BackgroundFive Asociación de Hemato‐Oncología de Centroamérica (AHOPCA) countries have used an adapted BFM‐based protocol for childhood acute lymphoblastic leukemia (ALL).ProcedureIn the AHOPCA‐ALL 2008 protocol, patients were stratified by age, white blood cell count, immunophenotype, central nervous system involvement, day 8 prednisone response, and morphologic bone marrow response to induction therapy. Patients at Standard Risk (SR) received a three‐drug induction regimen, a reinduction phase, and maintenance with protracted intrathecal therapy. Those at Intermediate (IR) and High Risk (HR) received, in addition, daunorubicin during induction therapy, a consolidation phase and two or three reinduction phases respectively.ResultsFrom August 2008 through July 2012, 1,313 patients were enrolled: 353 in SR, 548 in IR, 412 in HR. During induction therapy, 3.0% of patients died, 2.7% abandoned treatment, 1.1% had resistant ALL, and 93.2% achieved morphological complete remission (CR). Deaths and abandonment in first CR occurred in 2.7% and in 7.0% of patients, respectively. The relapse rate at a median observation time of 2.1 years was 15.0%. At 3 years, the event‐free survival (EFS) and overall survival (OS), with abandonment considered as an event, were 59.4% (SE 1.7) and 68.2% (SE 1.6). Three‐year EFS was 68.5% (SE 3.0), 62.1% (SE 2.6), and 47.8% (SE 3.2) for SR, IR, and HR groups. Adolescents had a significantly higher relapse rate (P = 0.001).ConclusionsThis experience shows that common international studies are feasible in lower‐middle income countries. Toxic deaths, abandonment of treatment, and relapses remain major obstacles to the successful treatment. Alternative treatment strategies may be beneficial. Pediatr Blood Cancer 2014;61:803–809. © 2013 Wiley Periodicals, Inc.

Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4+/-6.4%) than those with ALL (12.5+/-1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL.

Background: Countries with scarce resources have the right to appropriate essential health care but very few reports discuss how this can be achieved. We assessed the survival of a large cohort of pediatric oncological patients to provide hard data on which to base realistic evaluation and planning schemes.Patients and methods: This multicenter retrospective survey covered consecutively diagnosed and treated patients admitted to eight national level hospitals in seven countries in Central America and the Caribbean. The research protocol was discussed extensively, so the data to be collected and the criteria for their evaluation were clearly pre-defined. We analysed 2214 patients diagnosed between 1996 and 1999 with various cancers, classified as hemato-oncological disorders (70%) and solid tumors (30%).Results: Three-year overall survival was 48.4% [standard error (SE) 1.3]. Detailed analysis of acute lymphoblastic leukemia highlighted the wide intercountry variability: 3-year survival was 62.2% (SE 5.3) in Cuba, 74.2% (SE 3.3) in Costa Rica, 61.7% (SE 4.9) in Nicaragua, and lower in the other four countries.Conclusions: The yield of diagnostic-therapeutic protocols depends largely on the context of care in which they are applied. This paper documents the importance of including epidemiological research in interventions for cooperation in complex health areas such as pediatric oncology.

Lorenzana, R.*; Antillon, F. G.; Arevalo, X. L.*; Moller, A.*; Coustan-Smith, E.*; Wilimas, J. A.; Ribeiro, R. C.*; Bonilla, M.*; Campana, D.* Author Information

PURPOSE:To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. PATIENTS AND METHODS:Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Children's Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index < 1.16, age 12 months or younger, white blood cell count > or = 50 x 10(9)/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range I d-17 yrs), median leukocyte count was 15 (range 1-766) x 10(9)/L, and sex distribution was equal. RESULTS:Immunophenotypes were early beta-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was > or = 1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate +/- 1 standard error was 48 +/- 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 +/- 7% (n = 121) and 69 +/- 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 +/- 8% and 75 +/- 14%, respectively. CONCLUSIONS:These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.

Purpose To investigate the relationship between survival and malnutrition at the time of diagnosis among children treated for cancer in two developing countries. Patients and Methods We studied 443 children treated for cancer between 1995 and 1998 at two centers in San Salvador, El Salvador, and Recife, Brazil. Median age at diagnosis was 4.9 years; 283 children had leukemia and 160 had solid tumors. Z-scores were calculated for weight for age (WAZ), height for age (HAZ), and weight for height (WHZ) at diagnosis. Z scores <−2 indicated malnutrition. Patients were also stratified by low-risk disease (solid tumors: stage I, stage II, or localized; acute lymphocytic leukemia: white blood cell count <25,000/&mgr;L, no central nervous system involvement, no mediastinal mass and age >1 and <10 yrs) and high-risk disease (all other patients, including those with acute or chronic myelocytic leukemia). Results Z-scores indicated malnutrition in 23.5% (WAZ), 22.8% (HAZ), and 15.7% (WHZ) of patients. Z-score was not significantly related to overall survival rates, to survival rates analyzed by type of malignancy or risk status, or to survival rates at the end of the first month of treatment. Conclusions We found no relationship between nutritional status and survival in these patients. This implies that future protocols for use in developing countries can be designed to provide optimal treatment intensity despite the high incidence of malnutrition.

