Survival and toxicity outcomes of hematopoietic stem cell transplantation for pediatric patients with Fanconi anemia: a unified multicentric national study from the Spanish Working Group for Bone Marrow Transplantation in Children.

Hematopoietic stem cell transplantation (HSCT) is currently the only curative option for hematological manifestations in patients with Fanconi anemia (FA). We report the outcome of 34 patients with FA inside a collaborative multicenter national study based on recommendations of Spanish Working Group for Bone Marrow Transplantation in Children (GETMON) between 2009 and 2016. Fludarabine-based conditioning regimen was carried out in all patients, with low dose total body irradiation in unrelated transplants. Disease status before HSCT was bone marrow failure (BMF) in 30 patients and myelodysplastic syndrome (MDS) in four. Donors were matched siblings donors (MSD) in 18, matched unrelated donors (MUD) in 15, and one haploidentical donor. All except one patient engrafted. Cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) was 29% and 11% for chronic GVHD. Median follow-up after HSCT was 6.5 years. Seven patients (21%) died due to transplant-related causes, two (6%) because of MDS relapse, and one (3%) after a squamous cell carcinoma. Overall survival (OS) was 73% at 5 years post-transplant, with no differences between MSD and MUD transplants. OS for patients with BMF was 80% while for MDS was 25%. Our data suggest HSCT can cure hematologic manifestations of most FA patients with BMF.

Sección de Oncología y Hematología Pediátricas del Hospital General Universitario Gregorio Marañón / Pediatric Oncology and Hematology Area of the Hospital General Universitario Gregorio Marañón

La Unidad de Oncología y Hematología Infantil del Hospital Gregorio Marañón comenzó su andadura en los años 70, presentando desde entonces un crecimiento progresivo y una modernización acorde con la evolución de la propia especialidad. En esta monografía se describe la organización de la sección, así como los recursos estructurales, las características del trabajo asistencial, la actividad docente e investigadora y la participación en diversos grupos de trabajo colaborativos o multidisciplinares. Se destaca la capacidad de abordaje integral de este tipo de patologías en todas las fases de las mismas, desde el diagnóstico al tratamiento, sin Olvidar el aspecto psicosocial o la atención paliativa en su fase terminal, si fuera necesario. En conjunto, se dibuja un cuadro que es una obra coral de muchos profesionales sanitarios (personal médico, psicooncología, enfermería, auxiliares...) y no sanitarios, pero cuyo tema principal es proporcionar la mejor asistencia posible al niño y a su familia (AU)

The Pediatric Oncology and Hematology Unit at the Gregorio Marañón Children's Hospital began its activity in the 705, presenting since then a progressive growth and modernization in accordance with the evolution of the specialty itself… In this paper we describe the organization of the section, our structural resources, the characteristics of care work, teaching and research activities and our participation in various collaborative or multidisciplinary work groups. It is remarkable the ability to comprehensively address this type of pathologies in its different phases, from diagnosis to treatment, without forgetting to mention the psychosocial aspect or palliative care in its terminal phase, if necessary. Altogether, a choral picture is drawn with the work of many health professionals (medical, psycho-oncology, nursing, assistants …) and non—health, but the main theme is to provide the best care for the child and his family (AU)

Evaluación de la densidad mineral ósea en pacientes con enfermedad de células falciformes / Evaluation of bone mineral density in children with sickle cell disease

OBJETIVO: Evaluar la densidad mineral ósea (DMO) en niños con enfermedad de células falciformes (ECF) de la Comunidad de Madrid. MATERIAL Y MÉTODOS: Se valora la DMO en un total de 40 niños con ECF y rango de edad entre 3-16 años, mediante densitometría (DEXA) siguiendo las recomendaciones de la Sociedad Internacional de Densitometría Clínica (ISCD). RESULTADOS:La edad media en el momento del estudio fue de 7,97 ± 3,95 años; el valor medio de la DEXA expresado en Z-score es de -0,91 ± 1,46 con un rango de valores mínimo de -5,30 y máximo de 2,30. Un 57,5% de los niños tiene DMO normal (Z > -1), un 25% tienen DMO baja (Z entre -1 y -2) y un 17,5% presentan Z-score patológico con valores de osteoporosis (Z-score<-2). Los estudios de correlación solo encuentran una correlación lineal de Pearson significativa estadísticamente entre valor de Z-score y valor de Hb (r = 0,368, p = 0,019), no encontrando correlación con los niveles de 25 (OH) D. CONCLUSIÓN: Se necesitan estudios prospectivos, con mayor número de enfermos para conocer las implicaciones futuras de la densitometría alterada y los factores de riesgo asociados

