Impactos Psicossociais e na Qualidade de Vida do Tratamento Oncológico em Crianças e Adolescentes / Psychosocial and Quality-of-Life Impacts of Cancer Treatment in Children and Adolescents / Impactos Psicosociales y en la Calidad de Vida del Tratamiento del Cáncer en Niños y Adolescentes

Introdução: Tão importante quanto o diagnóstico e o tratamento do câncer pediátrico são os cuidados relacionados ao impacto psicossocial, educacional e emocional. Objetivo: Avaliar em crianças e adolescentes com diagnóstico de câncer os impactos psicossociais, de qualidade de vida e da presença de acompanhante durante os procedimentos. Método: Estudo transversal, descritivo, com pacientes de 8 a 18 anos e diagnóstico de neoplasia maligna. Os pacientes responderam aos questionários: PedsQL 4.0 Qualidade de Vida (8 a 12 anos), PedsQL 3.0 Módulo de Câncer (8 a 12 anos), PedsQL 4.0 Qualidade de Vida (13 a 18 anos), PedsQL 3.0 Módulo de Câncer (13 a 18 anos) e outro sobre acompanhantes elaborado pelos autores. Resultados: Foram incluídos 25 pacientes pediátricos oncológicos que se sentiam mais felizes na presença de um acompanhante e menos ansiosos durante os procedimentos. Foi percebido grande impacto na qualidade de vida. No questionário Qualidade de Vida, não houve diferença significativa (p=0,627) entre os grupos de pacientes com 8 a 12 anos e 13 a 18 anos, porém o grupo com 8 a 12 anos teve impacto significativamente maior no questionário Módulo de Câncer (p=0,0094). Conclusão: O impacto psicossocial e na qualidade de vida é razoavelmente grande em pacientes pediátricos oncológicos. Além disso, os mais jovens parecem sofrer um impacto psicossocial maior. Os pacientes se dizem mais felizes com a presença de acompanhante, e mais ansiosos na sua ausência.

Introduction: As important as the diagnosis and treatment of pediatric cancer are the care related to psychosocial, educational, and emotional impact. Objective: To evaluate in children and adolescents diagnosed with cancer the psychosocial and quality-of-life impacts and the presence of a companion during the procedures. Method: Cross-sectional descriptive study of patients aged 8 to 18 years of age diagnosed with malignant neoplasms. Patients responded the questionnaires PedsQL 4.0 Quality of Life (8 to 12 years), PedsQL 3.0 Cancer Module (8 to 12 years), PedsQL 4.0 Quality of Life (13 to 18 years), PedsQL 3.0 Cancer Module (13 to 18 years) and another about companions created by the authors. Results: There were 25 pediatric oncology patients included who felt happier in the presence of a companion, and less anxious during the procedures. A great impact on quality of life was perceived. In the Quality-of-Life questionnaire, no significant difference (p=0.627) between the groups of patients aged 8 to 12 years and 13 to 18 years were found, but the group aged 8 to 12 years had a significantly higher impact on the Cancer Module questionnaire (p= 0.0094). Conclusion: The impact on quality of life and psychosocial is fairly large in pediatric oncology patients. The youngest appear to suffer great psychosocial impact. Patients claim they are happier in the presence of a companion, and more anxious in its absence

Introducción: Tan importante como el diagnóstico y tratamiento del cáncer pediátrico, son los cuidados sobre el impacto psicosocial, educativo y emocional. Objetivo: Evaluar en niños y adolescentes diagnosticados de cáncer el impacto psicosocial y en la calidad de vida y la presencia de un acompañante durante los procedimientos. Método: Estudio transversal descriptivo de pacientes de 8 a 18 años con diagnóstico de neoplasia maligna. Los pacientes respondieron a los cuestionarios: PedsQL 4.0 Calidad de Vida (8 a 12 años), PedsQL 3.0 Módulo de Cáncer (8 a 12 años), PedsQL 4.0 Calidad de Vida (13 a 18 años), PedsQL 3.0 Módulo de Cáncer (13 a 18 años) y otro sobre cuidadores elaborado por los autores. Resultados: Se incluyeron 25 pacientes de oncología pediátrica que se sentían más felices con la presencia de un acompañante y menos ansiosos al realizar procedimientos. Se percibió un gran impacto en la calidad de vida. En el cuestionario de Calidad de Vida, no hubo diferencia significativa (p=0,627) entre los grupos de pacientes de 8 a 12 años y de 13 a 18 años, pero el grupo de 8 a 12 años tuvo un impacto significativamente mayor en el cuestionario del Módulo de Cáncer (p=0,0094). Conclusión: El impacto en la calidad de vida y psicosocial es razonablemente grande en los pacientes oncológicos pediátricos. Los de menor edad parecen sufrir un mayor impacto psicosocial. Los pacientes dicen sentirse más felices con la presencia de un acompañante, y más ansiosos en su ausencia.

