Effect of N-Acetylcysteine on Cisplatin Toxicity: A Review of the Literature.

N-acetylcysteine (NAC) is a membrane-permeable cysteine precursor capable of enhancing the intracellular cysteine pool, enhancing cellular glutathione (GSH) synthesis, and thus potentiating the endogenous antioxidant mechanism. Late administration of NAC after cisplatin has been shown in different in vivo studies to reduce the side effects caused by various toxicities at different levels without affecting the antitumor efficacy of platinum, improving total and enzymatic antioxidant capacity and decreasing oxidative stress markers. These characteristics provide NAC with a rationale as a potentially effective chemo protectant in cisplatin-based therapeutic cycles. NAC represents a potential candidate as a chemoprotective agent to decrease toxicities secondary to cisplatin treatment. It suggests that it could be used in clinical trials, whereby the effective dose, timing, and route should be adjusted to optimize chemoprotection. This review provides an overview of the effect of NAC on cisplatin toxicity, a drug widely used in the clinic in adults and children.

Haploidentical bone marrow transplantation in Mexico.

Haploidentical hematopoietic cell transplantation using CD34(+) cells depleted of T lymphocytes by the CliniMACS is a treatment for hematological malignancy. We report on four Mexican children, three with acute lymphocytic leukemia and one with chronic myelocytic leukemia, who was transplanted with 12 × 10(6) CD34(+) stem cells/kg body weight (98% of purity) with a follow-up of 9½ years. The engraftment was successful in three of the four children. All showed cytomegalovirus reactivation, and one died because of graft rejection and infectious complication. The risk of infections was a major problem.

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology.

BACKGROUND: Worldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City. METHODS: Included in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level). RESULTS: Although a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02). CONCLUSIONS: The frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica.

Father's occupational exposure to carcinogenic agents and childhood acute leukemia: a new method to assess exposure (a case-control study).

BACKGROUND: Medical research has not been able to establish whether a father's occupational exposures are associated with the development of acute leukemia (AL) in their offspring. The studies conducted have weaknesses that have generated a misclassification of such exposure. Occupations and exposures to substances associated with childhood cancer are not very frequently encountered in the general population; thus, the reported risks are both inconsistent and inaccurate. In this study, to assess exposure we used a new method, an exposure index, which took into consideration the industrial branch, specific position, use of protective equipment, substances at work, degree of contact with such substances, and time of exposure. This index allowed us to obtain a grade, which permitted the identification of individuals according to their level of exposure to known or potentially carcinogenic agents that are not necessarily specifically identified as risk factors for leukemia. The aim of this study was to determine the association between a father's occupational exposure to carcinogenic agents and the presence of AL in their offspring. METHODS: From 1999 to 2000, a case-control study was performed with 193 children who reside in Mexico City and had been diagnosed with AL. The initial sample-size calculation was 150 children per group, assessed with an expected odds ratio (OR) of three and a minimum exposure frequency of 15.8%. These children were matched by age, sex, and institution with 193 pediatric surgical patients at secondary-care hospitals. A questionnaire was used to determine each child's background and the characteristics of the father's occupation(s). In order to determine the level of exposure to carcinogenic agents, a previously validated exposure index (occupational exposure index, OEI) was used. The consistency and validity of the index were assessed by a questionnaire comparison, the sensory recognition of the work area, and an expert's opinion. RESULTS: The adjusted ORs and 95% confidence intervals (CI) were 1.69 (0.98, 2.92) during the preconception period; 1.98 (1.13, 3.45) during the index pregnancy; 2.11 (1.17, 3.78) during breastfeeding period; 2.17 (1.28, 3.66) after birth; and 2.06 (1.24, 3.42) for global exposure. CONCLUSION: This is the first study in which an OEI was used to assess a father's occupational exposure to carcinogenic agents as a risk factor for the development of childhood AL in his offspring. From our results, we conclude that children whose fathers have been exposed to a high level of carcinogenic agents seem to have a greater risk of developing acute leukemia. However, confounding factors cannot be disregarded due to an incomplete control for confounding.

