicina, dacarbazina (ABVPC) e 1 (25%) contra 15/45 (33,3%) dos que não receberam este esquema apresentaram ET (P=1). Conclusão devido ao risco de ET e aos bons índices de sobrevida, a atenção especial para criação de regimes de tratamento com cada vez menor toxicidade tardia, assistência médica para pacientes pós-tratamento e preparação dos médicos e sistemas de saúde são de suma importância para assegurar a qualidade de vida desses sobreviventes. / Introduction Hodgkin linfoma (HL) is a malignancy which typically affects children and adolescents, with a cure rate higher than 80%. Consequently, these patients may live for decades with treatment-related late effects (LE), which are persistent and emergent. These survivors possess increased risk for various diseases, including second malignancies, cardiac and pulmonary disease, endocrine dysfunction and infertility. Objectives Perform an epidemiological analysis of patients diagnosed with, and treated for, HL with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the Federal University Hospital of Porto Alegre (HCPA), focusing on each treatment’s late effects. Methods and statistical analysis This is a retrospective cohort study, performed by revising medical charts of patients diagnosed with HL and treated with first line chemotherapeutic regimens at the Pediatric Oncology Unit of the HCPA, from 1995 to 2012. Patient characteristics, response to therapy and late effects are reported via descriptive analysis. Continuous variables are reported via mean and standard deviation or median and interquartile ranges. Categorical variables are described by absolute and relative frequencies. The Kaplan-Meier method was used to estimate overall and event-free survival. The comparison between survival curves were performed with the log-rank test. To explore the association between categorical variables, the Pearson Chi-square test or Fisher’s exact test were employed. The relationship between late effects and mean chemotherapeutic dose was evaluated with the student’s T test. Results a total of 51 patients, of which 41 (80.3%) were males. Median follow-up time was of 6.9 years. Age at diagnosis varied between 3 and 17 years (mean 9.53; SD 3.85). The most common histological subtype was nodular sclerosis (56,5%). Overall survival (OS) was of 91.8% in 5 years and 82.7% in 10 years, and event-free survival (EFS) was 76.4% and 76.4% for 5 and 10 years, respectively. Eighteen (35.3%) patients presented at least one LE, being 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, 6 (11.8%) infertility, 8 (15.7%) pulmonary alterations, 9 (17.6%) thyroid alterations and none presented cardiac alterations. Thirty (58.8%) patients received radiotherapy and of these 13 (43.3%) presented LE, being 9 (17.6%) thyroid alterations, 8 (15.7%) pulmonary alterations, 6 (11.8%) infertility, 1 (2%) musculoskeletal alterations, 1 (2%) second malignancy, and none presented cardiac alterations. Eighteen (36.7%) patients received cervical radiotherapy, and of these 12 (66.7%) presented LE, against 6 (19.4%) of 31 patients who were not submitted to cervical radiotherapy and developed a LE (P=0.003). Twenty-three (46%) patients received mediastinal radiotherapy, and of these 13 (56.5%) presented LE, against 5 (18.5%) of 27 patients who did not receive this treatment and developed a LE (P=0,013). With regards to treatment, 26 (53.1%) patients received COPPABV and 10 (38.5%) of these presented LE, against 6 (26.1%) of 23 patients who did not receive COPPABV and presented LE (P=0.537). Fourteen (28.6%) patients received BEACOPP, and of these 3 (21.4%) presented LE, against 13 (37.1%) of the 35 patients who did not receive BEACOPP and presented LE (P=0.336). Seven (14.3%) patients received ABVD and only one (14.3%) presented LE in comparison to 15 (35.7%) of 42 patients who did not receive ABVD and presented LE (P=0.402); four (8.2%) patients received ABVPC and 1 (25%) presented LE, against 15 (33.3%) of 45 patients who did not receive ABVPC and presented LE (P=1). Conclusion Because of the high overall survival rates in children and adolescents diagnosed with, and treated for LH, special attention should be given to treatment regimens with reduced late effects burden. In order to guarantee the quality of life of LH survivors, adequate medical attention to patients should be provided post-treatment. Physicians and other health care professionals would also benefit from training sessions which focus on these issues.