OBJECTIVE: To evaluate bone mineral density (BMD) in children with sickle cell disease (SCD) in the Community of Madrid. MATERIAL AND METHODS: The BMD was estimated in 40 children with SCD, and with an age range between 3 and 16 years, using densitometry (DXA), as recommended by the International Society for Clinical Densitometry (ISCD). RESULTS: The mean age at the time of the study was 7.97 ± 3.95 years, the mean value of the DXA expressed in Z -score was -0.91 ± 1.46 with a range of minimum values - 5.30 and 2.30 maximum. More than half (57.5%) of all the children had normal BMD (Z > -1), 25% had low BMD (Z between -1 and -2), and 17.5% showed an abnormal Z -score values of osteoporosis (Z -score < -2). The Pearson linear correlation was statistically significant between Z -score value and the haemoglobin level (r = 0.368, p = .019), finding no correlation with the levels of 25 (OH) vitamin D. CONCLUSION: Prospective studies are needed with a larger number of patients to understand the future implications of bone densitometry changes and associated risk factors

[Evaluation of bone mineral density in children with sickle cell disease]. / Evaluación de la densidad mineral ósea en pacientes con enfermedad de células falciformes.

OBJECTIVE: To evaluate bone mineral density (BMD) in children with sickle cell disease (SCD) in the Community of Madrid. MATERIAL AND METHODS: The BMD was estimated in 40 children with SCD, and with an age range between 3 and 16 years, using densitometry (DXA), as recommended by the International Society for Clinical Densitometry (ISCD). RESULTS: The mean age at the time of the study was 7.97±3.95 years, the mean value of the DXA expressed in Z -score was -0.91±1.46 with a range of minimum values - 5.30 and 2.30 maximum. More than half (57.5%) of all the children had normal BMD (Z>-1), 25% had low BMD (Z between -1 and -2), and 17.5% showed an abnormal Z -score values of osteoporosis (Z -score<-2). The Pearson linear correlation was statistically significant between Z -score value and the haemoglobin level (r=0.368, p=.019), finding no correlation with the levels of 25 (OH) vitamin D. CONCLUSION: Prospective studies are needed with a larger number of patients to understand the future implications of bone densitometry changes and associated risk factors.

The treatment for primary immune thrombocytopenia with romiplostim in adult and paediatric patients: use experience at a Spanish university hospital.

WHAT IS KNOWN AND OBJECTIVE: Primary immune thrombocytopenia (ITP) is characterized by accelerated platelet destruction, as well as suboptimal platelet production. Thrombopoietin (TPO) receptor agonists bind to and activate human TPO receptor, and have been shown to increase platelet counts. In this study, we assessed the effectiveness and safety of long-term administration of TPO agonist romiplostim in adult and paediatric patients. METHODS: This is a retrospective observational study that included every ITP patient (adults and children) who received romiplostim since its inclusion in our institutional formulary. Data on patients' demographics, romiplostim doses, platelet counts, use of rescue medication and concurrent therapies were collected. Outcomes for effectiveness evaluation were proportion of patients who achieved a platelet response (platelet count >50 × 10(9) per litre and double the platelet count at baseline on any scheduled visit, excluding counts obtained within 8 weeks after receipt of rescue medications), proportion of patients who achieved a durable response (platelet responses during 6 or more weeks of the last 8 weeks of treatment), proportion of patients needing rescue medication, proportion of patients able to stop or reduce concurrent treatment and mean number of weekly platelet responses. Safety was assessed on the basis of the incidence of adverse events documented on the patients' medical records. RESULTS AND DISCUSSION: This study enrolled ten adults and four paediatric patients. None of the paediatric patients and one adult patient had been splenectomized (contraindicated in the other adults). In the adult population, eight achieved a response at least once during treatment, and 1 achieved a durable response. Four patients needed rescue medication (mostly intravenous immunoglobulins). Three patients were able to stop concurrent ITP therapies, and the mean number of weekly platelet responses was 6. All four paediatric patients achieved a response at least once during treatment, and three achieved durable responses. Three patients needed rescue medication. The only patient who was receiving concurrent ITP medication was able to stop it, and the mean number of weekly platelet responses was 25. No serious adverse events were registered during treatment in either population. WHAT IS NEW AND CONCLUSION: The effectiveness of romiplostim was variable with few adult patients achieving a durable response. Our paediatric patients responded better with most achieving a durable response. The treatment was safe for both groups of patients. Studies should be conducted to identify patients more likely to benefit from this treatment.

