Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes.

BACKGROUND/OBJECTIVES: High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes. METHODS: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation. RESULTS: Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006). CONCLUSION: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.

CAREST--Multilingual Regional Integration for Health Promotion and Research on Sickle Cell Disease and Thalassemia.

Sickle cell disease (SCD) is a significant problem in the Caribbean, where many individuals have African and Asian forebears. However, reliable prevalence data and specific health care programs for SCD are often missing in this region. Closer collaboration between Caribbean territories initiated in 2006 to set up strategies to promote better equity in the health care system for SCD patients led to the formation of CAREST: the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. We present the effectiveness of collaborations established by CAREST to promote SCD newborn screening programs and early childhood care, to facilitate health worker training and approaches for prevention and treatment of SCD complications, and to carry out inter-Caribbean research studies.

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.

Stroke Avoidance for Children in REpública Dominicana (SACRED): Protocol for a Prospective Study of Stroke Risk and Hydroxyurea Treatment in Sickle Cell Anemia.

BACKGROUND: In the Dominican Republic, where the burden of sickle cell anemia (SCA) is high, many children lack access to routine screening and preventative care. Children with SCA are at risk for stroke, an event that leads to significant morbidity and mortality. In the United States, screening via transcranial Doppler (TCD) identifies children with SCA at highest stroke risk, allowing early intervention with blood transfusions. The need for indefinite transfusions for primary stroke prevention limits their practicality in limited-resource countries. Hydroxyurea has been shown to lower TCD velocities and to prevent conversion from conditional (170 to 199 cm/sec) to abnormal (greater than or equal to 200 cm/sec) velocities. In resource-limited settings, implementation of a TCD screening program, coupled with hydroxyurea therapy, could reduce the burden of SCA and stroke. OBJECTIVE: The aims of the Stroke Avoidance for Children in REpública Dominicana (SACRED) trial are (1) to screen children with SCA for stroke risk using TCD and to determine the prevalence of elevated velocities in a cross-sectional sample; (2) to identify clinical and laboratory correlates of elevated velocities; and (3) to obtain longitudinal data on the natural history of TCD velocities and to measure therapeutic effects of hydroxyurea. METHODS: This prospective trial, designed and conducted by Cincinnati Children's Hospital Medical Center (CCHMC) and Hospital Infantil Robert Reid Cabral (HIRRC) with Centro de Obstetricia y Ginecología, includes a baseline cross-sectional epidemiological survey of the distribution of TCD velocities across a large cohort of children with SCA in the Dominican Republic. Children with conditional velocities are eligible to begin protocol-directed hydroxyurea if laboratory criteria are met. The treatment schedule begins with a fixed-dose of approximately 20 mg/kg/day for 6 months, after which it escalates to maximum tolerated dose (MTD). All participants undergo longitudinal annual TCD evaluation, while those on hydroxyurea have semi-annual evaluations during the 3-year study period. Data are collected using an Internet-based Research Electronic Data Capture (REDCap) system with forms translated into Spanish; both remote and on-site monitoring are used. RESULTS: To date, 122 children with SCA have enrolled in SACRED including 85 (69.7%, 85/122) with normal, 29 (23.8%, 29/122) with conditional, 5 (4.1%, 5/122) with abnormal, and 3 (2.5%, 3/122) with inadequate TCD velocities. Of the 29 children with conditional TCD velocities, 17 (59%, 17/29) have initiated hydroxyurea per protocol, with plans for escalation to MTD. CONCLUSIONS: The SACRED trial will provide novel epidemiologic data about the prevalence of children with SCA and increased stroke risk in the Dominican Republic. The study also includes an investigation of the impact of hydroxyurea at MTD on elevated TCD velocities, as well as clinical and laboratory parameters. The design and implementation of SACRED reflect a successful international institutional partnership, one that features local capacity building and training in research methods and clinical care. The trial's results have important implications for screening and prevention of primary stroke in children with SCA living in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02769845; https://www.clinicaltrials.gov/ct2/show/NCT02769845 (Archived by WebCite at http://www.webcitation.org/6qf6n0Egh).

Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: a perspective from Central America.