Early death in children with acute lymphoblastic leukemia: does malnutrition play a role?

The study aim was to correlate malnutrition and early death in children with acute lymphoblastic leukemia (ALL). A study was conducted in 100 consecutive children with ALL. An analysis included clinical and laboratory parameters as well as co-morbidity factors. Forty patients were standard risk and 60 high risk. Multivariate analysis showed variables of statistical importance, including female gender (p 010), ALL high-risk (p 04), and infection (p 036). Malnutrition (p 1.0) and poverty (p 0.5) did not influence. Early mortality was documented in 15/100 (15%) patients. The study shows that high-risk ALL and infection represent the leading causes of early mortality.

A greater birthweight increases the risk of acute leukemias in Mexican children-experience from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL).

In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case-control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency-matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight ≥2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight ≥3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight ≥2500 g and ≥3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03-1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight ≥4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight ≥3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children.

Toxicity prevention with amifostine in pediatric osteosarcoma patients treated with cisplatin and doxorubicin.

UNLABELLED: Amifostine has emerged as a pancytoprotectant shown protection against nephrotoxicity, neurotoxicity and ototoxicity in preclinical studies. METHODS: We designed a prospective comparative randomized trial to evaluate the cytoprotective effects of amifostine in patients with osteosarcoma receiving cisplatin and doxorrubicin. Patients were evaluated for renal, hearing and cardiac toxicity. RESULTS: We included 28 patients, mean age was 11.6 years, five had metastatic disease. Fifteen patients received amifostine and 13 did not. 20% of patients receiving amifostine developed renal toxicity compared to 30% in the control group (p = 0.318). Grade 1 and 2 audiologic toxicity was present in 100% of the experimental group against 85% of the controls (p = 0.501). Grade 1 cardiac toxicity was present in 2 patients in the control group (p = 0.175). There were no statistical significant differences between the two groups for chemotherapy-related toxicity. Response to chemotherapy was significantly better in the amifostine group. CONCLUSION: amifostine did not reduce the ototoxicity and nephrotoxicity of our treatment regime. It was not well tolerated due to emesis. It is a selective cytoprotectant without reducing the effect of chemotherapy.

[Medulloblastoma in pediatrics. Current prognosis and treatment]. / Meduloblastoma en pediatría. Pronóstico y tratamiento en la actualidad.

In Mexico, Central Nervous System (CNS) tumors are the third most common childhood cancers. Medulloblastoma constitutes 20% of the primary CNS tumors and 40% of all cerebellar tumors, the single most common brain tumor among children. It originates over the external granular layer that normally migrates from the vermis to the surface of the cerebellum hemispheres and from there to the deep portions of the internal granular layer. These tumors infiltrate profusely the cerebellar cortex. The dissemination process can occur through the spinal fluid with seeding along the subarachnoidal space and around the spinal chord They eventually produce metastasis mainly to bone, liver, and bone marrow. There is a group of well identified prognostic factors that are relevant for each individual patient and that can be applied for multidisciplinary treatment purposes. The objective of the present review is to emphasize on new research findings and the overall survival that can be achieved with modern treatment programs.

Early mortality in children with acute lymphoblastic leukemia in a developing country: the role of malnutrition at diagnosis. A multicenter cohort MIGICCL study.

The role of malnutrition at diagnosis as a predictor of early mortality in Mexican leukemia children remains controversial. The objective of present study was to investigate whether malnutrition was a predictor of early mortality during the first year of treatment in Mexican acute lymphoblastic leukemia (ALL) children through the first population-based study. A total of 794 newly diagnosed ALL pediatric patients from public hospitals of Mexico City were enrolled. A multivariate Cox proportional hazards regression model was constructed and adjusted by patient's age at diagnosis, gender, hospital of treatment, and socioeconomic status. Early mortality was high (12.1%) and malnutrition by different indicators was not associated with mortality at induction phase and at 6th month; a high risk of dying (RR = 2.08; 95% CI: 1.08-4.01) was observed in the group of malnourished children with a high-risk ALL.