Tumores vasculares en la infancia / Infantile vascular tumors

La utilización en el pasado de una terminología imprecisa para designar a los tumores vasculares infantiles ha contribuido durante años a diagnósticos incorrectos y, como consecuencia, a tratamientos inadecuados. En la infancia pueden presentarse diferentes tipos de tumores vasculares, como los hemangiomas infantiles, que son con diferencia los más frecuentes, y otros mucho más raros, como los hemangiomas congénitos (rápidamente involutivo y no involutivo), el hemangioendotelioma kaposiforme, el angioblastoma o angioma en penacho, o el granuloma piógeno. Su correcto conocimiento y diagnóstico, siempre en el contexto de un equipo multidisciplinario, es imprescindible para reducir errores diagnósticos, exámenes complementarios y pruebas invasivas innecesarias, y así, si fuera preciso, recibir el tratamiento más indicado y efectivo en cada caso. En el presente artículo revisamos la evolución histórica en cuanto a la nomenclatura y clasificación de las lesiones vasculares, las diferentes características clinicopatológicas de cada uno de los tumores vasculares, los exámenes complementarios indicados para llegar a un correcto diagnóstico, su diagnóstico diferencial y los distintos tipos de tratamiento que existen con sus indicaciones más reconocidas, en el momento actual, para los diferentes tumores vasculares y situaciones clínicas concretas (AU)

The use in the past of an imprecise terminology to designate vascular tumors has contributed to its incorrect diagnosis, and as a consequence, to inadequate treatment. In childhood, different types of vascular tumors may be present. Hemangiomas of infancy are by far the most frequent, and other less common types are congenital hemangiomas (rapidly involuting or RICH and non-involuting or NICH), kaposiform hemangioendothelioma, angioblastoma or tufted angioma and pyogenic granuloma. The correct knowledge and diagnosis, always in a multidisciplinary setting, is required to reduce incorrect diagnosis, unnecessary complementary examinations and invasive tests, and for the patient to receive the most effective and precise treatment in each case. This article reviews the historical evolution, nomenclature and classification of vascular lesions, the different clinical and pathological characteristics of each vascular tumor, the complementary examinations required correct diagnosis, the differential diagnosis, as well as highlighting the treatment options currently available for different vascular tumors and related clinical conditions (AU)

[Infantile vascular tumors]. / Tumores vasculares en la infancia.

The use in the past of an imprecise terminology to designate vascular tumors has contributed to its incorrect diagnosis, and as a consequence, to inadequate treatment. In childhood, different types of vascular tumors may be present. Hemangiomas of infancy are by far the most frequent, and other less common types are congenital hemangiomas (rapidly involuting or RICH and non-involuting or NICH), kaposiform hemangioendothelioma, angioblastoma or tufted angioma and pyogenic granuloma. The correct knowledge and diagnosis, always in a multidisciplinary setting, is required to reduce incorrect diagnosis, unnecessary complementary examinations and invasive tests, and for the patient to receive the most effective and precise treatment in each case. This article reviews the historical evolution, nomenclature and classification of vascular lesions, the different clinical and pathological characteristics of each vascular tumor, the complementary examinations required correct diagnosis, the differential diagnosis, as well as highlighting the treatment options currently available for different vascular tumors and related clinical conditions.

[Thrombocytosis in the oncology-haematology clinic: description, aetiological diagnosis and progression thrombocytosis]. / Trombocitosis en la consulta de oncohematología. Descripción, diagnóstico etiológico y evolución.

