Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia.

BACKGROUND: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). METHODS: A case-control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. RESULTS: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47-11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20-0.91). CONCLUSION: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS.

Persistent genomic instability in peripheral blood lymphocytes from Hodgkin lymphoma survivors.

Advances in cancer treatment have led to an increase in patient survival. However, exposure to genotoxic chemotherapeutic agents and ionizing radiation may induce persistent genetic damage in cancer survivors. In this study, we detected genomic instability in chromosomes of peripheral blood lymphocytes from Hodgkin lymphoma patients, 2-17 years after MOPP (nitrogen mustard, Oncovin, procarbazine, and prednisone) chemotherapy with or without radiotherapy. Samples were obtained from 11 healthy individuals, 5 pretreatment patients, and 20 posttreatment patients. Cytogenetic analysis with GTG banding was performed on 1,000 lymphocyte metaphases per donor to identify genomic instability, including numerical and structural chromosomal aberrations, at a resolution of 10 Mb across the entire genome. Our results showed that anticancer treatment did not induce significant differences in the frequency of aneuploidy among the three study groups. However, 1 of the 11 healthy individuals, and 13 of the 20 posttreatment patients had a high frequency of chromosomal breaks and gross chromosomal rearrangements. The types of aberrations observed were random and complex, consistent with persistent genomic instability that was induced by cancer treatment. Clonal expansion of cells with chromosomal lesions was observed in one posttreatment patient only. These findings show that anticancer treatments induce persistent genomic instability, but not aneuploidy. Chemotherapy may affect genes with a role in DNA damage surveillance or repair, which in turn allows the accumulation of nontargeted structural chromosomal damage in future generations of cells. This genomic instability may facilitate the development of second malignancies in Hodgkin lymphoma survivors.

Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome.

BACKGROUND: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. METHODS: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children < or = 6 and >6 years old. RESULTS: Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43-1.61), 1.70 (0.82-3.52); and 3.57 (1.59-8.05), respectively. A similar result was obtained when only ALL was analysed. CONCLUSION: We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL.

BCR-ABL, ETV6-RUNX1 and E2A-PBX1: prevalence of the most common acute lymphoblastic leukemia fusion genes in Mexican patients.

This study was conducted to determine the frequency of the most common fusion genes in Mexican pediatric patients with acute lymphoblastic leukemia (ALL). Molecular analysis using RT-PCR was carried out in 53-blood samples: 52 patients with de novo ALL and one with relapsed ALL. The ETV6-RUNX1 fusion was found in 7 cases (13.5%), BCR-ABL fusion was detected in 2 cases (3.8%), and 6 patients (11.5%) expressed the chimeric gene E2A-PBX1. The prevalence of E2A-PBX1 is one of the highest that has been described thus far in childhood ALL. Furthermore, we detected both the BCR-ABL, and E2A-PBX1 fusion in the relapsed patient. With regards to the immunophenotype, ETV6-RUNX1 was expressed in both pre-B and T-cell cases, while the presence of E2A-PBX1 and BCR-ABL was associated with the pre-B ALL phenotype. The prevalence of E2A-PBX1 in Mexican pediatric cases supports the existence of ethnic differences in the frequency of molecular markers of ALL.

A closer look at specific therapeutic strategies in leukemia.

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 and AML1-ETO, 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 represent an important target for new therapeutic agents. On the other hand, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways involved normally 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 present a closer look at our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction. In addition, the application of low molecular weight drugs for human leukemia treatment based in this knowledge results in durable clinical remission and acceptable risk of toxic effects that should increase the cure rate. We hope that this review will provide timely information to the readers.

Is autologous bone marrow transplant (ABMT) and high-dose chemotherapy an approach that can rescue some children with advanced cancer disease?

The object was to determine the role ABMT in children with advanced cancer Those included had failed to respond to conventional treatment with 4 different ablative chemotherapy regimens. Bone marrow stem cells were identified with CD34. Cellular viability was determined after the bone marrow extraction and before the infusion. Fifteen patients were included, whose ages ranged from 1 to 13 years old with a median of 7. Six had acute leukemia, 6 with primitive neuroectodermic tumors, and 3 with other tumors. The median disease-free survival for the whole group was of 2 months, range of 1 to 29 months and SD of 10.1. A total of 6 children are alive (40%) and without evidence of tumor activity from 1 to 29 months. The disease-free survival rate for these group was of 19.1 months, with an SD of 7.9 months.