Clinical impact of brachyury expression in Ewing sarcoma patients.

PURPOSE: The T-box transcription factor brachyury has been demonstrated as a prognostic factor in a variety of cancer types and considered a novel oncotarget in solid tumors. Brachyury acts as a regulator of the epithelial-mesenchymal transition (EMT) process, leading to more aggressive behavior and poorer prognosis. However, recent literature evidence suggests a tumor suppressor role in other neoplasms. In the present study, we aimed to study brachyury expression and its prognostic impact in Ewing sarcoma, an aggressive neoplasm of young individuals. METHODS: We analyzed the expression of brachyury by immunohistochemistry in a series of 96 Ewing sarcomas in a tissue microarray and investigated the association of the protein expression with the clinical parameters and overall survival. RESULTS: More than half of the cases (51%, n â€‹= â€‹49) depicted positive nuclear brachyury expression, while a lack of expression was observed in 49% (n â€‹= â€‹47) of cases. Nuclear brachyury staining was significantly associated with non-white ethnicity (p â€‹= â€‹0.04) and axial localization (p â€‹= â€‹0.025). Importantly, lack of brachyury expression was significantly associated with lower overall survival in multivariate analyses (hazard ratio - HR: 2.227, p â€‹= â€‹0.008). CONCLUSIONS: Our findings indicate, that brachyury is an independent prognostic biomarker in Ewing sarcoma, which might suggest a tumor suppressor role and which yet to be fully elucidated.

XAF1 as a modifier of p53 function and cancer susceptibility.

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants.

Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir-Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.

The Brazilian TP53 mutation (R337H) and sarcomas.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.

p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers.

Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186). Cancer-affected carriers had been diagnosed either with adrenocortical carcinoma (ACC, n = 29) or breast cancer (BC, n = 43). Allelic discrimation using TaqMan assay was used for genotyping MDM2 SNP 309 (rs2279744) as well as MDM4 (rs1563828) and USP7 (rs1529916) polymorphisms. We found significantly higher MDM2 SNP 309 GG genotype and G allele frequencies in the LFS cohort than in controls. Furthermore, median age at first diagnosis was earlier in MDM2 SNP309 GG carriers when compared to other genotypes for both cancers (ACC: age 1 vs. 2 years; BC: age 35 vs. 43 years, respectively), although not statistically different. The allelic and genotypic frequencies for all SNPs did not differ between cancer affected and unaffected carriers, neither between patients with ACC or BC. In conclusion, our results suggest that MDM2 SNP 309 may contribute to the LFL phenotype and also to an earlier age at diagnosis of ACC and BC cancer in carriers of the R337H founder mutation.

Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors.

AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival (OS). RESULTS: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. CONCLUSION: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT.

Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.

BACKGROUND: There are very few data about the mutational profile of families at-risk for hereditary breast and ovarian cancer (HBOC) from Latin America (LA) and especially from Brazil, the largest and most populated country in LA. RESULTS: Of the 349 probands analyzed, 21.5% were BRCA1/BRCA2 mutated, 65.3% at BRCA1 and 34.7% at BRCA2 gene. The mutation c.5266dupC (former 5382insC) was the most frequent alteration, representing 36.7% of the BRCA1 mutations and 24.0% of all mutations identified. Together with the BRCA1 c.3331_3334delCAAG mutation, these mutations constitutes about 35% of the identified mutations and more than 50% of the BRCA1 pathogenic mutations. Interestingly, six new mutations were identified. Additionally, 39 out of the 44 pathogenic mutations identified were not previously reported in the Brazilian population. Besides, 36 different variants of unknown significance (VUS) were identified. Regarding ancestry, average ancestry proportions were 70.6% European, 14.5% African, 8.0% Native American and 6.8% East Asian. MATERIALS AND METHODS: This study characterized 349 Brazilian families at-risk for HBOC regarding their germline BRCA1/BRCA2 status and genetic ancestry. CONCLUSIONS: This is the largest report of BRCA1/BRCA2 assessment in an at-risk HBOC Brazilian population. We identified 21.5% of patients harboring BRCA1/BRCA2 mutations and characterized the genetic ancestry of a sample group at-risk for hereditary breast cancer showing once again how admixed is the Brazilian population. No association was found between genetic ancestry and mutational status. The knowledge of the mutational profile in a population can contribute to the definition of more cost-effective strategies for the identification of HBOC families.

Oncogenetics service and the Brazilian public health system: the experience of a reference Cancer Hospital.