INTRODUCTION: Thrombocytosis is a common cause of patient referral to a paediatric haematologist specialist which requires a significant number of laboratory tests and visits to confirm the diagnosis. The aim of our study has been to analyse the characteristics of patients referred to our centre for specialised thrombocytosis assessment. Based on this assessment we established the criteria patients must fulfil to be recommend for further hospital study. PATIENTS AND METHODS: We categorised the 33 patients referred for thrombocytosis assessment according to sex, age, origin, personal and family history, platelet count at diagnosis and the reason why the red and white blood count at diagnosis (Haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin, leukocyte, neutrophils, lymphocyte and monocyte count), maximum platelet count during follow-up and other complementary examinations were done. The final diagnosis itself and number of previous visits before were also considered. The classification used to grade thrombocytosis was: low (500-700 X 10(3)/microl), mild (700-900 x 10(3)/microl), severe (900-1.000 x 10(3)/microl) and extreme (> 1.000 x 10(3)/microl). RESULTS: There was no predominance of males or females. 45 % of patients were under 2 years old and 55 % of them came from their primary care centre. The mean platelet count at the first medical visit was 669,000 (mild thrombocytosis). During follow-up, 24 % of the patients reached extreme platelets levels. In 28 % the initial blood count was performed because of an infection. The most frequently requested laboratory test was iron metabolism (82 % of the cases). All cases correspond to secondary thrombocytosis (48 % were reactive to infections, 24 % secondary to iron deficiency, and 15 % were associated to both causes). The mean number of visits before hospital discharge was 5.12. CONCLUSIONS: The finding of thrombocytosis in the majority of the cases studied was casual or in the context of an infectious process. Most of the thrombocytosis were mild. Due to the extremely low incidence of primary thrombocytosis in childhood and the fact that diagnosis is made by exclusion of other possibilities, the initial study of these patients should be done in primary care centres. The first conditions to be ruled out are infectious, inflammatory or bleeding processes. Once these causes are excluded, the most useful complementary test is to measure iron level given the relation between iron deficiency and thrombocytosis. Once these causes are ruled out and thrombocytosis persists, it would then be indicated to refer the patient to a paediatric oncology-haematology department for a more exhaustive follow-up.

Trombocitosis en la consulta de oncohematología. Descripción, diagnóstico etiológico y evolución / Thrombocytosis in the oncology-haematology clinic: Description, aetiological diagnosis and outcome

Introducción: La trombocitosis es un motivo frecuente de consulta en oncohematología infantil, y precisa un importante número de visitas y determinaciones analíticas para su diagnóstico o resolución. Nuestro objetivo ha sido evaluar las características de los pacientes derivados a nuestro servicio en los últimos meses para estudio de trombocitosis y establecer cuáles deberían ser los pacientes que precisan un estudio más exhaustivo en el hospital. Pacientes y métodos: Se determina en 33 pacientes derivados por este motivo el sexo, el rango de edad, la procedencia, los antecedentes personales y familiares, el grado de trombocitosis por la que se consulta y la cifra máxima durante el seguimiento, el motivo por el que se realiza la primera analítica, los valores hematimétricos en la primera analítica (hemoglobina [Hb], volumen corpuscular medio [VCM], hemoglobina corpuscular media [HCM], leucocitos [linfocitos y neutrófilos]), las exploraciones complementarias realizadas, el diagnóstico y el número de visitas que precisaron antes del alta. Se clasifica la trombocitosis en leve (500-700 × 103/μl), moderada (700-900 × 103/μl), grave (900-1.000 × 103/μl) y extrema (> 1.000 × 103/μl). Resultados: No hubo predominancia de sexos. El 45 % de los pacientes eran menores de 2 años. Procedían en un 55 % de su centro de salud. La cifra media de plaquetas por la que consultaron fue de 669.000 (trombocitosis leve). En el seguimiento llegaron a cifras extremas el 24 %. En el 28 % la analítica se había realizado por un cuadro infeccioso. La exploración complementaria más solicitada fue el metabolismo del hierro (en el 82 %). Todos se corresponden con trombocitosis secundarias (el 48 % reactivas a infecciones, el 24 % secundarias a ferropenia y el 15 % por ambas causas). El número medio de visitas ha sido de 5,12. Conclusiones: El hallazgo de la trombocitosis es en la mayoría de los casos casual o en el contexto de un cuadro infeccioso y, además, son leves. Dada la baja incidencia de trombocitosis primaria en la infancia y que el diagnóstico es de exclusión, se debería iniciar el estudio de la misma en la consulta de atención primaria, descartando inicialmente una causa infecciosa, inflamatoria o secundaria a sangrado. Una vez descartadas estas causas la prueba complementaria más rentable es el metabolismo del hierro, dada la asociación de ferropenia con trombocitosis. Si también se excluye esta etiología y se comprueba la persistencia de la trombocitosis, estaría indicado derivar al paciente a un servicio de oncohematología infantil para completar estudio (AU)

