Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.

OBJECTIVES: Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. METHODS: The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). RESULTS: A two-compartment model was built using 483 data points from 45 patients (0.33-17.83 years of age) treated with MTX (0.25-5 g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. CONCLUSION: The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.

Toll-like Receptors 2, 3, and 4 in Childhood Acute Lymphocytic Leukemia / Receptores do Tipo Toll 2, 3 e 4 em Leucemia Linfocítica Aguda Infanti / Receptores Tipo Toll 2, 3 y 4 en la Leucemia Linfocítica Aguda Infantil

Introduction: Acute lymphocytic leukemia (ALL) is the most common cancer type in children and accounts for 80% of pediatric leukemias. Novel targets are necessary to improve survival rates for refractory and relapsed disease. There is accumulating evidence that Toll-like Receptor (TLR) signaling may be associated with outcomes in cancer however little has been described in leukemias. Objective: Analyze the expression and contribution of TLRs to the development of childhood ALL. Method: To evaluate the effect of specific TLR2, TLR3, and TLR4 agonists on the viability and proliferation of childhood ALL cell lines and to analyzed the mRNA expression of these types of TLR in bone marrow blast cells at diagnosis (D0) and induction (D35) in pediatric ALL patients. Results: Treatment with TLR agonists reduced the cell viability of Jurkat and Sup-B15 cell lines. Cell cycle distribution in Jurkat was altered, reducing polyploid cells and increasing sub-G1 phase. Conclusion: It was observed that the cell viability of the cell lines responded with different sensitivities to the agonists. The polyploidy associated with tumor malignancy was reduced, in addition to the increase in the sub-G1 phase indicating an increase in apoptosis. There were differences in TLR expression at D35 between groups at risk of the disease. Patients with high expression of TLR2 and low expression of TLR4 on D35 demonstrated a worse prognosis

Introdução: A leucemia linfoblástica aguda (LLA) é o tipo de câncer mais comum em crianças e representa 80% das leucemias pediátricas. Novos alvos são necessários para melhorar as taxas de sobrevivência para doença refratária e recidivante. Há evidências acumuladas de que a sinalização de receptores Toll-Like (TLR) pode estar associada a resultados em câncer, embora pouco tenha sido descrito em leucemias. Objetivo: Analisar a expressão e a contribuição dos TLR para o desenvolvimento da LLA infantil. Método: Avaliar o efeito de agonistas específicos de TLR2, TLR3 e TLR4 na viabilidade e proliferação de linhagens celulares de LLA infantil e analisar a expressão do RNAm desses tipos de TLR em células blásticas da medula óssea no diagnóstico (D0) e na indução (D35) em pacientes LLA pediátricos. Resultados: O tratamento com agonistas de TLR reduziu a viabilidade celular das linhagens celulares Jurkat e Sup-B15. A distribuição do ciclo celular em Jurkat foi alterada, reduzindo as células poliploides e aumentando a fase sub-G1. Houve aumento na expressão dos receptores entre D0 e D35 em amostras de pacientes. Conclusão: Observou-se que a viabilidade celular das linhagens celulares respondeu com diferentes sensibilidades aos agonistas. A poliploidia associada à malignidade tumoral foi reduzida, além de o aumento da fase sub-G1 indicar aumento da apoptose. Houve diferenças na expressão de TLR em D35 entre os grupos de risco da doença. Pacientes com alta expressão de TLR2 e baixa expressão de TLR4 no D35 demonstraram pior prognóstico.

Introducción: La leucemia linfocítica aguda (LLA) es el tipo de cáncer más común en los niños y representa el 80 % de las leucemias pediátricas. Se necesitan nuevos objetivos para mejorar las tasas de supervivencia de la enfermedad refractaria y recidivante. Cada vez hay más pruebas de que la señalización del receptor Toll-Like (TLR) puede estar asociada con resultados en el cáncer, aunque se ha descrito poco en las leucemias. Objetivo: Analizar la expresión y la contribución de los TLR al desarrollo de la LLA infantil. Método: Evaluar el efecto de agonistas específicos de TLR2, TLR3 y TLR4 en la viabilidad y proliferación de líneas celulares de LLA infantil y analizar la expresión de ARNm de estos tipos de TLR en células blásticas de médula ósea en el momento del diagnóstico (D0) y la inducción (D35) en pacientes pediátricos con LLA. Resultados: El tratamiento con agonistas de TLR redujo la viabilidad celular de las líneas celulares Jurkat y sup-B15. Se alteró la distribución del ciclo celular en Jurkat, reduciendo las células poliploides y aumentando la fase sub-G1. Hubo un aumento en la expresión de los receptores entre D0 y D35 en muestras de pacientes. Conclusión: Se observó que la viabilidad celular de las líneas celulares respondía con distintas sensibilidades a los agonistas. Se redujo la poliploidía asociada con la malignidad del tumor, además de un aumento de la fase sub-G1 que indica un aumento de la apoptosis. Hubo diferencias en la expresión de TLR en D35 entre los grupos de riesgo de enfermedad. Los pacientes con alta expresión de TLR2 y baja expresión de TLR4 en D35 mostraron peor pronóstico