Cytotoxic effect of three arsenic compounds in HeLa human tumor and bacterial cells.

Numerous epidemiological studies suggest that arsenic (As) compounds are carcinogens, however, recent data have renewed the interest in their anticarcinogenic properties. The cytotoxic effects of three arsenic compounds were assessed: sodium arsenite, sodium arsenate and sodium cacodylate, representing the trivalent and pentavalent species of arsenic, along with a dimethylated pentavalent arsenic species. HeLa cells and Salmonella typhimurium (strains TA98 and TA100) were exposed to As compounds and the cytotoxic effects were evaluated. Alterations on RNA and DNA synthesis in HeLa cells were also examined. All arsenic compounds produced a dose-dependent inhibition on colony formation and DNA synthesis in HeLa cells, yet any of them significantly influenced RNA synthesis in these cells. No evidence of arsenic-induced mutagenicity or antimutagenicity was observed using the Ames assay. In bacterial cells, only sodium arsenite caused a dose-dependent inhibition of colony formation.Collectively, these results indicate that in both, HeLa and S. typhimurium cell systems, only trivalent sodium arsenite can act as an effective inhibitor of cell growth. The possible mechanism(s) of the cytotoxic effect of arsenite in these two different cell systems might be due to its reactivity with intracellular sulfhydryl groups.

Cytogenetics in acute lymphoblastic leukemia in Mexican children: an institutional experience.

BACKGROUND: Cytogenetic studies in acute lymphoblastic leukemia (ALL) have identified numerical and structural chromosomal abnormalities related to the disease's pathophysiologic characteristics. These findings correlate with prognosis and response to treatment in ALL patients. The purpose of this study was to define the frequency of chromosomal abnormalities in a group of Mexican children with ALL and to compare these data with those reported in the literature. METHODS: Bone marrow chromosome studies with GTG bands were performed in 150 pediatric patients with ALL who were naive to antileukemic treatment and aged from 5 months to 16 years; the majority was diagnosed as L1. RESULTS: Among 131 patients, 30 (22.9%) karyotypes were normal and the remaining 101 (77.1%) had abnormal karyotypes with numerical and/or structural abnormalities. Among patients with numerical abnormalities, the most frequent karyotypes were hyperdiploidy with 51-65 chromosomes (30 patients) and hyperdiploidy with 47-50 chromosomes (18 patients). Among recurrent, non-random, and primary structural abnormalities, the most frequent was t(9;22), followed by t(1;19). Aberrations involving band 11q23 were not detected, and only one of two patients with L3 had the t(8;14). Of the secondary non-random abnormalities, dup(1q), del(6q), and i(7)(q10) were found. CONCLUSIONS: The frequency and type of chromosomal abnormalities found was comparable to those reported in the literature with similar methodology and pediatric populations; however, the number of cases analyzed should be increased to create a database of Mexican children with ALL, and several patients require molecular analysis to identify chromosomal abnormalities not detected through conventional cytogenetic studies.

Pattern of childhood cancer mortality in Mexico.