[Molecular hemato-oncology and new specific treatment strategies for leukemia]. / La hemato-oncología molecular y las nuevas estrategias terapéuticas específicas en leucemia.

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Raralpha have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.

Corrigendum to "Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children".

[This corrects the article DOI: 10.1155/2016/4078215.].

Improved treatment results in Mexican children with acute myeloid leukemia using a Medical Research Council (MRC)-acute myeloid leukemia 10 modified protocol.

We analysed the results of three protocols from 1990 to 2005. Protocol I (1990-1996) consisted of a 2 year VAPA regime. Protocol II (1996-2003) on 1 year daunorubicin/cytarabine alternating with etoposide/cytarabine. Protocol III (2003-2005) on six cycles MRC AML 10 modified. Patients with de novo acute myeloid leukemia 0 to 18 years were included. Demographic and clinical characteristics were analysed. Patients with >100,000 leukocytes, M4 or M5 and primary CNS disease were considered high risk. We compared remission rate, overall and event-free survival. Descriptive statistics, chi square, Kaplan-Meier and long rank tests were used. One hundred forty-five patients were included, 46 in Protocol I; 60 in II and 39 in III. There were no differences in characteristics between groups, except for more low risk patients in Protocol II (61%vs. 43% and 41%. (p = 0.05). Remission rate for Protocol I was 52%, for II 50% and for III 92% (p = 0.0001). Relapse was 18, 30 and 35, respectively (p = 0.141). Five-year event-free survival was 17.9% +/- 6.6%, 15.5% +/- 4.1% and 43.5% +/- 4.1% (s.e) (p = 0.0002). Five-year overall survival was 19.5% +/- 8%, 17.2% +/- 5.9% and 51.2% +/- 4.1% (s.e) (p = 0.0002). The results were superior in the MRC-10 derived protocol.

Magnetic fields and acute leukemia in children with Down syndrome.

BACKGROUND: : We analyzed effects of exposure to magnetic fields on the expression of acute leukemia in children with Down syndrome (who have a 20-fold higher risk of leukemia). METHODS: : We performed a case-control study that included 42 children with both acute leukemia and Down syndrome as cases and 124 healthy children with Down syndrome as controls. We obtained demographic information concerning the children and took spot measurements of magnetic fields at each residence. RESULTS: : The odds ratio for direct measurements of magnetic fields >/=6.00 mG was 3.7 (95% confidence interval = 1.05-13.1). CONCLUSION: : The association between magnetic fields and leukemia in children with Down syndrome suggests the possibility of a causal role for magnetic fields in the etiology of leukemia among a genetically susceptible subgroup of children.

Neurocutaneous melanosis in association with the Dandy-Walker complex, complicated by melanoma: report of a case and literature review.

Neurocutaneous melanosis is a rare congenital neurocutaneous syndrome in which benign and malignant melanocytic tumors of the leptomeninges with large or numerous congenital melanocytic nevi develop. The Dandy-Walker malformation occurs as a broad posterior fossa with high insertion of the tentorium, hypoplasia or aplasia of the cerebellar vermis, and cystic dilation of the fourth ventricle communicating with the posterior fossa. Association of these entities is very unusual and only 10 previous reports were found in the literature. Our patient had multiple, medium-size to small melanocytic nevi present since birth. At 5 years of age the patient has intracranial pressure secondary to hydrocephalus. A diagnosis of Dandy-Walker malformation and suspected neurocutaneous melanosis was established after a skull computed tomography (CT) scan. Three months later the patient developed a right frontal tumor shown on the CT scan. The histologic finding was nevomelanocytic infiltration with strong pleomorphism. The tumor grew rapidly, producing neurogenic shock and death. The postmortem report indicated malignant melanoma.

