Germline mutations in pediatric cancer cohort with mixed-ancestry Mexicans.

BACKGROUND: Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. METHODS: We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. RESULTS: We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. CONCLUSIONS: This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.

Costs associated with adverse events from remission induction for children with Acute Lymphoblastic Leukemia (ALL).

BACKGROUND: ALL is the most frequent hematological tumor in children, so during remission induction chemotherapy protocol (RICP) adverse events (AEs) may appear. The public program in Mexico in charge of financial support to oncologic children without social security delivered a fix amount for ALL chemotherapy, but additional money needed to treat any other unexpected condition should be taken from the budget of the oncologic healthcare providers. So the purpose of our study was to estimate and evaluate the direct medical costs associated to EAs during RICP in children with ALL. METHODS: This study was retrospective, longitudinal, and observational based on medical records review of patients in RICP. The CTCAE was used to identify and classify AEs according to a SOC category. We focused on extracting resources data that were consumed both for inpatients and outpatients AEs. A micro-costing approach was adopted which involve quantification of each healthcare resource consumed by the hospital multiplying them by unit cost. The probability distributions of data were evaluated to identify the appropriated statistical tests to be used for comparisons between groups that were performed with Wilcoxon rank sum test. Generalized linear models (GLM) were adjusted to evaluate the effects of patient characteristics on total cost. RESULTS: Forty patients accumulated 204 inpatient and 81 outpatient AEs during RICP. Comparison of total costs between groups showed an incremental cost of $7,460.23 likewise attributable to AEs. The total cost of a pediatric patient undergoing RICP without adverse events was $3,078.36 and the total cost of a patient with AEs exceeds it threefold. CONCLUSIONS: The costs associated with AEs during RICP in Mexican children with ALL representing a high burden for the healthcare provider. Generalized linear models showed that variables such as sex, risk category and alive status are associated with the total costs of AEs. This is the first study aiming to analyze the effect of ALL-related AEs on health care costs in pediatric population, so our results may help not only to local decision making but also it may contribute to the research agenda in this field.

Decision-Making at End-of-Life for Children With Cancer: A Systematic Review and Meta-Bioethical Analysis.

BACKGROUND: Evidence shows that medical education includes a variety of basic and clinical skills. Ethical and human values are not typically considered in medical school curricula, and this is evident in medical practice in certain scenarios such as decision-making at pediatric cancer patients' end of life. METHODS: This study explores a bioethical approach to address complex decision-making at the end of life in children and adolescents with cancer. We are a cross-functional group of scientists from several academic disciplines who conducted a systematic review of the literature using our newly developed meta-bioethical analysis and synthesis of findings. The search was carried out in five databases, resulting in 10 research papers. Following quality screening, seven articles were ultimately selected for further analysis. RESULTS: Our focus is on the state of the art to better understand the bioethical deliberation at the end of life in pediatric oncology. Here, we report a systematic review that includes (i) classification of the screened articles by the type of decision-making they use, ii) the system values that are at the core of the decision-making at the end of life, and iii) bioethical and ethical discernment queries. We conclude with a discussion regarding the best practices of ethical discernment and decision-making at the end of life.This study highlights the need to develop more research to better understand the influence and origin of these multidimensional factors determining critical decisions that define the quality of life of patients in a highly sensitive moment. CONCLUSION: We conclude that personal aspects of the physician define their actions more than knowledge or organized structure. It is thus necessary that pediatric oncologists receive ethics and humanistic education.

Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma.

There is evidence that high circulating levels of IL-6 and IL-8 are markers of a poor prognosis in various types of cancer, including NB. The participation of these cytokines in the tumor microenvironment has been described to promote progression and metastasis. Our objective was to evaluate the prognostic role of genetic polymorphisms and serum levels of IL-6 and IL-8 in a cohort of Mexican pediatric patients with NB. The detection of the SNPs rs1800795 IL-6 and rs4073 and rs2227306 IL-8 was carried out by PCR-RFLP and the levels of cytokines were determined by the ELISA method. We found elevated circulating levels of IL-8 and IL-6 in NB patients compared to the control group. The genotype frequencies of the rs1800795 IL-6 and rs4073 IL-8 variants were different between the patients with NB and the control group. Likewise, the survival analysis showed that the GG genotypes of rs1800795 IL-6 (p = 0.014) and AA genotypes of rs4073 IL-8 (p = 0.002), as well as high levels of IL-6 (p = 0.009) and IL-8 (p = 0.046), were associated with lower overall survival. We confirmed the impact on an adverse prognosis in a multivariate model. This study suggests that the SNPs rs1800795 IL-6 and rs4073 IL-8 and their serum levels could be promising biomarkers of a poor prognosis, associated with overall survival, metastasis, and a high risk in Mexican children with NB.