Raul C Ribeiro (photo) is director of the International Outreach Program at St Jude Children's Hospital. Miguel Bonilla is president of the Association of Central American Pediatric Hematologists Oncologists. The successful treatment f acute lymphoblastic leukaemia (ALL) is one of the greatest breakthroughs of modern medicine. More than two thirds of children with ALL in more-developed countries are now likely to be cured. However, modern treatment for ALL is expensive and complex. In the USA, the average annual cost per child is about US$100 000. Financial, educational, and training constraints all but preclude such treatment in less-developed countries. In 1991, a Salvadoran mother, who had brought her child for treatment at the St Jude Children's Research Hospital, Memphis, TN, USA, established the Fundacion Ayudame a Vivir (the Help Me to Live Foundation) in E1 Salvador. Its purpose was to improve the outcome for children with cancer, but the odds against achieving this goal were overwhelming. El Salvador was emerging from a bloody 12-year civil war, and about half of the 6 million population lived in poverty. The Benjamin Bloom Hospital, San Salvador's tertiary paediatric centre, had no paediatric oncologist and no nurses who were trained in the treatment of leukaemia. The estimated mortality rate for Salvadoran children with leukaemia was greater than 90% in 1993. Today, after 7 years of collaboration among St Jude Hospital, the Fundacion Ayudame a Vivir, and Benjamin Bloom Hospital, the 4-year survival estimate for Salvadoran children with ALL has reached 50%. This experience has allowed us to identify components that are crucial for the successful development of such programmes. The first step in initiating the leukaemia treatment programme was a careful assessment of resources and needs. The two main resources were the hospital and the foundation, whose members had devoted 2 years to raising funds before even approaching St Jude Hospital. Their help in ensuring political support and in facilitating interactions with government and hospital representatives had been invaluable. The needs identified were those common to less-developed countries: money, drugs, physicians, nurses, support and services, information, and training. The second component was the training of essential staff. Training was done in Mexico to circumvent language barriers and inflexible training requirements. Hospital staff were offered opportunities to visit Memphis to learn applicable procedures and protocols. Paediatric oncology is poorly traded in most central and south American countries, so we supplemented salaries to enable physicians to practice this specialty full-time. A paediatric oncology training programme for nurses was set up within Benjamin Bloom Hospkal. We then had to convince the hospital administrators that the trained nurses were essential members of the team and should be permanently assigned to the oncology service. These nurses were eager to accept the increased work and responsibility despite little extra compensation. The implementation of standard diagnostic and therapeutic protocols was the third component. Bone-marrow samples were initially sent to Memphis by express mail for diagnostic testing. More recently, immunophenotyping services have been established locally. Flow cytometry data are electronically transferred to a physician at St Jude Hospital, who monitors quality control and gives continuing education. A standard therapy plan was implemented. Although the regimen had been very well tolerated at St Jude Hospital, seven of the first 25 patients treated in E1 Salvador died of toxic effects. Withdrawal of daunomycin from the protocol reduced the toxic effects. During this initial phase, a Spanish-speaking physician in Memphis was in daily communication with staff in E1 Salvador to offer continued training and ensure optimum care. Financial support for crucial operational needs was the fourth component. Treatment of a child with ALL in El Salvador costs about US$15 000 per year. About 75% of these costs are covered by the Foundation and the Salvadoran government. St Jude Hospital has spent an additional US$750 000 in the past 6 years—an annual expenditure similar to that of treating one child in the USA. This outreach initiative has shown that much can be accomplished locally and regionally. Physicians have been trained as paediatric oncologists and have formed an association of paediatric haematologists and oncologists. Nurses have gained better professional status and have become active in nursing societies. The level of care throughout the hospital has improved. International collaborations and friendships have developed. We believe that the survival and the quality of life of children with cancer worldwide can be rapidly improved through training of core teams of health-care providers, collaboration with parents' groups or voluntary community support groups, and financial support of developing programmes. This impetus will attract committed professionals to paediatric haematology and oncology in these countries. Their research in collaboration with institutions in more-affluent countries, will ultimately produce benefits for all children with cancer.

Bonilla, M.; Pedrosa, F.; Liu, A.; Smith, K.; Davis, D.; Ribeiro, R.; Willimas, J. Author Information

The properties of the Bel and Bel-Robinson tensors seem to indicate that they are closely related to the gravitational energy-momentum. We present some new properties of these tensors which might throw some light onto this relationship. First, for any spacetime we find a decomposition of the Bel tensor in terms of the Bel-Robinson tensor and two other tensors, which we call the “pure matter” super-energy tensor and the “matter-gravity coupling” super-energy tensor. We show that the pure matter super-energy tensor of any Einstein-Maxwell field is simply the “square” of the usual energy-momentum tensor. This, together with the fact that the Bel-Robinson tensor has dimensions of energy density square, leads us to the definition of square root for the Bel-Robinson tensor: a two-covariant symmetric traceless tensor with dimensions of energy density and such that its “square” gives the Bel-Robinson tensor. We prove that this square root exists if and only if the spacetime is of Petrov type O, N or D, and its general expression is explicitly presented. The properties of this new tensor are examined and some interesting explicit examples are analyzed. Of particular interest are an invariant function that appears in the spherically symmetric metrics and an expression for the energy carried out by pure plane gravitational waves. We also examine the decomposition of the whole Bel tensor for Vaidya's radiating metric and Kerr-Newman's solution. Finally, we generalize the definition of square root to a factorization of the Bel-Robinson tensor and get the general solution for all Petrov types.