Meduloblastoma en pediatría: pronóstico y tratamiento en la actualidad / Medulloblastoma in pediatrics: current prognosis and treatment

En México, los tumores del sistema nervioso central representan el tercer lugar de todas las neoplasias malignas. El meduloblastoma constituye 20% de los tumores primarios del sistema nervioso central y 40% de los que se originan en el cerebelo; es el tumor maligno más frecuente en la niñez. Su origen se sitúa en la capa granular externa, normalmente migra del vermis hacia la superficie de los hemisferios cerebelosos y de ahí hacia las porciones profundas para poblar la capa granular interna de las folias. Estos tumores infiltran difusamente a través de las capas moleculares de la corteza cerebelosa por debajo de la pía, similar a lo que ocurre normalmente en las etapas embrionarias. Se diseminan por la circulación del líquido cefalorraquídeo con siembras a lo largo del espacio subaracnoideo y alrededor de la médula espinal para eventualmente salirse del sistema nervioso central y diseminarse a hueso, hígado, médula ósea y otros sitios menos frecuentes. Existen en la actualidad factores pronósticos bien definidos, así como el concepto de tratamiento multidisciplinario que ha condicionado mejores expectativas de supervivencia. El objetivo de esta revisión es actualizar el conocimiento de este tipo de tumores en nuestro país, así como los resultados terapéuticos.

In Mexico, Central Nervous System (CNS) tumors are the third most common childhood cancers. Medulloblastoma constitutes 20% of the primary CNS tumors and 40% of all cerebellar tumors, the single most common brain tumor among children. It originates over the external granular layer that normally migrates from the vermis to the surface of the cerebellum hemispheres and from there to the deep portions of the internal granular layer. These tumors infiltrate profusely the cerebellar cortex. The dissemination process can occur through the spinal fluid with seeding along the subarachnoidal space and around the spinal chord They eventually produce metastasis mainly to bone, liver, and bone marrow. There is a group of well identified prognostic factors that are relevant for each individual patient and that can be applied for multidisciplinary treatment purposes. The objective of the present review is to emphasize on new research findings and the overall survival that can be achieved with modern treatment programs.

La hemato-oncología molecular y las nuevas estrategias terapéuticas específicas en leucemia / Molecular hemato-oncology and new specific treatment strategies for leukemia

En una elevada proporción de casos de leucemias de nuevo diagnóstico se detectan genes de fusión, los cuales frecuentemente presentan secuencias codificadoras de factores de transcripción. Se ha demostrado que algunas proteínas de fusión como Pml-Rarα inhiben la diferenciación celular, al reclutar complejos correpresores nucleares que mantienen una actividad de histona desacetilasa (HDAC en inglés) sobre promotores de genes específicos importantes en diferenciación de una determinada estirpe celular. Esta represión transcripcional dependiente de HDAC representa una vía común en el desarrollo de leucemia y por lo tanto puede ser un blanco importante de nuevos compuestos terapéuticos. Por otro lado, la oncoproteína Bcr-Abl muestra una alta actividad de tirosina-cinasa, la cual desregula vías de transducción de señales involucradas normalmente en proliferación y apoptosis. Esta actividad aberrante puede ser afectada por inhibidores de transducción de señales (STIs, del inglés), los cuales bloquean la ruta oncogénica y representan un gran avance terapéutico. En esta revisión analizamos con cierto detalle lo que se conoce en la actualidad sobre la represión transcripcional reversible controlada por HDAC y sobre la transducción de señales aumentada por Bcr-Abl. Adicionalmente indicamos que la aplicación de fármacos de bajo peso molecular para el control de las leucemias humanas, basada en el conocimiento de los mecanismos moleculares de la enfermedad, lleva a una remisión clínica, con bajo riesgo de efectos tóxicos secundarios, lo cual está aumentando la mejoría de una alta proporción de los enfermos.

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Raralpha have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.

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.