Introduction: Thrombocytosis is a common cause of patient referral to a paediatric haematologist specialist which requires a significant number of laboratory tests and visits to confirm the diagnosis. The aim of our study has been to analyse the characteristics of patients referred to our centre for specialised thrombocytosis assessment. Based on this assessment we established the criteria patients must fulfil to be recommend for further hospital study. Patients and methods: We categorised the 33 patients referred for thrombocytosis assessment according to sex, age, origin, personal and family history, platelet count at diagnosis and the reason why the red and white blood count at diagnosis (Haemoglobin, mean corpuscular volume, meen corpuscular haemoglobin, leukocyte, neutrophils, lymphocyte and monocyte count), maximum platelet count during follow-up and other complementary examinations were done. The final diagnosis itself and number of previous visits before were also considered. The classification used to grade thrombocytosis was: low (500-700 × 103/μl), mild (700-900 × 103/μl), severe (900-1.000 × 103/μl) and extreme (> 1.000 × 103/μl). Results: There was no predominance of males or females. 45 % of patients were under 2 years old and 55 % of them came from their primary care centre. The mean platelet count at the first medical visit was 669,000 (mild thrombocytosis). During follow-up, 24 % of the patients reached extreme platelets levels. In 28 % the initial blood count was performed because of an infection. The most frequently requested laboratory test was iron metabolism (82 % of the cases). All cases correspond to secondary thrombocytosis (48 % were reactive to infections, 24 % secondary to iron deficiency, and 15 % were associated to both causes). The mean number of visits before hospital discharge was 5.12. Conclusions: The finding of thrombocytosis in the majority of the cases studied was casual or in the context of an infectious process. Most of the thrombocytosis were mild. Due to the extremely low incidence of primary thrombocytosis in childhood and the fact that diagnosis is made by exclusion of other possibilities, the initial study of these patients should be done in primary care centres. The first conditions to be ruled out are infectious, inflammatory or bleeding processes. Once these causes are excluded, the most useful complementary test is to measure iron level given the relation between iron deficiency and thrombocytosis. Once these causes are ruled out and thrombocytosis persists, it would then be indicated to refer the patient to a paediatric oncology-haematology department for a more exhaustive follow-up (AU)

[Evaluation of systematic neonatal screening for sickle cell diseases in Madrid three years after its introduction]. / Evaluación en el tercer año de implantación del cribado neonatal universal de anemia falciforme en la Comunidad de Madrid.

BACKGROUND: Sickle cell anemia is a hereditary disease which, as a result of migration, constitutes one of the most frequent genetic disorders in northwest Europe. Complications secondary to this disease are common during the first 3 years of life and early diagnosis has been recommended to reduce their development. The autonomous community of Madrid began to perform universal neonatal screening for hemoglobinopathies in May 2003. This study presents the results of the first 32 months of this screening program. METHODS: A prospective, descriptive study was designed to include all the neonates born in centers in the autonomous community of Madrid from May 2003 to December 2005. A heel prick dried blood spot from the Guthrie card was analyzed by high-performance liquid chromatography to detect hemoglobin F, A, S, C, D and E. RESULTS: A total of 190,238 newborns were analyzed, and 1060 hemoglobin variants (5.57 for every 1000 births) were detected. Thirty-one were sickle cell diseases and appropriate antibiotics, vaccination and comprehensive care were initiated. Prenatal diagnosis of subsequent pregnancies was performed in three families after parental investigation. Carrier parents were from 44 countries of origin. CONCLUSIONS: Although sickle cell disease was considered anecdotic in Spain until recently, the diagnosis of this entity has markedly increased as a result of immigration. The universal screening program is expected to reduce morbidity and mortality in the first years of life.