BACKGROUND: The prevalence of malnutrition in children may exceed 50% in countries with limited resources. The aims of this study were to assess nutritional status at diagnosis in children and adolescents with cancer, and to correlate it with clinical outcomes in the Spanish speaking countries of Central America that formed the AHOPCA (Asociacion de Hemato-Oncologia Pediatrica de Centro America) consortium. METHODS: Patients aged 1-18 years, diagnosed with cancer between 1st October 2004 and 30th September 2007, were eligible for study. Weight (kg) and height or length (m), mid upper arm circumference--MUAC and triceps skin fold thickness--TSFT were measured and their Z-scores or percentiles were calculated. Three categories of nutritional status were defined according to these parameters. RESULTS: A total of 2954 new patients were enrolled; 1787 had all anthropometric measurements performed and 1513 also had measurements of serum albumin. By arm anthropometry 322/1787 patients (18%) had moderate nutritional depletion and 813/1787 patients (45%) were severely depleted. Adding serum albumin, the proportion classified as severely depleted rose to 59%. Malnourished children more often abandoned therapy and their event free survival was inferior to that of other children. CONCLUSIONS: Arm anthropometry in children with cancer is a sensitive measure of nutritional status. Since malnutrition at diagnosis was related to important clinical outcomes, an opportunity exists to devise simple, cost-effective nutritional interventions in such children that may enhance their prospects for survival.

Treatment for children with severe aplastic anemia and sickle cell disease in low income countries in Latin America: a report on the recent meetings of the Monza International School of Pediatric Hematology/Oncology (MISPHO): Part III.

Treatment of hematologic disorders in low-income countries (LIC) is difficult. This report summarizes treatment of sickle cell disease and aplastic anemia by pediatric hematologists from 15 LIC who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with severe sickle cell disease were treated with low dose hydroxyurea, which safely reduced vaso-occlusive crises. Patients with severe aplastic anemia fared poorly due to lack of availability and high cost of anti-thymocyte globulin and cyclosporine and lack of access to stem cell transplantation. Appropriate therapy was most likely to occur in MISPHO centers with an active twinning program with a center in a high-income country.

Cerebral blood flow in the evolution of infarction following unilateral carotid artery occlusion in Mongolian gerbils.

Cerebral blood flow (CBF) was measured in gerbils 2, 4, 7, and 12 hours after unilateral irreversible carotid artery ligation to determine if the delayed ischemic damage to nerve terminals that occurs over 8 hours after stroke could be due to changes in CBF. [14C]butanol (4.5 mu Ci in 45 microliter 0.9% saline) was injected into the femoral vein, and cpm accumulating in the cerebrum and in a catheter inserted in the abdominal aorta were measured. CBF (ml/100 g/min, mean +/- SEM) in sham-operated control gerbils was 108.4 +/- 37.5 in the left hemisphere and 123.8 +/- 37.1 in the right. CBF in the ischemic left cerebrum was 41.0 +/- 7.7 at 2 hours (n = 7), 21.6 +/- 7.2 at 4 hours (n = 4), 26.2 +/- 4.6 at 7 hours (n = 7), and 9.7 +/- 3.1 at 12 hours (n = 6). CBF in the nonligated right hemisphere was 115.0 +/- 15.3 at 2 hours, 70.4 +/- 23.3 at 4 hours, 80.4 +/- 14.6 at 7 hours, and 50.9 +/- 20.1 at 12 hours. As expected, CBF was significantly reduced in the ischemic left cerebral hemisphere compared with the nonligated right cerebral hemisphere at each time, but CBF in the ischemic left cerebral hemisphere was also significantly lower at 12 hours than at 2 hours (p = 0.002) and at 7 hours (p = 0.014). CBF in the nonligated right cerebral hemisphere was also lower at 12 hours than at 2 hours (p = 0.02). No changes in PCO2 or blood pressure accounted for these differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoamine neurotransmitters in the evolution of infarction in ischemic striatum: morphologic correlation.