Trk Inhibition Reduces Tumorsphere Formation and Changes Expression of Stemness Markers in SK-ES-1 Ewing Sarcoma Cells / Inibição de Trk Reduz a Formação de Tumoresferas e Modifica a Expressão de Marcadores Tronco Tumorais em Células de Sarcoma de Ewing SK-ES-1 / Inhibición de Trk Reduce la Formación de Esferoides Tumorales y Cambia la Expresión de Marcadores de Stemness en Células de Sarcoma de Ewing SK-ES-1

Introduction: Ewing sarcoma (ES) is a highly aggressive type of childhood cancer characterized by a chromosomal translocation resulting in fusions between the gene encoding EWS RNA Binding Protein 1 (EWSR1) and one gene of the ETS family, most frequently FLI-1, resulting in the EWS-FLI1 aberrant transcription factor. ES tumors can contain a subpopulation of cells showing cancer stem cell (CSC) features, which express stemness markers including CD133, OCT4 (Octamer-binding transcription factor 4), and NANOG, and display capacity to form tumorspheres likely enriched in CSCs. Neurotrophin (NT) receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) may play a role in stimulating ES progression, but their possible role in CSCs remains unknown. Objective: To verify the effect of Trks inhibition on the formation of tumorspheres as well as the gene expression of stem markers. Method: The cells were dissociated and the formation of spheres was induced with supplemented culture medium and the K252a treatment was performed. After RNA extraction, mRNA expression levels of target genes Prom1 (CD133), OCT4 (POU5F1), SOX2, and Musashi-1 (MSI1) were analyzed by qPCR. Results: The pan-Trk inhibitor K252a (100 or 500 mM) hindered tumorsphere formation in human SK-ES-1 ES cell cultures. K252a also reduced mRNA expression of Prom1 (CD133-coding gene) while enhancing expression of OCT4. No changes in mRNA levels of SOX2 or Musashi-1 were observed. Conclusion: These findings provide the first evidence suggesting that Trk activity can influence stemness in ES cells

Introdução: O sarcoma de Ewing (SE) é um tipo altamente agressivo de câncer infantil caracterizado por uma translocação cromossômica que resulta em fusões entre o gene que codifica a proteína de ligação a RNA EWS 1 (EWSR1) e um gene da família ETS, mais frequentemente o FLI-1, resultando no fator de transcrição aberrante EWS-FLI1. Os tumores de SE podem conter uma subpopulação de células com características de células-tronco tumorais (CTT), que expressam marcadores de pluripotência como CD133, OCT4 e NANOG, e têm a capacidade de formar esferas tumorais provavelmente enriquecidas em CTT. Os receptores de neurotrofinas (NT) da família de receptor de quinase de tropomiosina (Trk) (TrkA, TrkB e TrkC) podem desempenhar um papel no estímulo à progressão do SE, mas seu possível papel nas CTT permanece desconhecido. Objetivo: Verificar o efeito da inibição dos Trk na formação de tumoresferas, bem como na expressão gênica de marcadores de pluripotência. Método: As células foram dissociadas, a formação de esferas com meio de cultura suplementado foi induzida e realizou-se o tratamento com K252a. Após a extração de RNA, os níveis de expressão de mRNA dos genes-alvo Prom1 (CD133), OCT4 (POU5F1), SOX2 e Musashi-1 (MSI1) foram analisados por qPCR. Resultados: O inibidor pan-Trk K252a (100 ou 500 mM) impediu a formação de esferas tumorais em culturas de células de SE humanas SK-ES-1. O K252a também reduziu a expressão de mRNA de Prom1 (o gene que codifica CD133), enquanto aumentou a expressão de OCT4. Não foram observadas mudanças nos níveis de mRNA de SOX2 ou Musashi-1. Conclusão: Essas descobertas fornecem as primeiras evidências, sugerindo que a atividade dos Trk possa influenciar a pluripotência nas células de SE

Introducción: El sarcoma de Ewing (SE) es un tipo de cáncer infantil altamente agresivo caracterizado por una translocación cromosómica que resulta en fusiones entre el gen que codifica la proteína de unión a RNA EWS 1 (EWSR1) y un gen de la familia ETS, más frecuentemente FLI-1, lo que resulta en el factor de transcripción aberrante EWS-FLI1. Los tumores del SE pueden contener una subpoblación de células que presentan características de células madre cancerosas (CMC), las cuales expresan marcadores de pluripotencia como CD133, OCT4 y NANOG, y muestran la capacidad de formar esferas tumorales probablemente enriquecidas en CMC. Los receptores de neurotrofinas (NT) de la familia del receptor de quinasa de tropomiosina (Trk) (TrkA, TrkB y TrkC) podrían desempeñar un papel en el estímulo de la progresión del SE, pero su posible papel en las CMC aún es desconocido. Objetivo: Verificar el efecto de la inhibición de los Trk en la formación de esferoides tumorales, así como en la expresión génica de marcadores de pluripotencia. Método: Las células fueron disociadas e inducidas a formar esferas con un medio de cultivo suplementado y se realizó el tratamiento con K252a. Después de la extracción de ARN, los niveles de expresión de ARNm de los genes objetivo Prom1 (CD133), OCT4 (POU5F1), SOX2 y Musashi-1 (MSI1) se analizaron mediante qPCR. Resultados: El inhibidor pan-Trk K252a (100 o 500 mM) evitó la formación de esferas tumorales en cultivos de células de SE humanas SK-ES-1. El K252a también redujo la expresión de ARNm de Prom1 (el gen que codifica CD133), mientras que aumentaba la expresión de OCT4. No se observaron cambios en los niveles de ARNm de SOX2 o Musashi-1. Conclusión: Estos hallazgos proporcionan las primeras evidencias que sugieren que la actividad de Trk puede influir en la pluripotencia en las células del SE

Illness perceptions in childhood cancer survivor and caregivers' dyads.