Genomics of a pediatric ovarian fibrosarcoma. Association with the DICER1 syndrome.

Ovarian fibrosarcomas are extremely rare tumors with little genomic information available to date. In the present report we present the tumoral exome and transcriptome and the germinal exome of an ovarian fibrosarcoma from a 9-years old child. We found a paucity of mutations (0.77/Mb) and CNV alterations. Of these, the most relevant were a point mutation in the metal-binding site of the microRNA-processing DICER1 enzyme and a frame-shift alteration in the tumor suppressor gene NF1. We validated a germinal truncating mutation in DICER1, which was consistent with a DICER1 Syndrome diagnosis, providing the first example of an ovarian fibrosarcoma as the presenting neoplasia in this syndrome. Network and enrichment analyses showed that both a mesenchymal signature and a Hedgehog cascade could be driving the progression of this tumor. We were also able to find a global lincRNA deregulation, as the number of lincRNAs transcripts expressed in the tumor was decreased, with a concomitant upregulation of previously described non-coding transcripts associated with cancer, such as MALAT1, MIR181A1HG, CASC1, XIST and FENDRR. DICER1 Syndrome should be considered as a possible diagnosis in children ovarian fibrosarcoma. The role of lncRNAs in neoplasias associated with DICER1 alterations need to be studied in more detail.

Neoplasias malignas en el neonato / Malignant neoplasms in the neonate

El cáncer en la edad pediátrica presenta características que lo diferencian de otros tipos reportados en edades posteriores. La supervivencia global a 3 años es de hasta el 70%, dependiendo de la neoplasia estudiada. Los principales aparatos y sistemas afectados son el sistema hematopoyético, el sistema nervioso central y simpático, así como tejidos mesenquimatosos. El incremento en la incidencia de tumores neonatales observado en este y otros estudios se basa en el aumento del número de tumores sólidos (teratomas y neuroblastomas), ya que los casos de tumores en el sistema nervioso central y leucemias han permanecido constantes. La ultrasonografía es la primera línea de abordaje y puede detectar hasta el 70% de las anomalías fetales. La fisiología del neonato hace que el tratamiento multidisciplinario necesario en las enfermedades neoplásicas sea modificado sustancialmente en este grupo de edad, para evitar toxicidad y secuelas. El tratamiento más utilizado es la cirugía. Logrando el diagnóstico oportuno existen opciones terapéuticas efectivas para mejorar la supervivencia de estos pacientes.

Cancer in children has characteristics that differentiate it from other types reported in later ages. Overall survival at 3 years is up to 70% depending on the tumor studied. Major organs and systems affected are the hematopoietic system, central nervous system and sympathetic and mesenchymal tissues. The increased incidence of neonatal tumors observed in this and other studies is based on the increasing number of solid tumors (teratomas and neuroblastomas) because cases of central nervous system tumors and leukemias have remained constant. Ultrasonography is the first line of approach and can detect up to 70% of fetal anomalies. The physiology of the newborn causes the necessary multidisciplinary treatment in neoplastic disease to be modified substantially in this age group to avoid toxicity and sequelae. The most common treatment is surgery. Achieving timely diagnostic treatment options are effective in improving the survival of these patients.

[Malignant neoplasms in the neonate]. / Neoplasias malignas en el neonato.