Public and governmental concern regarding increasing cancer mortality trends in children in Mexico led us to investigate the current situation of childhood cancer in this country, as well as to discuss the reasons for which no decline in total and childhood cancer mortality has been documented during the past decades. The data used for analysis of total cancer mortality and study of the trends in mortality of specific childhood cancer in Mexico were retrieved from official Mexican Cancer Mortality Statistics for the period of 1955-1995, as well as from the latest official death records of the Mexican National Institute of Statistics, Geography and Informatics. Actual mortality rates from all sites of cancer in Mexico show a tendency to increase in adults and in children over the last decades. The mortality rate due to all malignant neoplasms in the Mexican population increased significantly, from 28.1 per 100,000 inhabitants in 1955 to 52.6 per 100,000 inhabitants in 1995, whereas the rate of total mortality tended to decrease. The death rate among Mexican children under 15 years of age from all malignant neoplasms increased from 1980-1995 by 20.3%. Although these findings offer some support for the suggestion that socioeconomic factors and delayed diagnosis and treatment may be the major contributors to childhood cancer death rates in Mexico, other explanations cannot be excluded. Further and more detailed research into the nature of the influence of environmental exposures, geographical distribution-including rural vs. city life-and purely biological factors concerned with the cancer situation is warranted. Predictions indicate that the increase of both total and childhood cancer mortality will continue. The pattern in the epidemiology of childhood diseases is changing in view of better national health measures to control infectious diseases, diarrheas, and neonatal problems. All these measures would lead to an increase in the incidence of childhood cancer in children who previously died of other causes. Therefore, improved registry, early diagnosis, better knowledge of the epidemiologic pattern of childhood cancer, appropriate treatment, and greater resources are necessary to solve this emerging health problem in Mexico.

Ewing's sarcoma: prognosis and survival in Mexican children from a single institution.

A retrospective analysis of 55 patients with Ewing's sarcoma from an institution in Mexico was done between 1980 and 1993. The ages ranged between 2 and 16 years (mean 9.78); 39 were male and 16 female. The most frequent primary sites were in the humerus in 13 of 55 patients (23.6%), followed by the pelvis in 10 out of 55 (18%). Sixty percent of the patients had metastasic disease at diagnosis; the lungs and bones were the most frequently affected sites. Patients with localized disease (n = 22) had a disease-free survival (DFS) of 44%, compared with 20% of those with pulmonary metastasic disease (n = 7) and 8% of patients with metastasic disease to the lungs and elsewhere (n = 26) (p = .00061). Patients in regimen 3 had a DFS of 47% at 36 months of follow-up compared to 20 and 25% for patients in regimens 1 and 2, respectively (p = .01). In those with trunk presentation the DFS was of 25% and in those with presentation in the extremities DFS was 50% (p = .01). Patients with pulmonary metastasic disease at diagnosis have a DFS of 20% in comparison to those without (44%) (p = .00061).

Pediatric oncology at the National Institute of Pediatrics in Mexico City.

The Instituto Nacional de Pediatría (National Institute of Pediatrics) is a referral, non-profit, teaching hospital. This government-funded institution is dedicated only and exclusively for clinical and research in pediatrics. In their 29 years, it has dictated the norms for patient care through a multitude of research projects in all fields of pediatrics. The purpose of our institution is to continue developing human professional resources in order to improve patient care across the country, especially in pediatric oncology, in which there is a tremendous shortage of professionals. We believe that all Mexican children with this disease have the right to have as good treatment and prognosis as the children from developed countries.

Is the ancillary chemotherapy approach of any value in the treatment of infratentorial primitive neuroectodermal tumors with surgery and radiotherapy?

A retrospective historical analysis of patients under 18 years of age with the histopathological diagnosis of infratentorial primitive neuroectodermal tumor (PNET) is presented. The survey embraced two different groups of children. Group 1 was defined as those patients treated from 1972 to 1984 with surgical resection plus neuraxis radiotherapy alone. Group 2 was made up of children treated from 1990 to 1996 with the same approach but with the addition of adjuvant chemotherapy: cisplatin (day 1) and etoposide (days 1-3) every 3 weeks for 6 months. Group 1 embraced 42 children with an age range of 1-16 years (mean 6 years, SD 4.4 years). In group 2 there were 34 children, their ages ranging from 1 to 18 years (mean 7.2, SD 4.6 years). The prevalence of stages T2M0 and T3M0 was similar in both groups, but in group 1 there were 4 patients (9.5%) whose spinal fluid was positive for tumor cells (M1), while in group 2 there were 7 children (20.5%) with positive spinal fluid. There was an unequivocal initial response to treatment in 86% of these children in group 1 and in 79% in group 2. The event-free survival (EFS) was 30% at 252 months in group 1, while for group 2 the EFS was 67.6% at 63 months (P 0.002). Mortality from tumor activity was noted in 26 patients (70%) in group 1, while in group 2 mortality attributable to tumor progression was documented in 11 children (32%). We conclude that the use of adjuvant chemotherapy in these patients improves survival without any significant morbidity.

