Chloroquine is grossly under dosed in young children with malaria : implications for drug resistance

Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.

Identificação de crianças e adolescentes com suspeita de câncer: uma proposta de intervenção

Unlike adult cancer, where cells usually originate from epithelial tissue and is linked to environmental factors, malignant tumors in childhood are mostly of embryonic origin and have a phase of rapid proliferation. When not started chemotherapy at this stage, the tumor increases in size, reducing their growth rate, thus reducing the response to chemotherapy. Childhood cancer is in Brazil, the second cause of mortality among children and adolescents from one to nineteen. His impact on the ranking of diseases becomes significantly important to public health since the first issue is related to accidents and violence. Many children are still sent to the centers of high complexity for cancer treatment with advanced stage disease. The delay in referral to diagnosis can be family, or the difficulty of access to the health sector, or the characteristics of the disease and lack of health staff regarding theme of childhood cancer. Before this problem, we aimed to assess the performance of health teams in the identification of child and adolescent symptoms of cancer in primary care, through the action research methodology, which includes the teaching-learning, seminars, describing the actions of the group and discussing the activities after the training. This study involved thirty-seven health professionals who provide care for children and adolescents in the USF Felipe Shrimp II, the Support Center for Children with Cancer and the pediatric hospital UFRN during the period from March to December 2010. The data were analyzed simultaneously to evaluate actions, following the direction of the analysis of ideas Freires, having as theoretical reference the primary health care. The diagnosis of current reality, as knowledge of the health team targeted for early identification of signs and symptoms raised through questioning, presented as generative themes: resistance to change, awareness of the need for apprehension of knowledge; prior knowledge through the media, fragmentation of the healthcare network, interfering with the operation of the reference and counter, the stigma of death, among others. The selected themes enabled the choice of content for the preparation of four seminars, such as implementation of collective action for discussion problematical. The teaching-learning process has allowed the study participants awareness of the problem and work through the knowledge acquired by interfering in decreasing the time interval between the identification of signs and symptoms of cancer and early specialist treatment. Their difficulties we are faced with a diagnosis of terminal cancer and associated with delayed access to laboratory tests and imaging necessary for the diagnosis of neoplasms. Thus, we find that when the team is consciously involved in the education process from identification of the problem situation, there may be significant changes in daily activities through awareness of being. However, we also realize that acquisition of knowledge and interest of the team are not enough, since to be efficiency of our service, we need an organization of cancer care network operating in the state of Rio Grande do Norte

Avaliação clínica da saúde bucal de crianças com neoplasias malignas atendidas no Hospital Infantil Varela Santiago em Natal-RN

The childhood cancer is characterized by a predominance of hematogenic and lymphatic system neoplasm, although a fTequency of the central nervous system tumors and sarcomas are widely common. Particularities of many childhood cancers and the adverses effect of the antineoplastic agents can change radically the oral environrnent and predisposes to the risk of oral complications. This study assessment clinically the oral health of 40 children on treatment for different types of malignant neoplasm with age range of O to 1S years old (Group I) and compared to 38 nonnal children in the same age range (Group lI). The results shown that nonnal patients had a gingival bleeding index (GBI) and caries experience minar than patients of Group lI, the visivel plaque index (VPI) was lightly higher in patients of Group 1. There was not difference statistically significant in the variables. Sixteen patients of Group I developed together 61 oral complications with predominance of mucositis, followed by spontaneous oral bleeding, candidiasis and xerostomy, that complication were most commons in patients with systemic neoplasm. Its was concluded that patients submitted to antineoplastic therapy with poor oral health had a higher risk to develop oral complications

Percepção de estigma e qualidade de vida em crianças com neoplasia

The increase in survival time and cure requires more extensive care about the quality of life of cancer patients, which begins soon after diagnosis. Thus, it seems reasonable to the emphasis on development of studies covering the psychosocial variables, such as stigma, treatment of childhood cancer aiming thereby to the attention of the overall needs of the child. Thus, this research aims to investigate the perception of stigma and quality of life in children with cancer. This is a cross-sectional research and understanding of the descriptive type, the type specimen being adopted for convenience. This consisted of thirty children with cancer and thirty children without chronic disease. The instruments used were the Quality of Life Questionnaire, the Perceived Stigma Scale and Technical Drawing Story with a Theme. The results indicate that the chronic condition, no interfered significantly in satisfaction with the quality of life in children with cancer and identified that the quality of life is not related to the stigma. Comparison with children with no chronic disease with infants with cancer, no significant differences were observed. However, the group mean contrast was lower, suggesting a greater impairment in quality of life of children with cancer compared to those without chronic disease. It is worth noting that the psychosocial effects and the limitations imposed by disease and treatment are presented as important factors in the design mode of subjective manifestations of children with cancer. Therefore, it is expected that knowledge elucidated by this study will assist, greatly to the promotion of improved emotional, biological and social development itself and the involvement of children with cancer treatment