Evolution of infarction following cerebral ischemia is a delayed process, with spongiform degeneration of the neuropil occurring 6 to 8 hours after onset of ischemia. The brains of gerbils with stroke following unilateral carotid artery ligation were examined for catecholamine-derived fluorescence (CADF) by the Falck-Hillarp technique to study the relationship of catecholamine (CA) metabolism with damage to the neuropil. CADF could still be identified in the striatum for up to 16 hours after stroke and there appeared to be spongiform degeneration of the neuropil in relation to accumulations of CADF at 7 and 16 hours after stroke. Pretreatment of gerbils with a-methyl-p-tyrosine 400 mg/kg 6 hours prior to carotid ligation depleted the striatum of CADF until 16 hours after stroke and appeared to reduce the spongiform degeneration of the neuropil, though it did not affect ischemic degeneration of neuronal cell bodies. The continued presence of CADF in the striatum for up to 16 hours after stroke supports the previously reported findings that CA nerve terminals are still functional for 8 hours after stroke and that CA metabolism continues even though levels of CA are reduced immediately after onset of ischemia due to carotid artery ligation.

Metabolism of monoamine neurotransmitters in the evolution of infarction in ischemic striatum.

The time course of changes in monoamine metabolism in ischemic striatum was assessed by measurement of levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxy-indole-acetic acid (5-HIAA) 2, 4, 7 and 16 hours after irreversible unilateral carotid ligation in Mongolian gerbils with stroke. DA was reduced to 30% of the level in the contralateral non-ischemic striata by 2 hours after stroke, but DOPAC was significantly elevated (p less than 0.01) to 227%, while HVA remained equal to control. At 4 hours after stroke, DOPAC was 86% of the contralateral non-ischemic striata but HVA had risen to 130%. At 7 hours after stroke, DOPAC in the ischemic striata was 148% of control, while HVA remained at 133%. By 16 hours after stroke, DA, DOPAC and HVA were depleted from the ischemic striata, corresponding to the time course for irreversible damage to the neurotransmitter uptake function of nerve terminals. 5-HT levels in the ischemic striata were 30% of control at 2 hours, 46% at 4 hours, 30% at 7 hours and 21% at 16 hours, while 5-HIAA remained equal to control throughout the time course. These studies indicate that monoamine metabolism continues in ischemic striatum for up to 8 hours after the onset of stroke following irreversible unilateral carotid ligation in the Mongolian gerbil, but metabolism of DA is disrupted by 16 hours after stroke while metabolism of 5-HT continues.

Nerve terminal damage in cerebral ischemia: greater susceptibility of catecholamine nerve terminals relative to serotonin nerve terminals.

The energy-dependent uptake of (3H)-dopamine (DA), (3H)-norepinephrine (NE) and (3H)-serotonin (5-HT) was measured in synaptosomes isolated from either the whole cerebral hemispheres or the striata of gerbils after cerebral ischemia. Ischemic stroke was induced in the Mongolian gerbil by left common carotid ligation. Uptake values in the affected hemisphere (expressed as a percent of the corresponding control hemisphere) were 32.6% for DA, 35.1% for NE, and 52.0% for 5-HT, 16 hours after stroke. The differential reduction in uptake of the catecholamines relative to 5-HT was significant (p less than 0.005). This differential persisted when measures were made on isolated striata from the ischemic and control hemispheres. In the latter measurements, uptake of DA was 20.7% of control and uptake of 5-HT was 44.7% of control. Uptake of both DA and NE were significantly reduced in animals exhibiting milder circling behavior, while uptake of 5-HT was not. There was no significant reduction of uptake in animals subjected to left common carotid ligation not exhibiting signs of stroke. These studies indicate a selective sensitivity of catecholamine nerve terminals to damage in ischemic stroke.

Nerve terminal damage in cerebral ischemia: protective effect of alpha-methyl-para-tyrosine.