<b><u>Introduction:</b></u> Some cancer survivors are known to have an elevated risk of morbidity and mortality from cardiovascular disease. An important cause of this elevated risk is recognised to be irradiation of normal tissues during radiotherapy received as part of cancer therapy. There are substantial difficulties in studying radiation-related cardiovascular disease (RRCD). The reasons for this include the complexities of measuring radiation normal tissue doses retrospectively and the prolonged latencies of many of the cardiovascular endpoints. A variety of complimentary research methodologies can help provide additional knowledge to guide the appropriate management of patients treated in the past and of new patients in the future. <b><u>Methods:</b></u> 1) A cohort study of mortality from circulatory disease in the nationwide British Childhood Cancer Survivor Study (BCCSS). 2) A case-control study of valvular heart disease (VHD) in Dutch Hodgkin lymphoma (HL) survivors, including retrospective radiation dosimetry to estimate the radiation dose to heart valves. 3) A dosimetric study of cardiovascular radiation doses in patients entered into the UK NCRI Lymphoma Study Group RAPID trial, including predictions of 15-year cardiac mortality using innovative methods. 4) A modelling study to predict mean whole heart dose (MWHD) from involved field radiotherapy (IFRT) for HL using anatomical measures. 5) A prospective study using cardiovascular magnetic resonance (CMR) imaging to characterise the heart in women receiving radiotherapy for breast cancer. <b><u>Results:</b></u> 1) The risks of all types of circulatory mortality are elevated in survivors of childhood cancer. The absolute excess risks continue to increase 40+ years following diagnosis. The risk of death from cardiomyopathy and heart failure increased substantially with the introduction of anthracycline chemotherapy. There is no evidence of a reduction in risk of circulatory mortality in more recent eras of diagnosis. 2) There is a strong relationship between estimated radiation dose to the affected heart valve and the risk of subsequent VHD (p<0.001). This effect was modelled to allow prediction of the risk of VHD. 3) A proportion of patients treated with IFRT received a substantial cardiac radiation dose (MWHD = 8.8 Gy, SD = 5.6) but, on average, the predicted 15-year cardiac mortality following treatment is low (absolute risk 0.2%, range 0.0 to 2.7%). 4) It is possible to estimate the mean whole heart dose from IFRT prior to detailed radiotherapy planning based on pre-treatment diagnostic imaging to an accuracy of 5-6% of the prescribed dose. 5) Although women received low cardiac doses (MWHD = 1.5 Gy, SD = 0.8) and have a low predicted risk of cardiac radiation-related morbidity and mortality, there is some evidence of subclinical effects on strain and strain rate imaging of the anterior portions of the left ventricle that receive the highest radiation dose. <b><u>Conclusions:</b></u> Using a variety of methods these studies have all succeeded in adding to knowledge about the nature, magnitude and timing of RRCD. This knowledge can be used to help the future management of cancer patients. In addition, each of the studies has natural and planned extensions and will continue to contribute further knowledge into the future.

The most common form of childhood cancer is Acute Lymphoblastic Leukemia (ALL). Patients treated for ALL may experience short- and long-term physiological and cognitive effects due to treatment. However, delayed emotional and behavioral effects in pediatric survivors, as well as risk-factors that may make them more susceptible to developing problems with psychological and behavioral functioning are less understood. Studies investigating pediatric survivors have demonstrated that negative emotional and behavioral late effects can and do occur (Hobbie et al., 2000; Buizer et al. 2006; Novakovic et al., 1996; Mulhern, Wasserman, Friedman, & Fairclough, 1989), and it has been purported that survivors experience higher rates of depression, anxiety and low self-esteem (Koocher, O’Malley, Gogan, & Foster, 1980; Kazak, 1994). Anxiety in particular, has been identified as one of the longest lasting psychological sequelae of cancer (Kazak, 1994). Still, the data on long-term psychological sequelae is mixed, with some studies suggesting healthy, long-term, psychological adjustment (Brown et al., 1992; Fritz, Williams & Amylon, 1988; Greenberg, Kazak, & Meadows, 1989). This pilot study attempted to investigate emotional and behavioral late effects of cancer as reported by survivors and their caregivers on the Behavior Assessment System for Children, Second Edition (BASC-2). This study also investigated potential risk factors that made it more likely to develop emotional and behavioral late-effects. This study hypothesized that females, those undergoing high intensity chemotherapy, and those starting chemotherapy at an earlier age, would report significantly more internalizing and externalizing problems. Analysis revealed significant differences in reporting of anxiety, depression, attention and hyperactivity symptoms combined based on the age when treatment started. No other significant findings were uncovered; however, in an effort to provide directions for future research, patterns in the data were examined by comparing overall means on BASC-2 subscales. For example, females reported more hyperactive symptoms than males. In general, individuals who started treatment at younger ages reported more difficulty with emotional and behavioral functioning. Additionally, males and females adaptive behavior fell within normal limits. Overall, no BASC-2 mean scores were in the at-risk or clinically significant range of impairment suggesting adequate emotional, behavioral and adaptive functioning overall. / text