The identification of families at-risk for hereditary cancer is extremely important due to the prevention potential in those families. However, the number of Brazilian genetic services providing oncogenetic care is extremely low for the continental dimension of the country and its population. Therefore, at-risk patients do not receive appropriate assistance. This report describes the creation, structure and management of a cancer genetics service in a reference center for cancer prevention and treatment, the Barretos Cancer Hospital (BCH). The Oncogenetics Department (OD) of BCH offers, free of charge, to all patients/relatives with clinical criteria, the possibility to perform i) genetic counseling, ii) preventive examinations and iii) genetic testing with the best quality standards. The OD has a multidisciplinary team and is integrated with all specialties. The genetic counseling process consists (mostly) of two visits. In 2014, 614 individuals (371 families) were seen by the OD. To date, over 800 families were referred by the OD for genetic testing. The support provided by the Oncogenetics team is crucial to identify at-risk individuals and to develop preventive and personalized behaviors for each situation, not only to the upper-middle class population, but also to the people whose only possibility is the public health system.

Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome.

Germline mutations in TP53 are the underlying defects in Li-Fraumeni syndrome (LFS) and its variant, Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders that are characterized by predisposition to multiple early onset cancers. Here, we identified rs78378222 (A > C), a rare variant that is located in the 3' untranslated region (3' UTR) of TP53, in 7 probands (5.4%) of a cohort from LFS/LFL patients without TP53 germline mutations in the coding regions. To support its association with the LFS/LFL phenotype, we assessed p53 expression in tumor specimens and fibroblasts from rs78378222[C] carriers. Additionally, we investigated using in silico tools the evolutionary conservation and whether rs78378222[C] affects microRNA (miRNA) binding sites in the 3' UTR of TP53 mRNA. We found lower p53 protein levels in biological samples from rs78378222[C] carriers. Additionally, we showed that rs78378222[C] could interfere with a putative target site of miR-545-3p, a novel miRNA that is predicted to directly target the 3' UTR TP53. To our knowledge, this is the first description of rs78378222[C] in LFS/LFL patients. Moreover, these findings suggest that rs78378222[C] lead to haploinsufficiency of p53, a new mechanism of carcinogenesis in LFS/LFL.

Measles and rubella antibody status in children after treatment for acute lymphoblastic leukemia

OBJETIVO: Avaliar a história vacinal e a situação da proteção vacinal contra sarampo e rubéola em crianças portadoras de leucemia linfóide aguda após o término do tratamento. MÉTODOS: O estado imunológico contra o sarampo e a rubéola foi avaliado pela técnica ELISA em 22 crianças com leucemia linfóide aguda após o término do tratamento. RESULTADOS: Dos 22 pacientes, 20 haviam recebido previamente duas doses da vacina do sarampo, e 18 deles, uma dose da vacina da rubéola. Soropositivos para sarampo e rubéola resultaram em 65 e 88,9 por cento, respectivamente, sem correlação com idade do paciente, agressividade do tratamento ou tempo decorrido entre final do tratamento e coleta da amostra. CONCLUSÃO: Detectamos falha na proteção vacinal contra sarampo e rubéola em 35 e 11,1 por cento dos casos, respectivamente. Recomendamos, ao final do tratamento para leucemia linfóide aguda, aplicar reforço da vacina contra sarampo, avaliar o estado imunológico contra rubéola e, se necessário, revacinar o paciente.

OBJECTIVE: To assess the vaccination history and the status of vaccine-induced protection from measles and rubella in children after treatment for acute lymphoblastic leukemia. METHODS: Measles and rubella immunological status was assessed by the ELISA technique for 22 children previously treated for acute lymphoblastic leukemia. RESULTS: From the total of 22 patients, 20 had been given two doses of measles vaccine and 18 had had one dose of rubella vaccine. The percentage of patients seropositive for measles and rubella were 65 and 88.9 percent, respectively, with no correlation with age of patient, aggression of treatment or the time passed between the end of treatment and sample collection. CONCLUSIONS: We detected that vaccination had failed against measles and rubella in 35 and 11.1 percent of cases, respectively. We recommend that a measles booster be given after the completion of treatment for acute lymphoblastic leukemia and that rubella immunity status should be assessed at this point, with revaccination performed when necessary.

Measles and rubella antibody status in children after treatment for acute lymphoblastic leukemia.

OBJECTIVE: To assess the vaccination history and the status of vaccine-induced protection from measles and rubella in children after treatment for acute lymphoblastic leukemia. METHODS: Measles and rubella immunological status was assessed by the ELISA technique for 22 children previously treated for acute lymphoblastic leukemia. RESULTS: From the total of 22 patients, 20 had been given two doses of measles vaccine and 18 had had one dose of rubella vaccine. The percentage of patients seropositive for measles and rubella were 65 and 88.9%, respectively, with no correlation with age of patient, aggression of treatment or the time passed between the end of treatment and sample collection. CONCLUSIONS: We detected that vaccination had failed against measles and rubella in 35 and 11.1% of cases, respectively. We recommend that a measles booster be given after the completion of treatment for acute lymphoblastic leukemia and that rubella immunity status should be assessed at this point, with revaccination performed when necessary.