Experiências maternas de perda de um filho com câncer infantil: uma compreensão fenomenológico-existencial

Death due to childhood cancer reflects an early outcome of life, which can cause a strong repercussion in the mother s existence - figure to whom the greatest part of responsibilities during the child s illness is commonly allocated. The aim of this study is to understand the experience of mothers who have lost a kid as a consequence of childhood cancer, approaching the personal senses of this fact. Following a qualitative research design, with an exploratory and comprehensive approach, the study used the narrative method, which was obtained from a semi-structured interview, as the data generation procedure. The research counted on the participation of three adult mothers who had lost their kids because of childhood cancer, after - at least - a six-month period of oncologic treatment. The proposal of analysis follows the parameters of the phenomenological method and the data are based on Martin Heidegger s existential analytic. The results were structured into three thematic axes: previous History, child illness and its repercussions; The network of support and care; Loss and after loss: facing and signifying. It was possible to comprehend that the emergence of cancer in childhood promotes, since the diagnosis, a disruption of everyday meanings, accentuating the fragile condition of human life. In this specific circumstance of childhood illness, all the participants restricted their possibilities of being-in-the-world, dedicating exclusively to the practice of maternity. Concerning their relationship with their children in treatment, the narratives unveiled, in a convergent manner, the existence of care in a substitutive mode. In the network of support - primarily constituted by family, the health team and the support institutions - the relations were marked by proximity and detachment movements. With the child s death, mothers began to live a way of being-with the absent child , ensuring the continuity of the relationship with the dead infant. From the results exposed above, we can understand the motherly mourn as a singular experience in constant resignification, in which the subjective time overlaps the cronological time. The increment of anguish, resulting from the mother s confrontation to the question of finitude, mobilizes a process of change in their way of being-in-the-world, promoting an openness to new possibilities in their lives. Singular attention to the mother, during the process of illness and child loss, turns out to be fundamental

Genotoxicity of cigarette smoking in maternal and newborn lymphocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ventricular systolic reserve in asymptomatic children previously treated with low doses of anthracyclines: A longitudinal, prospective exercise echocardiography study

Background: The time course of mild cardiotoxicity induced by anthracycline remains unknown. The aim of this study was to evaluate the long-term evolution of decreased myocardial reserve in children previously treated with a cumulative dose of anthracycline up to 100mg/m 2. Patients and Methods: Twenty-seven asymptomatic cancer survival patients (25 with lymphoblastic leukemia), in continuous remission and off treatment for >12 months with no alterations in conventional echocardiograms were evaluated by exercise echocardiography at 37±15.4 months (T1) and 101±24 months (T2) after finishing treatment (ADRIA group). This group was compared with 25 healthy individuals (control group) similar to the ADRIA group with respect to age and body surface area (BSA). All individuals underwent treadmill exercise testing according to Bruce protocol. Echocardiograms were performed before and immediately after exercise. Results: The groups were similar regarding cardiac structure and left ventricular (LV) systolic function at rest at T1 and T2. The growth of LV posterior wall thickness related to BSA was lower in the ADRIA group at T2. Post exercise, smaller LV ejection indexes and attenuated changes in the afterload in ADRIA group were observed at T1 and T2. Conclusion: The decreased systolic reserve induced by a low dose of anthracycline in asymptomatic children and adolescents remains unaffected over a 5-year period, suggesting that positive outcomes in chronic cardiotoxicity would be expected in patients with mild impairment after anthracycline treatment. © 2011 Wiley Periodicals, Inc.