Surviving childhood cancer is a difficult experience for children and their caregivers, it can produce long-term emotional distress. Illness perceptions refer to the way people understand the different aspects related to illness from their individual and collective experiences. OBJECTIVE: to compare the illness perceptions of adolescent childhood cancer survivors and their caregivers and examine the relationship between illness perception of childhood cancer survivors, their caregivers, and sociodemographic, illness, and treatment variables. Forty-three survivor-caregiver dyads (the mean age of a survivor 17.05 years old; the mean age of caregivers 47.53 years old) participated in the study and answered the Brief Illness Perception Questionnaire (Brief IPQ) and Demographics data. RESULTS: Results showed significant differences in the illness perceptions of survivors and caregivers. Caregivers presented more negative cognitive perceptions than survivors (t = -6.701, p < 0.001), especially in the identity dimension (t = -4.327, p < 0.001), and more negative emotional perceptions than survivors (t = -4.132, p < 0.001), both in concern (t = -3.695, p < 0.001) and emotional representation (t = -3.466, p < 0.001). No significant correlations were found between survivors' and caregivers' illness perceptions and sociodemographic illness variables. CONCLUSION: These findings showed that even though dyads went through cancer together, survivors' and caregivers' perceptions of childhood cancer are different, indicating the need to better understand how children growing up with a chronic disease develop such illness perceptions and their experience.

Investigation of oral and general health status and IL-1ß gene polymorphism as risk factors for oral mucositis in hematopoietic stem cell transplantation patients.

The aim of the present study was to analyze the relationship of OM with possible risk factors such as oral health condition, immunological status and IL-1ß profile in patients submitted to hematopoietic stem cell transplantation (HSCT). Fifty-four individuals submitted to HSCT were included. All patients received previous dental treatment and photobiomodulation (PBM) as the institutional OM preventive protocol. OM scores, immune status, and IL-1ß levels were determined during the conditioning period and at D+3 and D+8 after HSC infusion. IL-1ß gene polymorphism was also analyzed during conditioning. Possible associations of OM with risk factors were analyzed using conditional Fisher's exact test. OM was observed in 34 patients (62.9%) classified as Grade 1 (13 patients/24.1%), Grade 2 (14 patients/25.9%), Grade 3 (3 patients/5.5%), and Grade 4 (4 patients/7.4%). Allogeneic HSCT individuals exhibited a higher OM grade than autologous subjects. Moreover, an association was observed between severe OM and severe gingivitis (p = 0.01), neutropenia (p = 0.03), and leukopenia (p = 0.04). A significant association between OM and lower IL-1ß levels was detected at three time points, i.e., conditioning (p = 0.048), D+3 (p = 0.01), and D+8 (p = 0.005). The results showed that IL-1ß gene polymorphism was not associated with OM. Our study provided important insights into the scope of OM risk factors in the setting of HSCT. Patients submitted to HSCT with severe gingivitis prior to chemotherapy and with severe neutropenia and leukopenia exhibited a higher OM grade. Further investigation will be necessary to better understand the exact role of IL-1ß in the context of OM pathobiology and to validate cytokine analysis in larger cohorts.

Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis.

OBJECTIVES: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the development of OM in pediatric cancer patients. METHODS: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients. RESULTS: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta-analysis showed that groups submitted to high-risk chemotherapy for OM had a 2.79-fold increased risk of OM. CONCLUSIONS: Identifying risk factors for OM is essential in order to allow individualized and early prevention treatment.

Potential medication incompatibilities in pediatric oncology prescriptions

Introduction: Pediatric oncology patients have a limited number of venous access routes and need a large number of drugs during hospitalization. This study evaluates potential medication incompatibilities (MI) in pediatric oncology prescriptions and identifies possible factors associated with the risk of their occurrence. Methods: This cross-sectional study evaluated prescriptions from a tertiary universitary hospital from December 2014 to December 2015. The association between variables and the risk of potential incompatibilities between drugs was determined by Student's t-test and Pearson's chi-square, considering p < 0.05 significant. The odds ratio was calculated considering a 95% confidence interval for each drug. Results: 385 prescriptions were evaluated. The mean age of 124 patients was 9.22 years old (SD = ± 5.10), and 50.65% were male. The most frequent diagnosis and reason for hospitalization were leukemia (27.30%) and chemotherapy (36.10%). The totally implantable catheter was the most commonly used venous access (61.30%). In 87.5% of prescriptions, there was the possibility of MI, and 2108 incompatibilities were found, considering 300 different combinations between two drugs. Age, diagnosis, reason for hospitalization, and type of venous access were risk factors for potential incompatibilities (p < 0.05). The following drugs present higher risk of potential incompatibilities: leucovorin, sodium bicarbonate, cefepime, diphenhydramine, dimenhydrinate, hydrocortisone, and ondansetron, with a significant odds ratio. Conclusion: The possibility of MI in prescriptions for pediatric oncology patients is frequent. Thus, the identification of risk factors may contribute to patient safety and to the rational use of drugs.