Mongolian gerbils were treated with alpha-methyl-para-tyrosine methyl ester (AMPT, a tyrosine hydroxylase inhibitor), in order to decrease brain levels of catecholamines. Six hours later, unilateral ischemic stroke was induced by ligation of the left common carotid artery. The delayed degeneration of nerve terminals was studied sixteen hours later by measuring the high-affinity uptake of radiolabeled transmitters by isolated synaptosomes. Dopamine, serotonin and glutamate terminals were studied. AMPT-treated gerbils were compared to untreated (no AMPT) animals; 220 gerbils were studied. AMPT pretreatment (100, 250 and 400 mg/kg) produced a dose-dependent protection of all three types of nerve terminals. In the absence of AMPT pretreatment, the uptake of radiolabeled transmitters by the ischemic hemisphere, expressed as a percentage of that seen in the contralateral (unaffected) side of the brain, was as follows (mean +/- SEM): 27.3 +/- 5.2% for dopamine terminals, 49.5 +/- 6.2% for serotonin terminals, and 42.7 +/- 5.3% for glutamate terminals. Protection was essentially complete at a dose of 400 mg AMPT per kg. The number of animals with significant damage to nerve terminals was reduced from 38.5% in untreated animals to 11.1% in animals treated with AMPT 400 mg/kg. Although the nerve terminals were protected, gerbils still showed the behavioral signs of unilateral stroke due to the permanent occlusion of the left carotid. These results indicate that endogenous dopamine may play a significant role in ischemic damage to nerve terminals in the cerebrum.

Frequent use of lubricants for anal sex among men who have sex with men: the HIV prevention potential of a microbicidal gel.

OBJECTIVES: This study assessed frequency of rectal lubricant use, opinions about rectal microbicidal gels, and willingness to participate in acceptability trials of rectal microbicides among Latino men who have sex with men (MSM). METHODS: Latino MSM (N = 307) living in New York City were surveyed from October 1995 through November 1996. Eleven Latino MSM participated in a focus group. RESULTS: Among those having anal sex during the prior year, 93% used lubricants (59% always and 74% in at least 80% of sexual encounters) regardless of condom use. Of the 29 men who practiced anal sed but did not use condoms, 90% used lubricants with similar frequency. Of those using lubricants, 94% used at least 1 teaspoon per occasion. A transparent product, free of smell and taste, was favored. Of the MSM in the sample, 92% said that they would use a lubricant with an anti-HIV microbicidal agent, and 87% expressed interest in participating in an acceptability trial. Product and dispenser preferences also were discussed. CONCLUSIONS: A rectal lubricant with microbicidal properties appears acceptable and desirable to Latino men who have anal sex with other men.

Substance use and sexual risk behavior: understanding their association among four ethnic groups of Latino men who have sex with men.

PURPOSE: To explore the association between substance use in conjunction with sex and unprotected anal sex among Colombian, Dominican, Mexican, and Puerto Rican men who have sex with men (MSM), considering ethnicity, acculturation, and mediating variables. METHODS: A New York City convenience sample of 307 men provided information on past year's sexual behavior, substance use, acculturation, attendance at bars, discos, and parties, self-worth, machismo, and sensation seeking. RESULTS: Alcohol use and drug use were positively associated with unprotected anal sex, particularly with casual partners. Different rates of substance use among the four ethnic groups were found, but were not significant when adjusting for acculturation. Among men who engaged in both unprotected and protected anal sex, substance use was not more common on unprotected occasions than on protected occasions. Attendance at bars, clubs, etc. was not associated with unprotected anal sex. Sensation seeking, self-worth, and machismo were related to substance use and unprotected anal sex. In multivariate analyses, the substance use/unprotected sex association remained when adjusting for ethnicity, acculturation, partner type, attendance at bars, and personality variables. IMPLICATIONS: Substance use and unprotected sex are associated among these Latino MSM. However, there does not appear to be a simple causal relationship between the variables. Several other variables co-vary with these factors but did not statistically explain their association.

Direct evidence of acute, massive striatal dopamine release in gerbils with unilateral strokes.

Dopamine release into the extracellular space was measured with in vivo electrochemical detection in the ipsilateral and contralateral striata in Mongolian gerbils that suffered a stroke after acute unilateral carotid artery ligations. A sevenfold increase in the dopamine signal occurred within 15 minutes of carotid ligation in the ischemic side, while the unlesioned side had no significant change. Increased extracellular levels of dopamine persisted throughout the 3-hour recording period. Pretreatment with alpha-methyl-p-tyrosine 6 hours prior to recording significantly attenuated the signal increase. This study is the first direct demonstration of the marked, continuous dopamine release that occurs during acute cerebral ischemia.