Cancer in children has characteristics that differentiate it from other types reported in later ages. Overall survival at 3 years is up to 70% depending on the tumor studied. Major organs and systems affected are the hematopoietic system, central nervous system and sympathetic and mesenchymal tissues. The increased incidence of neonatal tumors observed in this and other studies is based on the increasing number of solid tumors (teratomas and neuroblastomas) because cases of central nervous system tumors and leukemias have remained constant. Ultrasonography is the first line of approach and can detect up to 70% of fetal anomalies. The physiology of the newborn causes the necessary multidisciplinary treatment in neoplastic disease to be modified substantially in this age group to avoid toxicity and sequelae. The most common treatment is surgery. Achieving timely diagnostic treatment options are effective in improving the survival of these patients.

Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia.

BACKGROUND: Interleukin-1 receptor antagonist polymorphism (ILRN) 2 (ILRN*2) has been associated with a poor outcome in septic patients because of an elevated production of anti-inflammatory cytokines. In >70% of patients, morbidity and mortality in childhood acute lymphoblastic leukemia is caused by infections. The aim of this study was to determine the association between this polymorphism and the frequency of septic shock from the time of diagnosis until completion of treatment. METHODS: This cohort study was conducted in 57 consecutive children with acute lymphoblastic leukemia. At the end of follow-up, children were stratified according to their IL1RN polymorphism (ILRN*1/ILRN*2), evaluating the impact of genotype on the severity of febrile neutropenic events during their treatment. RESULTS: Overall survival was 80% at 55 months after treatment. The average number of febrile neutropenic events in this cohort was 2.82 per patient. Genotype distribution was 50.9% for homozygote IL-1RN*1, 38.6% for heterozygote ILRN*1/ILRN*2 and 10.5% for homozygote IL-1RN*2. The risk of presenting septic shock for homozygote IL1RN*2/IL1RN*2 and heterozygote ILRN*1/ILRN*2 patients was significantly greater (odds ratio, 45; P = 0.001) adjusted for age, gender, risk of leukemia and presence of pathogenic bacteria. Genotype IL-1RN*2 is associated with the risk of development of septic shock in children with acute lymphoblastic leukemia. Further research in larger population-based studies is needed to replicate these findings. CONCLUSIONS: This information would allow us to identify more predictive factors in this group of acute lymphoblastic leukemia patients in whom this information is lacking to establish an earlier and more aggressive approach.

Síndrome de Pierre-Robin y hepatoblastoma: reporte de un caso / Pierre-Robin syndrome and hepatoblastoma: a case report

Introducción. La secuencia de Pierre-Robin (SPR) es una afección congénita caracterizada por micrognatia, glosoptosis y fsura del paladar blando. La prevalencia es 1:8500 recién nacidos (RN) vivos. El hepatoblastoma (HB) es el tumor maligno primario de hígado más frecuente en pediatría. Afecta niños menores de 3 años. Caso clínico. Se trata de un paciente masculino de 2 años de edad, producto de la gesta II, de término, obtenido por cesárea, peso al nacer de 2, 750 g, con diagnóstico de SPR. A los 2 años se detecta masa abdominal dependiente de hígado. Se diagnostica HB, por lo que requiere quimioterapia y cirugía (lobectomía izquierda). A 5 años de seguimiento está vivo sin actividad tumoral. Conclusiones. La asociación de SPR y HB no se encontró reportada previamente en la literatura. Ambas presentan alteraciones en el cromosoma 2. Dado que el cáncer cursa con alteraciones citogenéticas, debemos de establecer asociaciones entre aquellos pacientes que cursan con síndromes genéticos. Esto permite evaluar blancos moleculares útiles y diseñar terapias dirigidas. También permite detectar poblaciones de riesgo de padecer cáncer y crear programas de seguimiento y evaluación que permitan una detección temprana para mejorar la sobrevida de dichos grupos. Se trata del primer caso de asociación entre estas dos patologías reportado en nuestro instituto y en el mundo.