Investigation of oral and general health status and IL-1β gene polymorphism as risk factors for oral mucositis in hematopoietic stem cell transplantation patients

Abstract: The aim of the present study was to analyze the relationship of OM with possible risk factors such as oral health condition, immunological status and IL-1β profile in patients submitted to hematopoietic stem cell transplantation (HSCT). Fifty-four individuals submitted to HSCT were included. All patients received previous dental treatment and photobiomodulation (PBM) as the institutional OM preventive protocol. OM scores, immune status, and IL-1β levels were determined during the conditioning period and at D+3 and D+8 after HSC infusion. IL-1β gene polymorphism was also analyzed during conditioning. Possible associations of OM with risk factors were analyzed using conditional Fisher's exact test. OM was observed in 34 patients (62.9%) classified as Grade 1 (13 patients/24.1%), Grade 2 (14 patients/25.9%), Grade 3 (3 patients/5.5%), and Grade 4 (4 patients/7.4%). Allogeneic HSCT individuals exhibited a higher OM grade than autologous subjects. Moreover, an association was observed between severe OM and severe gingivitis (p = 0.01), neutropenia (p = 0.03), and leukopenia (p = 0.04). A significant association between OM and lower IL-1β levels was detected at three time points, i.e., conditioning (p = 0.048), D+3 (p = 0.01), and D+8 (p = 0.005). The results showed that IL-1β gene polymorphism was not associated with OM. Our study provided important insights into the scope of OM risk factors in the setting of HSCT. Patients submitted to HSCT with severe gingivitis prior to chemotherapy and with severe neutropenia and leukopenia exhibited a higher OM grade. Further investigation will be necessary to better understand the exact role of IL-1β in the context of OM pathobiology and to validate cytokine analysis in larger cohorts.

The effect of hospital care volume on overall survival of children with cancer in Southern Brazil.

PURPOSE: The purpose of this study was to analyze the effect of hospital care volume on the overall survival of children with cancer in Southern Brazil. PATIENTS AND METHODS: We performed a retrospective cohort study of 1378 cancer patients aged 0-19 years, diagnosed with cancer between August 1, 2009 and December 31, 2015 in Rio Grande do Sul, who received hospital treatment in institutions affiliated with the Universal Health Care System (Sistema Único de Saúde [SUS]). RESULTS: Most children and adolescents were male (56.9%) and White (75.8%). The most common types of cancer in our cohort were acute leukemia (40.7%), followed by lymphoma (15.9%) and central nervous system tumors (8.8%). Ninety-five percent of the patients were treated in specialized pediatric oncology centers. The cumulative probability of survival at 5 years for all patients was 73.8% (95% confidence interval [CI] 71.4-76.0%). Survival was significantly higher for patients younger than 4 years of age (P = .012) compared to all other age groups. Patients treated in institutions with a pediatric oncology patient volume of less than 15 patients/year were 41% more likely to die than patients treated in institutions with a volume of 60 patients/year or more (P = .029). CONCLUSION: Cancer is the leading cause of death by natural causes in all age groups in Brazil, but, even so, childhood tumors are rare. This complexity makes childhood cancer care a challenge. In this study, we reiterate that pediatric cancer patients demonstrate better overall survival when treated in high-volume hospitals.

Subjective global nutritional assessment: applicability in children and adolescents with malignant tumors

Introduction: This study investigated the applicability of the Subjective Global Nutritional Assessment (SGNA) tool to evaluate the nutritional status of pediatric cancer patients. Methods: This was a multicenter, observational cohort study of infants, children, and adolescents diagnosed with malignant tumors. Participants were evaluated at the moment they were diagnosed with a malignant tumor (EV1) and at the third month of treatment (EV2). Objective data were collected and the SGNA questionnaire was applied. Correlation between the methods was performed using the Kendall test. Results: We evaluated 216 patients at EV1 and 172 patients at EV2. During EV1, 7% of patients presented with some degree of malnutrition, according to objective measures, and 35.7% according to the SGNA. During EV2, they presented 6.4% and 26.8%, respectively. The SGNA showed ability to diagnose more malnutrition than objective indicators and the agreement found between both methods was moderate and weak. We observed a significant correlation between the SGNA and the nutritional indicators (p = <0.002), thus proving its efficacy in assessing nutritional status. Conclusion: The SGNA was applicable for evaluating the nutritional status of children and adolescents diagnosed with malignant tumors, and effective in tracking malnutrition prevalence when compared to objective nutritional assessment methods. (AU)

Nutritional status and nutritional therapy in pediatric and adolescent patients submitted to autologous hematopoietic stem cell transplantation