Análises moleculares da região controle do DNA mitocondrial de astrocitomas na população paraense

O câncer do sistema nervoso central representa 2% de todas as neoplasias malignas na população mundial e 23% dos casos de câncer infantil. No Brasil, estimam-se 4.820 casos deste câncer em homens e 4.450 em mulheres para o ano de 2012. Os gliomas são tumores do sistema nervoso central formados a partir de células da glia e somam mais de 70% do tumores cerebrais. A propriedade mais importante dos gliomas é sua capacidade de evasão imunológica. Idade, etnia, gênero e ocupação podem ser considerados fatores de risco para o surgimento de gliomas, e são duas vezes mais frequentes em afro-americanos. O astrocitoma é o tumor glial mais frequente, constituindo cerca de 75% dos casos de gliomas. Estes tumores são classificados em quatro graus, de acordo com a Organização Mundial de Saúde. O DNA mitocondrial está relacionado com o desenvolvimento e a progressão de vários tipos de tumores. A mitocôndria é responsável pelo balanço energético celular e está envolvida no disparo da apoptose em resposta ao estresse oxidativo. Mutações na D-LOOP podem alterar a taxa de replicação do DNA e aumentar o risco do desenvolvimento do câncer. Neste estudo foram analisadas 29 amostras de astrocitoma classificados de acordo com a OMS. Nossos dados sugerem que os astrocitomas de baixo grau podem estar relacionados à herança genética, tornando portadores de alguns polimorfismos ou mutações específicas, mais suscetíveis ao risco de desenvolver a doença, e os de alto grau podem estar relacionados à exposição prolongada aos agentes carginógenos. Foram identificados polimorfismos e mutações onde alguns apresentaram relação com o risco do desenvolvimento de astrocitomas e com a progressão da doença. A inserção de dois ou mais nucleotídeos nas regiões de microssatélites pode causar sua instabilidade e contribuir com o surgimento do câncer. A deleção no sítio 16132 pode ser um marcador para astrocitoma de alto grau, assim como a inserção de duas ou mais citosinas no sítio 16190 pode ser um marcador específico para astrocitomas. As mutações heteroplásmicas podem ser determinantes para o surgimento e/ou progressão de astrocitomas de alto grau.

DNA-Reparatur-assoziierte genetische und epigenetische Faktoren für die Zweittumorentstehung nach Tumoren im Kindes- und Jugendalter

Die Ursachen der Zweittumorentwicklung bei Personen, die eine Krebserkrankung in der Kindheit überlebten, sind weitgehend unklar. Strahlenexposition oder Chemotherapie führen in normalen somatischen Zellen zu DNA-Schäden, welche bei fehlerhafter Reparatur eine Karzinogenese auslösen können. Es ist denkbar, dass genetische Unterschiede z. B. in den Signalwegen der Zellzykluskontrolle und der DNA-Reparatur nach therapieinduzierten DNA-Schäden eine entscheidende Rolle bei der Zweittumorentwicklung spielen. Im Rahmen dieser Arbeit wurden 20 Personen, die eine Krebserkrankung in der Kindheit überlebten und einen unabhängigen Zweittumor entwickelten, mit 20 gematchten Kontrollpersonen ohne Zweittumorentwicklung verglichen. Die primären Fibroblasten der Patienten wurden auf somatische, genetische und/oder epigenetische Unterschiede in DNA-Reparaturnetzwerken untersucht. Die biologisch relevantesten Ergebnisse lieferten Proteinuntersuchungen mittels Antikörper-Microarrays. Hierbei wurde eine konstitutiv erniedrigte Menge an RAD9A und einigen anderen DNA-Reparatur-Proteinen (BRCA1, DDIT3, MSH6, p53, RAD51) in den Zweittumorpatienten im Vergleich zu den Eintumorpatienten festgestellt. Nach einer DNA-Schädigung durch 1 Gray Bestrahlung erhöhte sich die RAD9A-Proteinmenge, wobei die Zweittumorpatienten eine geringere Induktion als die Eintumorpatienten zeigten. Bei der Quantifizierung der mRNA-Expression mittels RTq-PCR wurde ein niedrigerer RAD9A-mRNA-Level sowohl in den unbehandelten und als auch in den 1 Gray bestrahlten Zellen der Zweittumorpatienten festgestellt. SNP-Array und Methylierungsanalysen konnten keine Auffälligkeiten im RAD9A-Lokus nachweisen. Diese Ergebnisse unterstützen die Hypothese, dass Modulationen von RAD9A und anderen Zellzyklusarrest- und DNA-Reparaturproteinen zum Risiko einer Zweittumorentwicklung in Kinderkrebspatienten beitragen. Bei einem diskordanten monozygoten Zwillingspaar wurde in ca. 20% der Zellen des Zweittumorzwillings eine Hypermethylierung des Tumorsuppressorgens BRCA1 festgestellt, die mit einer konstitutiv erniedrigten BRCA1-Proteinexpression einhergeht und einen möglichen Krebsrisikofaktor darstellt. Die partielle Deletion des Gens RSPO3, die wahrscheinlich als somatisches Zellmosaik beim Zweittumorzwilling vorliegt, korreliert mit einer niedrigeren RSPO3-mRNA-Expression und ist vermutlich auch mit einer erhöhten Krebsprädisposition assoziiert.