Background. Pierre-Robin Sequence (PRS) is a congenital disease characterized by micrognatia, glosoptosis and U-shaped posterior cleft palate. Its prevalence is 1:8500 newborns. Hepatoblastoma (HB) is the most frequent hepatic malignant tumor in childhood and affects patients <3 years of age. Case report. A 2-year old male with PRS was diagnosed with HB. The boy was the product of the second full term pregnancy. He was born by cesarean with a birth weight of 2750 g. The patient presented with a 1-month history of abdominal mass. Diagnosis of HB was done by biopsy. The patient received chemotherapy with cisplatin, vincristin and 5-fuorouracil as well as left lobectomy. Five years later he is alive without tumor activity. Conclusions. PRS and HB association has not been reported in the literature. Both entities have chromosome 2 alterations. Because cancer is associated with cytogenetic alterations, future considerations must be made to fnd a relationship between cancer patients and other genetic entities. This will be useful for fnding molecular targets. We can also detect the at-risk population in order to create follow-up programs that will allow an early diagnosis with an improved better survival. It is the frst case of PRS and HB reported in either the national or international literature.

Calidad de vida en niños con leucemia linfoblástica aguda durante la inducción a la remisión mediante el PedsQL Cancer Module© / Quality of life in children with acute lymphoblastic leukemia during induction therapy with PedsQL Cancer Module©

Introducción. Con los tratamientos disponibles en la actualidad, más de 80% de los niños con leucemia aguda linfoblástica (LAL) pueden sobrevivir. En general, y específicamente en nuestra institución, no se conoce bien la calidad de vida (CV) de estos niños. El objetivo de este estudio fue medir la CV en niños durante la inducción a la remisión (primera fase del tratamiento) con el PedsQL Cancer Module©. Métodos. Se realizaron 2 mediciones a niños con LAL de diagnóstico reciente. Se incluyeron 26 pacientes estables de 2 a 18 años de edad con LAL, a las 2 semanas y a los 2 meses del diagnóstico. Se dividieron en 4 grupos: 2-4, 5-7, 8-12 y 13-18 años. Resultados. Se determinó que la CV se modificó al finalizar la inducción a la remisión. En la segunda medición se observó mejor CV con relación a un proceso de posible adaptación al tratamiento, así como por mejoría de los síntomas relacionados a la enfermedad. Conclusión. El PedsQL Cancer Module© fue útil para medir la CV y detectar cambios en los niños con LAL en inducción a la remisión.

Introduction. Survival of children with acute lymphoblastic leukemia (ALL) is 80% in accordance with actual protocols. We ignore quality of life (QoL) during these chronic treatments, especially in our institution. The aim of this pilot study was to measure QoL in stable children with ALL during the first part of treatment (induction therapy) with PedsQL Cancer Module©. Methods. We made two measurements in children with recent diagnosis of ALL and determined changes in the QoL between the beginning and the end of induction therapy. We included 26 patients from 2 to 18 years of age with ALL, at 2 weeks and 2 months after diagnosis, and divided them into four groups: 2-4, 5-7, 8-12, and 13-18 years of age. Results. In the second measurement, we observed a better QoL in relation to an adaptation process in the child and remission of symptoms. Conclusions. PedsQL Cancer Module© was a useful instrument for measuring QoL and detected changes in children with ALL during induction therapy.

Enterocolitis neutropénica en niños: una serie de casos de autopsias / Neuropenic enterocolitis in children: a case series of autopsies

Introducción. La enterocolitis neutropénica (EN) es un hallazgo frecuente en autopsias de niños con leucemia o algún otro padecimiento causante de neutropenia primaria o secundaria. En este estudio se describen las características clinicopatológicas de 32 casos de autopsia.Material y métodos. De las autopsias realizadas de enero de 1983 a diciembre de 1998 se revisaron las que tenían diagnóstico de neoplasias malignas, enfermedades hematológicas, deficiencias inmunológicas y trasplante. Los datos clínicos se obtuvieron de los expedientes.Resultados. Se encontraron 32 casos con EN: 20 casos (62.5 por ciento) tenían leucemia aguda; 18 fueron del sexo femenino y 14 del masculino, las edades variaron entre 18 meses y 18 años. La cifra de leucocitos en 30 casos fue de 100 a 6 300/mm3 y los neutrófilos totales en 13 casos de 100 a 1 296; 81 por ciento había recibido quimioterapia dentro de los 30 días anteriores. El cuadro final de estos pacientes incluyó: fiebre en 26 casos, diarrea en 16, vómitos en 12, dolor abdominal en 11, sangre en heces en 9 y distensión abdominal en 6. Los segmentos del aparato digestivo afectados con mayor frecuencia fueron: colon, íleon terminal y ciego. Los gérmenes aislados con mayor frecuencia de los cultivos post mortem fueron: Klebsiella pneumoniae, Pseudomonas aeruginosa y Escherichia coli. En la mayoría de los casos se atribuyó la muerte a septicemia y mielosupresión.Conclusión. Como se ha mostrado en estudios similares, las leucemias agudas en niños son las enfermedades que se asocian con mayor frecuencia a EN. En este estudio se encontró que las alteraciones en la médula ósea son graves y están relacionadas con la enfermedad principal o su tratamiento. Es necesario realizar estudios prospectivos para evaluar el efecto de los diversos factores que intervienen en la patogénesis de EN.