Introduction: To assess the use of nutritional support in children and adolescents submitted to autologous hematopoietic stem cell transplantation (HSCT), and analyze changes in nutritional status at hospital discharge after HSCT. Methods: A retrospective observational study was conducted on pediatric oncology patients hospitalized for autologous HSCT between 2010 and 2017. Nutritional therapy was evaluated based on the duration of enteral tube feeding (ETF) and parenteral nutrition (PN), either alone or in combination. The length of hospital stay was measured in days. Nutritional status was assessed at admission and discharge, and classified according to World Health Organization criteria. Results: The sample consisted of 68 patients, 54.4% of whom were boys. Most participants (89.7%) had solid tumors. Nutritional therapy was required in over half (52.9%) of cases, with PN being the most common indication. There was a reduction in the percentage of overweight patients and an increase in the percentage of underweight patients at discharge relative to admission. Conclusions: The use of nutritional therapy is highly prevalent in this population, and HSCT has a negative impact on nutritional status at discharge. (AU)

Expression of neurotrophins and their receptors in primary osteosarcoma. / Expressão de neurotrofinas e de seus receptores no osteossarcoma primário.

OBJECTIVE: to determine the expression of neurotrophins and their tyrosine-kinase receptors in patients with osteosarcoma (OS) and their correlation with clinical outcomes. METHODS: we applied immunohistochemistry to biopsy specimens of patients consecutively treated for primary OS at a single institution between 2002 and 2015, analyzing them for expression receptors of tyrosine kinase A and B (TrKA and TrKB), neural growth factor (NGF) and brain derived neurotrophic factor (BDNF). Independently, two pathologists classified the immunohistochemical markers as negative (negative or weak focal) or positive (moderate focal/diffuse or strong focal/diffuse). RESULTS: we analyzed data from 19 patients (10 females and 9 males), with median age of 12 years (5 to 17.3). Tumors' location were 83.3% in the lower limbs, and 63.2% of patients had metastases at diagnosis. Five-year overall survival was 55.3%. BDNF was positive in 16 patients (84%) and NGF in 14 (73%). TrKA and TrKB presented positive staining in four (21,1%) and eight (42,1%) patients, respectively. Survival analysis showed no significant difference between TrK receptors and neurotrophins. CONCLUSION: primary OS samples express neurotrophins and TrK receptors by immunohistochemistry. Future studies should explore their role in OS pathogenesis and determine their prognostic significance in larger cohorts.

OBJETIVO: determinar a expressão de neurotrofinas e seus receptores tirosina quinases em pacientes com osteossarcoma (OS) e sua correlação com desfechos clínicos. MÉTODOS: biópsias de tumores primários de pacientes com OS tratados em uma única instituição, consecutivamente, entre 2002 e 2015, foram analisados através de imuno-histoquímica para expressão de receptores de tirosina quinase A e B (TrKA e TrKB), fator de crescimento neural (NGF) e fator neurotrófico derivado do cérebro (BDNF). De forma independente, dois patologistas classificaram os marcadores de imuno-histoquímica como negativos (negativos e focais fracos) ou positivos (moderado focal/difuso ou forte focal/difuso). RESULTADOS: foram analisados dados de 19 pacientes (10 do sexo feminino e 9 do masculino) com mediana de idade de 12 anos (5 a 17,3 anos). Dos tumores, 83,3% estavam localizados em membros inferiores e 63,2% dos pacientes eram metastáticos ao diagnóstico. A sobrevida global em cinco anos foi de 55,3%. BDNF foi positivo em 16 pacientes (84%) e NGF em 14 pacientes (73%). TrKA e TrKB apresentaram coloração positiva em quatro (21,1%) e oito (42,1%) pacientes, respectivamente. A análise de sobrevida não demonstrou diferença significativa entre receptores TrK e neurotrofinas. CONCLUSÃO: amostras de OS primário expressam neurotrofinas e receptores TrK através de imuno-histoquímica. Estudos futuros podem auxiliar na identificação do papel das mesmas na patogênese do OS e determinar se há possível correlação prognóstica.

Expressão de neurotrofinas e de seus receptores no osteossarcoma primário / Expression of neurotrophins and their receptors in primary osteosarcoma

RESUMO Objetivo: determinar a expressão de neurotrofinas e seus receptores tirosina quinases em pacientes com osteossarcoma (OS) e sua correlação com desfechos clínicos. Métodos: biópsias de tumores primários de pacientes com OS tratados em uma única instituição, consecutivamente, entre 2002 e 2015, foram analisados através de imuno-histoquímica para expressão de receptores de tirosina quinase A e B (TrKA e TrKB), fator de crescimento neural (NGF) e fator neurotrófico derivado do cérebro (BDNF). De forma independente, dois patologistas classificaram os marcadores de imuno-histoquímica como negativos (negativos e focais fracos) ou positivos (moderado focal/difuso ou forte focal/difuso). Resultados: foram analisados dados de 19 pacientes (10 do sexo feminino e 9 do masculino) com mediana de idade de 12 anos (5 a 17,3 anos). Dos tumores, 83,3% estavam localizados em membros inferiores e 63,2% dos pacientes eram metastáticos ao diagnóstico. A sobrevida global em cinco anos foi de 55,3%. BDNF foi positivo em 16 pacientes (84%) e NGF em 14 pacientes (73%). TrKA e TrKB apresentaram coloração positiva em quatro (21,1%) e oito (42,1%) pacientes, respectivamente. A análise de sobrevida não demonstrou diferença significativa entre receptores TrK e neurotrofinas. Conclusão: amostras de OS primário expressam neurotrofinas e receptores TrK através de imuno-histoquímica. Estudos futuros podem auxiliar na identificação do papel das mesmas na patogênese do OS e determinar se há possível correlação prognóstica.