Strengths and vulnerabilities of a sample of gay and bisexual male adolescents in Puerto Rico

La adolescencia es un proceso de desarrollo de múltiples dimensiones que incluyen los significados sociales que se le atribuyen colocando a la juventud en un limbo social; no son niños o niñas pero todavia no son adultos. Es importante contextualizar las dificultades que enfrentan los adolescentes gay debido a su identidad sexual, su vulnerabilidad social asociada a su particular etapa de desarrollo y su etnicidad. Exploramos las vulnerabilidades y fortalezas de una muestra de jóvenes adolescentes gay puertorriqueños. Participaron 61 jóvenes gay y bisexuales de alto nivel educativo, que residían en Puerto Rico. Examinamos los niveles de depresión, el apoyo social percibido, el uso de alcohol y drogas y la conducta sexual. Los resultados demuestran que el 45 por cento de los participantes informaron altos niveles de depresión. Sin embargo los participantes también mostraron un bajo consumo de alcohol y drogas, poca o ninguna actividad sexual de riesgo y una gran satisfacción con el apoyo social recibido. Los participantes mostraron gran resiliencia asociada a sus redes de apoyo social, el uso consistente de protección en las conductas sexuales de alto riesgo y capacidad para integrar su orientación sexual en su desarrollo personal en una sociedad latina y heterosexista. Apesar de que los resultados no pueden generalizarse a toda la población de jóvenes adolescentes gay en Puerto Rico, esta información es útil para apoyar la necesidad de intervenciones a nivel de comunidad que manejen las fortalezas de esta población

In vivo transfer of ascorbate and dehydroascorbate to the aqueous humor of the eye in the domestic cat and the rhesus monkey

Se ha estudiado in vivo, en gatos domésticos y en macacos thesus, la incorporación de ascorbato y dehidroascorbato (DHA) al humor acuoso.l En el gato se encontró que los niveles de ayunas de ascorbato en el humor acuoso (1.49 mg%) se mantienen unas 6 veces por encima de los séricos, lo cual se ha tomado como undcación de la existencia de un proceso de transporte activo para ascorbato en el cuerpo ciliar de este animal. También se ha determinado que la transferencia de ascorbato al humor acuoso en el gato tiene dos componentes, uno saturable, mediado, con parámetros cinéticos Tm = 4.9 mg% y Kt = 0,53 mg%, que debe ser responsable del transporte activo, y otro que nos es saturable, sino tipo difusión sencilla. En el mono se detectó un sistema de transporte mediado, sin componente difusivo, con Tm = 22.6 mg% y Kt = 0.28mg%, y capaz de mantener en el humor acuoso una concentración de ascorbato 25 veces mayor que en el plasma. Los valores de ayunas de ascorbato en el suero del mono (0.69 mg%) se mantienen sobre el suero del mono (0.69 mg%) se mantienen sobre el nivel de saturación del sistema de transporte, a diferencia de lo que ocurre en el gato. DHA no pudo detectarse en el plasma del gato ni del mono, ni en el humor acuoso del gato. Sí pudo detectarse, sin embargo, en el humor acuoso del mono, a niveles de un 3% de la concentración de ascorbato total. La cinética de la incorporación de ascorbato al ojo del gato y del mono tras la inyección intravenosa de DHA apoya la idea de que la especie molecular que el cuerpo ciliar transporta es la forma reducida, ascorbato, y no DHA. Este sería convertido intravascularmente (leucocitos y hematíes) a ascorbato, antes de incorporarse al humor acuoso

Esferocitosis hereditaria en niños / Hereditary Spherocytosis in children

Comunicamos seis casos con diagnóstico de esferocitosis hereditaria, realizados en la Clínica Infantil Dr. Robert Read Cabral. Se discute el valor del diagnóstico en pacientes con trastorno hemolítico, ausencia de hemoglobinopatía y test de Coombs negativo. Se destaca el papel curativo que tiene la esplenectomía en relación a las manifestaciones clínicas de la enfermedad