Quimioterapia neoadyuvane en pacientes pediátricos con hepatoblastoma: experiencia del Hospital Infantil de México Federico Gómez / Neoadyuvante chemotherapy in children with hepatoblastoma: the Hospital Infantil de Mexico experiences

Introducción. El hepatoblastoma (HB) es la neoplasia maligna de hígado más frecuente en pediatría. Antes de la década de los noventas, la sobrevida de los pacientes con HB era inferior al 25 por ciento. La introducción de quimioterapia neoadyuvante (QTN) en el tratamiento del HB ha facilitado su manejo quirúrgico, disminuyendo la mortalidad perioperatoria e incrementando la sobrevida a más de 70 por ciento. Material y métodos. Siete pacientes con diagnóstico histológico de HB fueron incluidos en el estudio para evaluar el papel de la QTN como parte esencial del tratamiento y valorar la utilidad de la alfafetoproteína (AFP) y colesterol como indicadores de respuesta, al correlacionarlos con la respuesta clínica, tomográfica e histopatológica. Se administraron 4 ciclos de QTN con cisplatino, 5 fluoracilo y vincristina, seguidos de resección quirúrgica del tumor primario y 2 ciclos de quimioterapia posterior a ésta. Resultados. Se obtuvo respuesta en todos los casos. La resección completa fue posible en 5. En 2 pacientes con grandes tumores sólo hubo respuesta parcial, siendo necesario modificar el esquema de tratamiento; la mala respuesta se correlacionó con niveles séricos persistentemente elevados de AFP y colesterol. Conclusión. La QTN demostró ser el tratamiento de elección para los tumores primarios de hígado, ya que permite obtener resecciones completas en tumores inicialmente irresecables, controlar metástasis y evaluar quimiosensibilidad. El colesterol se relacionó con la respuesta obtenida a QTN. Hepatoblastoma; quimioterapia neoadyuvante; indicadores de respuesta.

Ciclofosfamida a dosis escaladas en tumores sólidos malignos en población pediátrica: Experiencia en el Hospital Infantil de México Federico Gómez / Cyclophosphamide dose escalation in solid tumors in children

Introducción. La ciclofosfamida a dosis escaladas incrementó su citotoxicidad en tumores sensibles a ésta, sin aumento de sus efectos tóxicos. Material y métodos. Se evaluaron 50 pacientes con tumores sólidos, en los que se utilizó ciclofosfamida en dosis escaladas de 2.5 g hasta 4.5 g/m² de superficie corporal como esquema de primera línea o de rescate, con uroprotector y factor estimulante de colonia en cada ciclo. La toxicidad y la respuesta fueron basadas en criterios de la Organización Mundial de la Salud. Resultados. Los diagnósticos más frecuentes fueron tumores del sistema nervioso central y retinoblastoma con 18 y 9 pacientes respectivamente. Cuarenta y cinco pacientes (90 por ciento) presentaron respuesta a quimioterapia, ya sea completa (72 por ciento) o parcial. Sólo en 5 pacientes no hubo respuesta. Se presentaron 3 episodios de cistitis hemorrágica. Conclusiones. Se comprobó que la ciclofosfamida a dosis escalada es activa en un grupo heterogéneo de pacientes con tumores sólidos y que esta modalidad terapéutica no incrementa el riesgo de toxicidad