ABSTRACT Objective: to determine the expression of neurotrophins and their tyrosine-kinase receptors in patients with osteosarcoma (OS) and their correlation with clinical outcomes. Methods: we applied immunohistochemistry to biopsy specimens of patients consecutively treated for primary OS at a single institution between 2002 and 2015, analyzing them for expression receptors of tyrosine kinase A and B (TrKA and TrKB), neural growth factor (NGF) and brain derived neurotrophic factor (BDNF). Independently, two pathologists classified the immunohistochemical markers as negative (negative or weak focal) or positive (moderate focal/diffuse or strong focal/diffuse). Results: we analyzed data from 19 patients (10 females and 9 males), with median age of 12 years (5 to 17.3). Tumors' location were 83.3% in the lower limbs, and 63.2% of patients had metastases at diagnosis. Five-year overall survival was 55.3%. BDNF was positive in 16 patients (84%) and NGF in 14 (73%). TrKA and TrKB presented positive staining in four (21,1%) and eight (42,1%) patients, respectively. Survival analysis showed no significant difference between TrK receptors and neurotrophins. Conclusion: primary OS samples express neurotrophins and TrK receptors by immunohistochemistry. Future studies should explore their role in OS pathogenesis and determine their prognostic significance in larger cohorts.

Gene expression changes associated with chemotherapy resistance in Ewing sarcoma cells.

Ewing Sarcoma (ES) is a highly aggressive bone and soft tissue childhood cancer. The development of resistance to chemotherapy is common and remains the main cause of treatment failure. We herein evaluated the expression of genes associated with chemotherapy resistance in ES cell lines. A set of genes (CCAR1, TUBA1A, POLDIP2, SMARCA4 and SMARCB1) was data-mined for resistance against doxorubicin and vincristine, which are the standard drugs used in the treatment of patients with ES. The expression of each gene in SK-ES-1 ES cells was reported before and after exposure to a drug resistance-inducing protocol. There was a significant downregulation of CCAR1 and TUBA1A in doxorubicin-resistant cells, with low expression of TUBA1A in vincristine-resistant cells. By contrast, POLDIP2 was significantly upregulated in cells resistant to either drug, and the expression of the SMARCB1 and SMARCA4 genes was upregulated in doxorubicin-resistant cells. These findings indicate that resistance to specific chemotherapeutic agents was accompanied by differential changes in gene expression in ES tumors.

Microbiological profile and nutritional quality of a regular diet compared to a neutropenic diet in a pediatric oncology unit.

It has been hypothesized that a neutropenic diet has lower microbe content. Here, the microbiological and nutritional contents of regular and neutropenic diets offered to pediatric patients were analyzed. Microbiological contamination was detected in five of 36 of the food samples analyzed, yet there was no statistical differences between the diets (P = 1.00) or in their odds ratio (0.62) (95% CI = 0.05-6.35; P = 0.63). The strict neutropenic diet did have less fiber (P = 0.05) and vitamin C (P = 0.01). Thus, the regular diet appears safe, and possibly provides greater benefits, for pediatric patients with neutropenia.

Perfil nutricional e qualidade de vida de cuidadores de crianças e adolescentes com câncer / Nutritional profile and quality of life of caregivers of children and adolescents with cancer

Introdução: Verificar o perfil nutricional e a qualidade de vida dos cuidadores de crianças e/ou adolescentes com câncer durante os primeiros 6 meses de tratamento oncológico. Métodos: Estudo de coorte realizado no período de julho/2015 a novembro/2016 em três momentos: até 2 semanas (T0) e em 3 (T1) e 6 (T2) meses após o diagnóstico. Foram aplicados um questionário sociodemográfico, um recordatório alimentar de 24 horas e o instrumento 36-Item Short-Form Health Survey (SF-36), e foi realizada a antropometria. Foram excluídos do estudo cuidadores gestantes, menores de 19 anos, responsáveis por pacientes em cuidados paliativos e em recidivas. A análise estatística utilizou o teste de dupla análise de variância de Friedman, e foram considerados significativos valores de p < 0,05. Resultados: Foram avaliados 42 cuidadores Os cuidadores mais frequentes foram mães (81%), e a média de idade foi de 34,17 anos (DP = 8,94). Observou-se aumento no peso corporal, no índice de massa corporal, na circunferência abdominal e na dobra cutânea tricipital (p < 0,05). Foi constatada uma redução no consumo de calorias totais e de macronutrientes (p < 0,05), e o consumo de fibras ficou abaixo das recomendações. No aspecto qualidade de vida, o domínio vitalidade teve redução significativa (p = 0,042). Conclusões: Os cuidadores de crianças e/ou adolescentes com câncer apresentam tendência a um consumo inadequado de alimentos. Os estados nutricionais predominantes foram o sobrepeso e a obesidade, com depósito de gordura visceral. Assim, o diagnóstico de câncer infantil interfere no estado nutricional e na qualidade de vida do cuidador durante os primeiros 6 meses do tratamento oncológico. (AU)