Niño con fiebre prolongada, hepatoesplenomegalia, pancitopenia y alteración multisistémica / Male child with prolonged fever, hepatosplenomegaly, pancytopenia and multisystemic alteration

No disponible

[Sickle cell disease: registry of the Spanish Society of Pediatric Hematology]. / Enfermedad de células falciformes: registro de la Sociedad Española de Hematología Pediátrica.

INTRODUCTION: Sickle cell disease (SCD), a genetic anemia, is currently an emerging health problem in Spain. Since 2000, The Spanish Society of Pediatric Hematology has maintained a registry of these patients. The data corresponding to 2004 are presented herein. PATIENTS AND METHODS: Information was sent by different national hospitals. Pediatric patients with SCD followed-up during 2003 were registered in the first quarter of 2004. Data on epidemiology, diagnosis, treatment and outcome in each patient were gathered. RESULTS: A total of 138 patients in 24 national hospitals were registered. Of these, 99 were still under follow-up. There was no significant difference in sex. The mean age was 8.2 years. Seventy-eight percent of the patients were homozygous. Forty-four percent were born in Africa but 76% had abnormal genes originating in Africa. Neurophysiologic disorders were detected in 36% of the patients. Symptomatic treatment was given in 65%, hydroxyurea in 27%, hypertransfusional therapy in 3%, and chelation therapy, indicated for ferric overload, was provided in 4%. None of the patients underwent stem cell transplantation. Acute complications requiring hospitalization occurred in 21%, and chronic complications were observed in 27%. The most frequent chronic complications were delayed height and weight gain and liver and biliary tract disorders. Two patients died. CONCLUSIONS: This study confirms a highly significant increase in the prevalence of pediatric patients with SCD in the last 4 years, requiring greater resources to be devoted to the diagnosis and follow-up of this disease.

Enfermedad de células falciformes: registro de la Sociedad Española de Hematología Pediátrica / Sickle cell disease: registry of the spanish society of pediatric hematology

Introducción La enfermedad de células falciformes (ECF), anemia de origen genético, es un problema de salud emergente en España. La Sociedad Española de Hematología Pediátrica realiza desde el año 2000 un registro de estos pacientes. Se presentan los datos correspondientes a la recogida de 2004. Pacientes y métodos De la información enviada por diferentes hospitales nacionales se registraron en el primer trimestre de 2004 los pacientes pediátricos con ECF en seguimiento en 2003 y se recogieron variables epidemiológicas, relativas al diagnóstico, tratamiento y evolución de cada paciente. Resultados Se registraron un total de 138 enfermos, 99 aún en seguimiento, de 24 hospitales nacionales, sin diferencia significativa entre sexos y con una media de edad de 8,2 años. Eran homozigotos (SS) el 78 %. El 44 % habían nacido en África, pero tenían genes anómalos procedentes de África el 76 %. Se detectaron anomalías neuropsiquiátricas en el 36 % de los pacientes investigados. Se hizo tratamiento sólo sintomático en el 65 %, tratamiento con hidroxiurea en el 27 %, terapia hipertransfusional en el 3 % y quelación por sobrecarga férrica en el 4 %. Ningún paciente fue sometido a trasplante de progenitores hematopoyéticos ese año. Presentaron complicaciones agudas con necesidad de hospitalización el 21 % y complicaciones crónicas el 27 %. De éstas, las más frecuentes fueron los retrasos en la curva ponderoestatural y trastornos hepatobiliares. Dos pacientes fallecieron. Conclusiones Se confirma en los últimos 4 años un incremento nacional muy significativo de pacientes pediátricos con ECF, que obligaría a un mayor esfuerzo en su diagnóstico y seguimiento