Background: Heart damage from cancer therapy is a significant problem for survivors. Some of the most effective treatments, such as anthracyclines, cause heart toxicity that can lead to significant morbidity and mortality. Cardiotoxicity also contributes to the loss of promising cancer drugs in early development and is notoriously difficult to predict. This translational project employs parallel pre-clinical and clinical studies to explore circulating biomarkers and cardiac magnetic resonance imaging (CMR) during development of anthracycline associated cardiotoxicity with the aim of finding biomarkers to aid clinical decision making and enable forward/back translation. Methods: Pre-clinical work: A rat model of chronic anthracycline-induced cardiomyopathy was developed involving 8 weekly intravenous boluses of doxorubicin followed by a 4 week ‘washout’ period. A time course assessment of cardiac function using multiple MRI parameters was performed alongside a panel of circulating biomarkers measured prior to dosing. Clinical work: In parallel following ethical approval, 30 cancer patients receiving standard anthracycline chemotherapy were recruited. Serial CMR scans were performed using standard and new exploratory techniques before, during and after treatment and blood was taken to evaluate a similar panel of cardiotoxicity biomarkers using multiplex ELISA at corresponding time points. Results: Pre-clinical results: Systolic and diastolic function declined progressively, culminating in left ventricular dysfunction (LVEF < 50%) by 12 weeks. Myocardial electron microscopy revealed myofibrillar and mitochondrial damage after one dose and gross histopathological damage after 5 doses. Myocardial contrast enhancement and troponin I increased significantly after eight doses and preceded LV dysfunction. Extensive fibrosis was seen 1 month after drug cessation. Clinical results: LVEF declined progressively in all patients and 7 patients (23%) had persistent LV dysfunction 12 months after therapy. Troponin I elevations were seen towards the end of therapy and peak troponin I corresponded with LVEF decline. None of the other circulating biomarkers correlated strongly with outcome. Lower baseline extracellular volume (ECV) was associated with greater LVEF decline but little change in ECV was seen over time. Baseline dyssynchrony was associated with worse outcome and deteriorated with time alongside LVEF decline. Conclusions: Results suggest that troponin I and cardiac MRI are sensitive translational tools in drug induced cardiotoxicity. However, troponin I is a relatively late marker, peaking after substantial myocardial damage, too late to halt or change reatment. The imaging suggests that fibrosis and inflammation cannot be detected within a year of chemotherapy but baseline ECV and strain analysis may have a role in risk stratification.

This diploma thesis is trying to figure out how is oncological disease and it´ s treatment affecting survivors life after curing the disease. Acute leukemia and its challenging and often aggressive treatment leaves many different late effects. Quality of life is a subjective assessment which to some extent depends on the nature of the individual. Even so, it is necessary to evaluate and examine the quality of life beacuse the results of researches can help other patients, but also nurses, doctors, psychologists and other helping professions. The theoretic part of the thesis describes the current state of the problem, introduces the basic and fundamental specifics of children's cancer, the treatment, the after-effects, deals with the description of the psychological problems of patients and their caregivers, which provides diagnosis itself, but also the treatment of the disease. It also introduces the psychological care about oncological ill patiens and the roles of the nurses in careing for the oncological patiens. Another part of the theoretical work is an introduction to the measurement and evaluation of quality of life. Work also introduces the leukemia disease, which is one of the most commonly diagnosed cancer diseases in children. The thesis has three goals. The first one is to determine how the treatment of the oncological disease affects life of survivors. The second one is to determine how children perceive various limitations of social contact that the treatment brings. The last third objective is to determine whether the cancer experience affects the attitude of the survivor children to live. In the practical part of the research was used quantitative research. The technique of data collection was standardized questionnaire Minneapolis Manchester Quality of Life Instrument which is divided into two versions for younger and older children. The research was also used for statistical evaluation of hypotheses. The questionnaire was distributed to children aged 8 - 18 years who were 2 - 5 years after treatment. The control group were the same aged healthy peers. Four hypotheses were determined. H1: Cured children have more difficulties in social functioning than healthy children. It was found that cured children have better outcomes in social functioning than their peers, hypothesis H1 is thus not confirmed. H2: Cured children have less energy for physical activities than healthy children. This hypothesis was confirmed neither in older or younger children. H3: Cured children are more satisfied with their appearance than healthy children. This hypothesis was based on the research and statistical verification verified. Last investigated hypothesis was H4: Cured children have more problems in cognitive functioning than healthy children. Based on the statistical verification hypothesis was not confirmed. The research and statistical studies show that cured children have the same or in some areas even better quality of life than their healthy peers 2 - 5 years after the end of active treatment. The nurse should be able to help and advise the patient and should emphatically and nicely cooperate with the family for which it is often even worse than for the patients themselves. This diploma thesis will be used for making of an internal seminars for nurses working at the Clinic of Pediatric Oncology. Nurses working at the bedsides of the patiens can use this theses as a feedback of thein work. Knowledge of late effects of anticancer therapy is essential to providing a high - quality care and application of evidence - based nursing in practice.