Introduction: To assess the nutritional profile and quality of life of caregivers of children and adolescents with cancer during the first 6 months of cancer treatment. Methods: A cohort study was conducted from July, 2015 to November, 2016 at three time points: up to 2 weeks (T0) and at 3 (T1) and 6 months (T2) after diagnosis. A sociodemographic questionnaire, a 24-hour recall, and a 36-Item Short-Form Health Survey (SF-36) questionnaire were applied, and anthropometry was performed. Pregnant caregivers, caregivers under 19 years old, and caregivers of patients in palliative care and of patients with recurrence were excluded from the study. The statistical analysis was performed using Friedman's two-way analysis of variance. P-value < 0.05 was considered significant. Results: We evaluated 42 caregivers. Mothers played the role of caregivers more frequently (81%), and mean age was 34.17 years (SD = 8.94). There was an increase in body weight, body mass index, waist circumference, and triceps skinfold thickness (p < 0.05). There was also a reduction in the consumption of total calories and macronutrients (p < 0.05), and fiber consumption was below recommendations. In terms of quality of life, vitality reduced significantly (p = 0.042). Conclusion: Caregivers of children and/or adolescents with cancer tended to show inadequate food consumption. The prevailing nutritional states were overweight and obesity, with visceral fat deposit. Thus, the diagnosis of childhood cancer interferes in the nutritional status and quality of life of a caregiver during the first 6 months of cancer treatment.

Avaliação da Força de Preensão Palmar e Qualidade de Vida de Crianças com Câncer Submetidas à Quimioterapia com Vincristina / Evaluation of Handgrip Strength and Children's Quality of Life with Cancer Submitted to Chemotherapy with Vincristine / Evaluación de la fuerza de Asimiento Palmar y Calidad de Vida de Niños con Cáncer Sometidos a la quimioterapia con Vincristina

Introdução: com a quimioterapia, os pacientes podem apresentar diversas alterações; entre elas, polineuropatia e mudança na qualidade de vida, tanto à criança como aos familiares. Objetivo: avaliar a força de preensão palmar e a qualidade de vida de crianças e adolescentes com câncer submetidos à quimioterapia com vincristina. Método:trata-se de um estudo, no qual os pacientes responderam aos questionários de anamnese e PedsQLTM 3.0 Câncer Module, em três momentos diferentes do tratamento. um dos seus responsáveis foi convidado a responder ao mesmo questionário. a força de preensão palmar foi aferida por meio de um dinamômetro, nos mesmos momentos. Resultados: a amostra foi composta por sete pacientes com mediana 7 (5-15 anos); com predomínio de meninas, residentes em Porto alegre, rs, e diagnóstico prevalente de leucemia linfoide aguda, internados na primeira semana após o diagnóstico de câncer. a força de preensão palmar apresentou redução significativa para ambos os membros (p=0,018, membro superior direito; p=0,030, membro superior esquerdo). apesar de não apresentar resultado significativo, na maioria dos domínios do questionário de qualidade de vida, ocorreu declínio nas respostas, principalmente nas dos pais. Conclusão: a quimioterapia com vincristina reduz a força muscular periférica em pacientes com câncer, nos 30 primeiros dias. em relação à qualidade de vida, não foi apresentada diferença significativa. Porém, dentro dos domínios, pôde-se perceber algumas alterações. sendo assim, fica clara a importância do acompanhamento contínuo da fisioterapia junto a uma equipe preparada para esses pacientes e seus familiares

Introduction: With chemotherapy, patients may have several changes. among them: polyneuropathy and change in the quality of life, both the children and the family. Objective: to evaluate the handgrip's power and the life quality in these children and teens with cancer undergoing to chemotherapy with vincristine. Method: This is a study in which patients responded the questionaries of anamnsis and PedsQLTM 3.0 Cancer Modulein three different moments of the treatment. one of your responsible was invited to answer separately the same questionarie. The handgrip's power was measured by dynamometer, in the same moments. Results: The sample was composed for seven patients with average 7 (5-15 years); The most of them were girls, residing in Porto alegre-rs, with a prevalent diagnostic of acute lymphoid leukemia and who were hospitalized in the first week after the diagnosis of cancer. The handgrip's strength show significant reduction for all of the limbs (p=0,0018, right upper limb; p=0,0030, left upper limb). although of not show significant results, in most areas of the questionnaire of quality of life ocurred decline in the answers, mainly in the parents awnsers. Conclusion: The chemotherapy with vincristine, decrease in the peripheral muscle strength in the patients with cancer, in the first 30 days. in relationship of quality of life, there was no significant diference, however we could perceive some trends. Therefore, it is clear the importance of the continuous monitoring of physiotherapy with a team prepared for these patients and their families