Introduction Sickle cell disease (SCD), a genetic anemia, is currently an emerging health problem in Spain. Since 2000, The Spanish Society of Pediatric Hematology has maintained a registry of these patients. The data corresponding to 2004 are presented herein. Patients and methods Information was sent by different national hospitals. Pediatric patients with SCD followed-up during 2003 were registered in the first quarter of 2004. Data on epidemiology, diagnosis, treatment and outcome in each patient were gathered. Results A total of 138 patients in 24 national hospitals were registered. Of these, 99 were still under follow-up. There was no significant difference in sex. The mean age was 8.2 years. Seventy-eight percent of the patients were homozygous. Forty-four percent were born in Africa but 76 % had abnormal genes originating in Africa. Neurophysiologic disorders were detected in 36 % of the patients. Symptomatic treatment was given in 65 %, hydroxyurea in 27 %, hypertransfusional therapy in 3 %, and chelation therapy, indicated for ferric overload, was provided in 4 %. None of the patients underwent stem cell transplantation. Acute complications requiring hospitalization occurred in 21 %, and chronic complications were observed in 27 %. The most frequent chronic complications were delayed height and weight gain and liver and biliary tract disorders. Two patients died. Conclusions This study confirms a highly significant increase in the prevalence of pediatric patients with SCD in the last 4 years, requiring greater resources to be devoted to the diagnosis and follow-up of this disease

Aristolochic acid nephropathy in a Chinese patient: time to abandon the term "Chinese herbs nephropathy"?

The causal role of aristolochic acid (AA) in the so-called Chinese herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.

DNA adduct formation by the ubiquitous environmental contaminant 3-nitrobenzanthrone in rats determined by (32)P-postlabeling.

Diesel exhaust is known to induce tumors in animals and is suspected of being carcinogenic in humans. Of the compounds found in diesel exhaust and in airborne particulate matter, 3-nitrobenzanthrone (3-NBA), is a particularly powerful mutagen. We investigated the capacity of 3-NBA to form DNA adducts in vivo that could be used as agent-specific biomarkers of exposure. Female Sprague-Dawley rats were treated orally with 2 mg/kg body weight of 3-NBA, and DNA from various organs was analyzed by (32)P-postlabeling. High levels of 3-NBA-specific adducts were detectable in all organs. Both enrichment versions nuclease P1 digestion and n-butanol extraction resulted in patterns consisting of either 3 or 4 adducts remarkably similar in all tissues examined. The highest level of DNA adducts was found in the small intestine (38 adducts per 10(8) nucleotides) followed by forestomach, glandular stomach, kidney, liver, lung and bladder. To provide information on the nature of the adducts formed in vivo in rats, DNA adducts were cochromatographed in 2 independent systems with standardized deoxyguanosine adducts and deoxyadenosine adducts produced by reaction of 3-NBA in the presence of xanthine oxidase with deoxyribonucleoside 3'-monophosphates in vitro. In both systems, each of the rat adducts comigrated either with a deoxyguanosine or a deoxyadenosine-derived 3-NBA adduct. Our results demonstrate that 3-NBA binds covalently to DNA after metabolic activation, forming multiple DNA adducts in vivo, all of which are products derived from reductive metabolites bound to the purine bases (deoxyguanosine 60% and deoxyadenosine 40%).

The anticancer agent ellipticine on activation by cytochrome P450 forms covalent DNA adducts.

Ellipticine is a potent antitumor agent whose mechanism of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Using [3H]-labeled ellipticine, we observed substantial microsome (cytochrome P450)-dependent binding of ellipticine to DNA. In rat, rabbit, minipig, and human microsomes, in reconstituted systems with isolated cytochromes P450 and in Supersomes containing recombinantly expressed human cytochromes P450, we could show that ellipticine forms a covalent DNA adduct detected by [32P]-postlabeling. The most potent human enzyme is CYP3A4, followed by CYP1A1, CYP1A2, CYP1B1, and CYP2C9. Another minor adduct is formed independent of enzymatic activation. The [32P]-postlabeling analysis of DNA modified by activated ellipticine confirms the covalent binding to DNA as an important type of DNA modification. The DNA adduct formation we describe is a novel mechanism for the ellipticine action and might in part explain its tumor specificity.

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

BACKGROUND: Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS: The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS: Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS: The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.