B-lineage acute lymphoblastic leukemia of childhood. An institutional experience.

A total of 119 children (1990-95) with acute lymphoblastic leukemia (ALL) B-lineage either CD10+ or CD10- were registered into a single non-randomized chemotherapy protocol. Only untreated patients with standard risk were included in the study. Their ages ranged from 1.8-10 years with a mean of 5.1 years. There were 82 (68%) children with early pre B-All, 35 (29%) with pre B-ALL and 2(1.6%) with transitional pre B-ALL (p < 0.00001). The patients were divided according to CD10 reactivity, either + (94 children) or -(25 patients). The event-free survival (EFS) at 60 months for the CD10+ children was of 78% (alive 73/94), while for the CD10- was 71% (alive 18/25) (p = 0.6) and 74% for both groups. The factors that influenced favorably the survival in the CD10+ group were the age between 3 to 5.99 years (p < 0.00001), sex (either male or female), leukocyte count between 10-24.9 x 10(9)/l (p < 0.00001), LDH under 300 U/I (p < 0.00001) and L1 bone marrow cytomorphology (p < 0.00001). In the CD10- patients, the EFS was favorably influenced by the female sex (p = 0.04), leukocyte count under 10 x 10(9)/l (p = 0.05) and LDH < 300 U/l (p = 0.02). CNS infiltration was documented in 4.2% (5/119). Mortality secondary to chemotherapy was seen in 7%. In conclusion, this is the first large series in Mexican children with B-lineage ALL published. Because of the relatively small number of patients in each group (pre B and transitional pre B), all the patients in the current series were treated alike. When the 119 patients were divided only on the basis of CD10 reactivity, the EFS for both groups (CD10+ and-) was similar; therefore, the reactivity to CD10 has no prognostic value in this type of ALL.

[1st pediatric consensus on acute lymphoblastic leukemia in Mexico]. / Primer consenso de leucemia aguda linfoblástica pediátrica en México.

The meeting was held in the city of Morelia in October of 1996. The objective of the meeting was to establish the diagnostic criteria, prognosis and the general basis of treatment for Mexican children with ALL. The participants were 43 hematologists or hemo-oncologists from institutions involved in the primary care of children with ALL in the major cities of Mexico. Seven topics were discussed: laboratory workup, risk factors, treatment of standard risk ALL, treatment of high risk non-T ALL, treatment of T-ALL and the leukemia-lymphoma syndrome, treatment of extramedullary ALL, and treatment of relapsing ALL. The proposals and conclusions are presented in this document for distribution to physicians interested in pediatric ALL.

Langerhans cell histiocytosis in children under 2 years of age.

This is a retrospective study of 55 children under the age of 2 years diagnosed with Langerhans cell histiocytosis (LCH). They were classified according to age and organ function and dysfunction following Lahey's criteria. The studied population was divided into four groups by age of diagnosis (0-6, 7-12, 13-18, and 19-24 months). Statistical analysis showed no significant difference in outcome between age groups, although the population under 6 months had a 81.3% fatality rate. The presence of organ dysfunction was a major cause of death in all age groups, being statistically significant in outcome (P > 0.005) compared with patients without organ dysfunction. The presence of thrombocytopenia and/or respiratory dysfunction was also highly associated with a fatal outcome. In the surviving population, no second malignancies have been reported. The late secondary effects of therapy include endocrine, orofacial, and osseous pathologies.

[Epidemiological aspects of bilateral retinoblastoma]. / Los aspectos epidemiológicos en el retinoblastoma bilateral.

Retinoblastoma (RB) is the most frequent solid tumor in the Instituto Nacional de Pediatría, México (INP). The bilateral presentation occurs in 25% of all patients. We present some epidemiological data of this form of the disease, in learn these epidemiological variables in our series. We reviewed the clinical charts from 1972 to 1994. We analyzed age, sex, timing of presentation of the second affected eye, positive family history, clinical staging, and the development of secondary malignancies. A total of 105 cases were detected from 412 RB total cases (25%). We observed a male predominance 1.6:1.0 p = 0.04 versus females. The clinical staging showed: retinal stage 9/102, ocular stage 58/102, orbital stage 26/102 and non classified 9/102 p < 0.00001. The asynchronous form is a rare presentation in our experience: 16/105 cases p = 0.00001 (15%). Only 16/105 patients had a positive family history of RB (15%). We found 2 of 105 cases with secondary malignancies (0.01%). The asynchronous form constitutes a rare presentation. We cannot explain the etiology for the high prevalence of bilateral disease. The frequency of secondary malignancies is lower than that reported in the literature.

[Lymphoblastic lymphoma in children. Poor response in advanced disease with chemotherapy for non-Hodgkin's lymphoma]. / Linfoma linfoblástico en niños. Respuesta pobre en enfermedad avanzada con quimioterapia de linfoma no Hodgkin.

Fifty three pediatric patients with the histopathological diagnosis of lymphoblastic lymphoma (LL) were studied in a retrospective analysis during a 14 year period. Their age ranged from 1 to 16 years with a median of 7 years. Clinical staging was performed according to Murphy's system. There was one child in stage I (2%), 11 in stage II (21%), 14 stage III (26%) and 27 stage IV (51%). Patients in stage IV, 21 (78%) had initial bone marrow involvement, 4 (15%) central nervous system (CNS) infiltration and 2 (7%) simultaneous infiltration to the bone marrow and the CNS. The chemotherapy program consisted of induction, consolidation and maintenance with CNS prophylaxis. The whole program lasted 36 months. Out of 53 patients there were only 45 evaluable for treatment analysis response. A total of 14 (31%) are alive and in a continuous complete remission, with a median duration of remission of 66 months, 8 (18%) children abandoned treatment with a median duration of remission of 10 months. Twenty three patients (51%) are dead. The actuarial survival at 11 year is of 39% +/- 11% with a median remission rate for the whole group of 11.8 months. No patient in complete remission for more than 24 months has relapsed. We conclude that our chemotherapy program is more than adequate for early stages, but for advanced disease it has been a failure. There is a need to modify the chemotherapy program using a very similar protocol as the one used in high risk childhood acute lymphoblastic leukemia.

Leiomiosarcoma hepático como segunda neoplasia: informe sobre un niño con leucemia aguda linfoblástica y tumor hepático / Hepatic leiomyosarcoma as a second malignancy: report in a child with acute lymphoblastic leukemia and hepatic mass

Los pacientes pediátricos con leucemia aguda linfoblástica (LAL) presentan alto índice de curación, pero con mayor incidencia de segundas neoplasias condicionadas por la radioterapia, por la quimioterapia con agentes alquilantes o las epipodofilotoxinas. Se presenta un paciente con LAL en el Instituto Nacional de Pediatría, quien durante el tratamiento de LAL sin presentar alteración citogénica demostrable, desarrolla un leiomiosarcoma hepático de focos primarios múltiples, no existieron antecedentes de uso de manera importante de agentes alquilantes, epipodofilotoxinas ni radiaciones ionizantes. Consideramos la posibilidad de una susceptibilidad genética, que no podemos demostrar actualmente, como condicionante para el desarrollo de esta segunda neoplasia con patrón de presentación clínica poco usual

[Chromosomal translocation (2;13) in disseminated rhabdomyosarcoma]. / Translocación cromosómica (2;13) en un rabdomiosarcoma diseminado.

A 12-year-old male with a disseminated alveolar rhabdomyosarcoma is reported. The diagnosis was difficult because of the clinical manifestations and the histological patterns of the bone marrow and a chest wall tumor. Diagnosis was confirmed through the histologic picture of a gum biopsy and the karyotype of the tumoral cells of the bone marrow. Chromosome study revealed a hypotetraploid cell line with the translocation (2;13) characteristic of this type of neoplasias. The usefulness of chromosome studies in solid tumors of childhood is emphasized.