Introducción: con la quimioterapia, los pacientes pueden presentar varias modificaciones. entre ellas: polineuropatía y cambio en la calidad de vida, tanto del niño y de los familiares. Objetivo: evaluar la fuerza de asimiento palmar y la calidad de vida de niños y adolescentes con cáncer sometidos a la quimioterapia con vincristina. Método: se trata de un estudio, en el cual los pacientes respondieron a los cuestionarios de anamnesis y PedsQltM 3.0 cáncer Module, en tres momentos diferentes del tratamiento. uno de sus responsables fue invitado a responder el mismo cuestionario. la fuerza de asimiento palmar fue evaluada por medio de un dinamómetro, en los mismos momentos. Resultados: la muestra fue compuesta por siete pacientes con mediana 7 (5-15 años); teniendo más niñas, residentes en Porto alegre-rs, con diagnóstico prevalente de leucemia linfoide aguda y que estaban internadas en la primera semana después del diagnóstico de câncer. la fuerza de asimiento palmar presentó una reducción significativa para ambos miembros (p=0,018, miembro superior derecho, p=0,030, miembro superior izquierdo). a pesar de no presentar resultados significativos, en la mayoría de los dominios del cuestionario de calidad de vida ocurrió declinación en las respuestas, principalmente en la respuesta de los padres. Conclusión: la quimioterapia con vincristina reduce la fuerza muscular periférica en pacientes con cáncer, en los 30 primeros días. en cuanto a la calidad de vida, no se presentó una diferencia significativa. sin embargo, dentro de los dominios se pode percibir algunos cambios. Por lo tanto, queda claro la importancia del acompañamiento continuo de la fisioterapia junto a un equipo preparado para esos pacientes y sus familiares

Avaliação Nutricional Subjetiva Global: aplicabilidade em crianças e adolescentes com neoplasia maligna - resultados preliminares / Subjective Global Nutritional Assessment: applicability in children and adolescents with malignant neoplasm ­ preliminary results

Introdução: Crianças e adolescentes com câncer apresentam alterações provenientes tanto da patologia quanto do tratamento que podem refletir no estado nutricional (EN) ao diagnóstico e ao longo do tratamento. O objetivo primário do estudo foi avaliar a aplicabilidade do instrumento Avaliação Nutricional Subjetiva Global (ANSG) na avaliação do Estado Nutricional (EN) de pacientes oncológicos pediátricos. Métodos: Estudo de coorte observacional e descritivo com lactentes, crianças e adolescentes diagnosticados com neoplasia maligna. Os participantes do estudo foram avaliados ao diagnóstico (AV1) e ao terceiro mês de tratamento (AV2). Dados objetivos foram aferidos e o instrumento ANSG foi aplicado. O teste de Kendall foi utilizado para analisar a correlação entre os métodos. Resultados: Realizadas 42 avaliações ao diagnóstico e 26 ao terceiro mês de tratamento. Observou-se predominância de pacientes bem nutridos nos dois momentos da avaliação. Na AV1, 7,2% dos pacientes foram identificados com algum grau de desnutrição conforme indicadores objetivos e 38,1% de acordo com o ANSG. Na AV2, houve redução na prevalência de pacientes desnutridos. O método ANSG mostrou correlação significativa com os indicadores nutricionais peso-para-idade e estaturapara- idade e foi eficaz no rastreamento de desnutrição. Conclusão: A ANSG é um instrumento útil na identificação de risco nutricional e pode ser utilizado na prática clínica assistencial, em conjunto com outros métodos de avaliação nutricional. O monitoramento do EN da população oncológica pediátrica é fundamental, a fim de intervir de maneira adequada. (AU)

from both the pathology itself and the treatment, which can reflect on their nutritional status (NS) at diagnosis and throughout the treatment. The primary objective of the study was to assess the applicability of the Subjective Global Nutritional Assessment (SGNA) tool to assess the NS of pediatric oncology patients. Methods: This was a descriptive, observational cohort study including infants, children and adolescents diagnosed with malignant neoplasia. Participants were assessed at diagnosis (NA1) and in the third month of treatment (NA2). Objective data were measured and the SGNA tool was applied. The Kendall test was used in order to analyze the correlation between the methods. Results: A total of 42 assessments were performed at diagnosis and 26 in the third month of treatment. A prevalence of well-nourished patients was observed in the two assessment moments. During NA1, 7.2% of the patients presented some degree of malnutrition according to objective indicators and 38.1%, according to SGNA. During NA2, there was a reduction in the prevalence of malnourished patients. The SGNA method showed a significant correlation with weightfor- age and height-for-age nutritional indicators and was efficient to trace malnutrition. Conclusion: The SGNA is a useful tool for the identification of nutritional risk and may be used in the clinical practice in combination with other nutritional assessment methods. The monitoring of the NS of pediatric patients who have cancer is vital in order to ensure adequate intervention. (AU)

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome.

OBJECTIVE: To describe survival and neurological outcomes after HSCT for these disorders. METHODS: Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. RESULTS: Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. CONCLUSION: Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.