Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Oral Nutritional Supplementation in Children Treated for Cancer in Low- and Middle-Income Countries Is Feasible and Effective: the Experience of the Children's Hospital Manuel De Jesus Rivera "La Mascota" in Nicaragua.

Children with cancer are particularly vulnerable to malnutrition, which can affect their tolerance of chemotherapy and outcome. In Nicaragua approximately two-thirds of children diagnosed with cancer present with under-nutrition. A nutritional program for children with cancer has been developed at "La Mascota" Hospital. Results of this oral nutritional intervention including difficulties, benefits, and relevance for children treated for cancer in low- and middle-income countries are here reported and discussed.

Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases.

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD.

Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA): a model for sustainable development in pediatric oncology.

Bridging the survival gap for children with cancer, between those (the great majority) in low and middle income countries (LMIC) and their economically advantaged counterparts, is a challenge that has been addressed by twinning institutions in high income countries with centers in LMIC. The long-established partnership between a Central American consortium--Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA)--and institutions in Europe and North America provides a striking example of such a twinning program. The demonstrable success of this endeavor offers a model for improving the health outcomes of children with cancer worldwide. As this remarkable enterprise celebrates its 15th anniversary, it is appropriate to reflect on its origin, subsequent growth and development, and the lessons it provides for others embarking on or already engaged in similar journeys. Many challenges have been encountered and not all yet overcome. Commitment to the endeavor, collaboration in its achievements and determination to overcome obstacles collectively are the hallmarks that stamp AHOPCA as a particularly successful partnership in advancing pediatric oncology in the developing world.

Childhood acute lymphoblastic leukemia in Nicaragua: long-term results in the context of an international cooperative program.

BACKGROUND: The aim of this paper is to describe the results of acute lymphoblastic leukemia (ALL) treatment in Nicaragua from 1995 to 2005 in the context of an international cooperation program. PROCEDURES: Patients <18 years with ALL were treated with two consecutive protocols (1995 and 2000). After a steroid prophase, a three-drug induction was administered in protocol 1995, and a four-drug induction, including asparaginase, was administered in protocol 2000. In protocol 2000, a modified BFM phase IB with cyclophosphamide, 6-mercaptopurine and cytosine arabinoside was administered to patients at high risk (HR), who also received IV methotrexate (500 mg/m(2)) in the consolidation phase. Reinduction consisted of dexamethasone, vincristine, doxorubicin, cytosine arabinoside, and 6-thioguanine administered over 7 (protocol 1995) or 4 (protocol 2000) weeks; reinduction was repeated twice for patients at HR. Maintenance consisted of p.o. 6-mercaptopurine and methotrexate, and vincristine and dexamethasone pulses were added in the 2000 study. The total duration of therapy was 24 months. RESULTS: In total, 540 patients were treated. Overall, 7% of patients died during induction, and 9% abandoned treatment. At 5 and 10 years from diagnosis, event-free survival (EFS) rates of 38.1% and 36.6%, respectively, and overall survival rates of 48.0% and 39.6%, respectively, were obtained, considering abandonment as an event. CONCLUSIONS: In our experience, a 10-year EFS of 36.6% was achieved in a country with limited resources. Factors limiting a higher success rate were treatment abandonment and a high relapse rate.

ETV6-RUNX1 fusion gene and additional genetic changes in infant leukemia: a genome-wide analysis.

Acute lymphoblastic leukemia (ALL) in infants is characterized by a high frequency of MLL gene rearrangements. By contrast, the t(12;21) ETV6-RUNX1 fusion gene is typically detected in children older than 2 years. In a series of Brazilian infant leukemia cases, however, four younger cases harbored ETV6-RUNX1, at ages 2, 3, 5, and 7 months. This finding could represent a unique model for delineating the additional genomic hits required to accelerate the emergence of a frank leukemia in these t(12;21)-positive cases. We applied a whole-genome copy number analysis with single-nucleotide polymorphism (SNP) arrays, comparing t(12;21) infants with older pediatric age groups. Recurrent deletions, including 9p21.3 (CDKN2A, CKDN2B, and MTAP), 11p13 (CD44), 12p13.2 (ETV6), and patient-specific abnormalities were identified. Although infant cases with t(12;21) did not display specific genetic abnormalities explaining the short latency to overt leukemia, the frequency of copy number abnormalities increased proportionally with age. This novel SNP array analysis in an extremely rare series of cases opens new ideas about the etiology of ETV6-RUNX1-positive ALL.

A simplified minimal residual disease polymerase chain reaction method at early treatment points can stratify children with acute lymphoblastic leukemia into good and poor outcome groups.

BACKGROUND: Minimal residual disease is an important independent prognostic factor in childhood acute lymphoblastic leukemia. The classical detection methods such as multiparameter flow cytometry and real-time quantitative polymerase chain reaction analysis are expensive, time-consuming and complex, and require considerable technical expertise. DESIGN AND METHODS: We analyzed 229 consecutive children with acute lymphoblastic leukemia treated according to the GBTLI-99 protocol at three different Brazilian centers. Minimal residual disease was analyzed in bone marrow samples at diagnosis and on days 14 and 28 by conventional homo/heteroduplex polymerase chain reaction using a simplified approach with consensus primers for IG and TCR gene rearrangements. RESULTS: At least one marker was detected by polymerase chain reaction in 96.4% of the patients. By combining the minimal residual disease results obtained on days 14 and 28, three different prognostic groups were identified: minimal residual disease negative on days 14 and 28, positive on day 14/negative on day 28, and positive on both. Five-year event-free survival rates were 85%, 75.6%, and 27.8%, respectively (p<0.0001). The same pattern of stratification held true for the group of intensively treated children. When analyzed in other subgroups of patients such as those at standard and high risk at diagnosis, those with positive B-derived CD10, patients positive for the TEL/AML1 transcript, and patients in morphological remission on a day 28 marrow, the event-free survival rate was found to be significantly lower in patients with positive minimal residual disease on day 28. Multivariate analysis demonstrated that the detection of minimal residual disease on day 28 is the most significant prognostic factor. CONCLUSIONS: This simplified strategy for detection of minimal residual disease was feasible, reproducible, cheaper and simpler when compared with other methods, and allowed powerful discrimination between children with acute lymphoblastic leukemia with a good and poor outcome.