Practices of pediatric oncology and hematology providers regarding fertility issues: A European survey.

BACKGROUND Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe. PROCEDURES On behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation. RESULTS One hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions. CONCLUSIONS There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility. Pediatr Blood Cancer 2014;9999:1-5. © 2014 Wiley Periodicals, Inc.

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children

AIM To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. PATIENTS & METHODS Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. RESULTS Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). CONCLUSION Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

Identification of genetic risk factors for cerebellar mutism in pediatric brain tumor patients

Following posterior fossa surgery for resection of childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET), cerebellar mutism (CM) may develop. This is a condition of absent or diminished speech in a conscious patient with no evidence of oral apraxia, which can be accompanied by other symptoms of the posterior fossa syndrome complex, which includes ataxia and hypotonia. Little is known about the etiology. Therefore, we conducted a SNP, gene, and pathway-level analysis to assess the role of host genetic variation on the risk of CM in M/PNET subjects following treatment. Cases (n= 20) and controls (n= 53) were recruited from the Childhood Cancer Epidemiology and Prevention Center, in Houston, TX. DNA samples were genotyped using the Illumina Human 1M Quad SNP chip. Ten pathways were identified from logistic regression used to identify the marginal effect of each SNP on CM risk. The minP test was conducted to identify associations between SNPs categorized to genes and CM risk. Pathways were assessed to determine if there was a significant enrichment of genes in the pathway compared to all other pathways. There were 78 genes that reached the threshold of min P ≤0.05 in 948 genes. The Neurotoxicity pathway was the most significant pathway after adjusting for multiple comparisons (q=0.040 and q=0.005, using Fisher's exact test and a test of proportions, respectively). Most genes within the Neurotoxicity pathway that reached a threshold of minP ≤0.05 were known to have an apoptosis function, possibly inducing neuronal apoptosis in the dentatothalamocortical pathway, and may be important in CM etiology in this population. This is the first study to assess the potential role of genetic risk factors on CM. As an exploratory study, these results should be replicated in a larger sample. ^

ATTITUDES AND PRACTICES OF GENETIC COUNSELORS IN PROVIDING PREDICTIVE TESTING TO MINORS AT RISK FOR LI-FRAUMENI SYNDROME

Li- Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome caused by mutations in the TP53 gene that predisposes individuals to a wide variety of cancers, including breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, and adrenocortical carcinomas. Individuals found to carry germline mutations in TP53 have a 90% lifetime cancer risk, with a 20% chance to develop cancer under the age of 20. Despite the significant risk of childhood cancer, predictive testing for unaffected minors at risk for LFS historically has not been recommended, largely due to the lack of available and effective screening for the types of cancers involved. A recently developed screening protocol suggests an advantage to identifying and screening children at risk for LFS and we therefore hypothesized that this alongside with the availability of new screening modalities may substantiate a shift in recommendations for predictive genetic testing in minors at risk for LFS. We aimed to describe current screening recommendations that genetic counselors provide to this population as well as explore factors that may have influenced genetic counselors attitude and practice in regards to this issue. An online survey was emailed to members of the National Society of Genetic Counselors (NSGC) and the Canadian Association of Genetic Counsellors (CAGC). Of an estimated 1000 eligible participants, 172 completed surveys that were analyzed. Genetic counselors in this study were more likely to support predictive genetic testing for this population as the minor aged (p

Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia

The TEL (ETV6)−AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in ≈25% of the most predominant subtype of leukemia— common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia.