NPM1, FLT3 and CEBPA mutations in pediatric patients with AML from Argentina: incidence and prognostic value.

Mutations in NPM1, FLT3 and CEBPA genes are found in 25-35 % of adult acute myeloblastic leukemia (AML) cases and correlate with prognosis. To date, there have been no reports about these mutations in pediatric AML from Argentina. The aims of the present study were to describe the incidence of NPM1, FLT3 and CEBPA mutations and to analyze their prognostic impact in this population. The incidences of these mutations within a population of 216 pediatric AML cases were: NPM1-mutated 4.2 %, CEBPA-mutated 1.9 %, FLT3-ITD 10.2 % and FLT3-TKD 7.9 %. Among 33 patients with normal karyotype, we found significantly higher frequencies for NPM1-mutated 24.2 % and CEBPA-mutated 12.1 %. Overall survival (pOS) for the 163 eligible non-acute promyelocytic leukemia cases was 46.2 ± 4.3 %, while leukemia-free survival probability was 51.0 ± 4.4 % (n = 135). The NPM1-mutated/FLT3-ITD-negative genotype showed better outcome than any other combined NPM1/FLT3 genotype; this difference was statistically significant within the group of high-risk patients (pOS ± SE 83.3 ± 15.2 % versus 33.1 ± 4.7 %; p = 0.0251). This is the first report of the frequencies of these mutations in Argentina. Despite the limited number of patients, a favorable prognosis of AML with genotype NPM1-mutated/FLT3-ITD-negative was confirmed. This is especially relevant within the high-risk group of patients, as it may contribute to the detection of patients with better prognosis, and thus avoid unnecessary treatment intensification.

[Undifferentiated high-grade pleomorphic sarcoma of the orbit: a case report]. / Sarcoma pleomorfo indiferenciado de alto grado orbitario: a propósito de un caso.

CASE REPORT: A 27-year-old female presented to us with a complaint of proptosis of her right eye. Imaging tests showed an extraconal mass in the medial orbital wall, which affected the medial rectus. The tumor was removed and adjuvant radiotherapy was required. The histological examination showed an undifferentiated high-grade pleomorphic sarcoma of the orbit. There has not been recurrence after 6 years of follow-up. DISCUSSION: Undifferentiated high-grade pleomorphic sarcoma is an uncommon cause of malignant orbital mass. It grows fast and can metastasize, so extension studies are required. Surgical excision is the treatment of choice.

Duplication dup(1)(q41q44) defined by fluorescence in situ hybridization: delineation of the 'trisomy 1q42-->qter syndrome'.

We report on a novel case of pure partial tandem duplication 1q42q43 confirmed by fluorescence in situ hybridization (FISH). We compare the manifestations of our patient with similar cases previously reported. We conclude that the most common clinical manifestations of trisomy 1q42qter are prenatal and postnatal growth retardation, relative macrocephaly, triangular face, prominent forehead, broad nasal bridge, abnormal philtrum, micro/retrognathia, cardiac defects and mental retardation. We would like to emphasize the importance of the FISH technique in the identification of the duplicated segment.

Evolución y progresos en el tratamiento de la leucemia finfoblastica aguda / Progress in the treatment of acute lymphoblastic leukemia

Muchos avances se han logrado en los últimos 30 años en el tratamiento de la leucemia linfoblástica aguda (LLA) pediática, a nivel mundial y tamibén en nuestro Hospital. Después de su apertura en agosto de 1987 hasta noviembre de 2002 fueron ingresados 989 pacientes con diagnóstico de LLA de los cuales 896 fueron evaluables. Los mismos fueron tratados con 3 protocolos sucesivos: 92 (7 LLa 87), 374 (1 LLA 90) y 430 (1 LLA 96). Las tasas de remisión completa (RC) fueron de 95,6 en el primer protocolo, 94,4 en el segundo y 96,9 en el tercero y un 2,1, 2,9 y 1,8 de los pacientes fallecieron durante la inducción en los respectivos estudios. El principal evento observado fue la recaída de la enfermedad y fallecieron en RC 6 de los pacientes del 7 LLA 87, 4,8 del 1 LLA 90 y 4,3 del 1 LLA 96. La pSLE (EE) fue de 61 (5), 63 (5) y 72 (6), respectivamente, siendo esta diferencia estadísticamente significativa (p=0,0237). El Hospital ha incorporado los métodos diagnósticos necesarios para una mejor estratificicón de los pacientes, y fueron mejoradas las medidas de soporte ofrecidas a los pacientes. Como consecuencia de los logros mencionados se observó una disminución en las tasas de muerte durante la inducción y en RC, con un aumento gradual y significativo de la pSLE. Estos resultados muestran una mejora a lo largo del tiempo y nuestros esfuerzos deben orientarse a una aún mejor optimización de las herramientas diagnósticas, terpéuticas y de soporte para lograr alcanzar los estándares internacionales pra esta población de pacientes.

Nuevos blancos terapéuticos en leucemia aguda pediatrica: caracterización de las mutaciones del gen FLT3 / Newer therapeutic targets in acute limphoblastic leukemia: characterization of mutations of the gene FLT3

El tratamiento de elección para las leucemias agudas pediátricas es la quimioterapia convencional, que ha permitido obtener tasas de sobrevida que actualmente parecen difíciles de superar. En los últimos años se han intensificado las investigaciones dirigidas a descubrir nuevos blancos terapéuticos, entre los que se encuentra el receptor FLT3. Los blastos leucémicos puede presentar formas mutadas de dicho receptor, siendo las más frecuentes mutaciones internas en tándem (FLT3 ITD) y mutaciones puntuales en la zona de activación (FLT3 ALM). Objetivos: Poner a punto la detección de mutacoines de FLT3, analizar su prevalencia en nuestra población de pacientes con diagnóstico de Leucemia Mieloblástica Aguda (LMA) o de Leucemia Linfoblática Aguda en infantes (LLA I), y evaluar su asociación con parámetros clínicos y de laboratorio. Pacientes y Método: El estudio de las mutaciones se realizó por RT PCR, en un total de 122 pacientes (92 LMA y 30 LLA 1). Resultados: Se detectaron mutaciones en el 15,2 de las LMA y en 10 de las LLA -1. La prevalencia de las FLT3 ITD mostró un aumento gradual con la edad de los pacientes, y la media de edad fue significativamente mayor. Con respecto a asociaciones con recuentos leucocitarios, alteraciones genéticas, subtipos FAB y valor pronóstico, si bien hubo difrencias éstas no furon significtivas. Conclusiones: Este es el primer estuido de mutaciones en FLT3 realizado en población pediátrica en nuestro país. La detección de estas mutaciones permitirá individualizar, en el futuro, a los niños candidatos a recibir drogas inhibidoras de FLT3, actualmente en desarrollo.

[Focal fatty liver lesions: infrequent ultrasonographic presentation]. / Esteatosis focal hepática: presentación ecográfica infrecuente.

We present case of focal fatty liver lesions. Echography images revealed multiple hyperechogenic lesions similar to those observed in metastatic disease. Aspiration was negative and diagnosis was based on the results of liver biopsy alone, carried out during laparoscopy. The difficulty of determining the etiology of this type of lesión by echography is discussed.

Good outcome of children with acute myeloid leukemia and t(8;21)(q22;q22), even when associated with granulocytic sarcoma: a report from a single institution in Argentina.

BACKGROUND: The association between t(8;21) and granulocytic sarcoma (GS) is well known, but to the authors' knowledge the prognostic significance of GS in these patients has not been defined clearly. METHODS: Between January 1990 and July 1999 174 children with acute myeloid leukemia were admitted to the study institution. Translocation (8;21) was identified in 20 patients (11.5%). Eighteen patients were evaluable for the current study and 8 presented with GS at the time of diagnosis (GS+). RESULTS: The authors defined two groups of patients: those who were GS+ and those who were GS-. One patient in the GS+ group and two patients in the GS- group died during the induction phase of the study. Complete remission was achieved in seven patients in the GS+ group and eight patients in the GS- group. Two patients developed a recurrence in the GS+ group as did one patient in the GS- group. The event free-survival probability (the standard error) was 58% (18%) in the GS+ group and 70% (14%) in the GS- group. Localization of GS was in only one site in seven patients and at multiple sites in one patient. Patients with an epidural mass received local radiotherapy (one patient) or surgery (two patients). Two of these patients developed paraplegia as sequelae: one patient after surgery and one patient after radiotherapy. One patient with orbital GS received local radiotherapy because of progressive proptosis. The remaining four patients had a complete resolution of the GS with chemotherapy only. CONCLUSIONS: In the current study of patients with t(8;21)(q22;q22), the presence of granulocytic sarcoma was not found to be an adverse prognostic factor. However, careful attention should be paid, especially to patients with an epidural site, to avoid sequelae. Chemotherapy appears to be the optimum treatment for these children.

[Translocation t(9;11) in acute childhood lymphoblastic leukemia]. / Traslocación t (9;11) en leucemia linfoblástica aguda en pediatría.

We report a case of a de novo acute lymphoblastic leukaemia (ALL) with t(9;11) (p21;q23) and a novel translocation t(2;8) (p15;q24). The former is characteristic of acute nonlymphoblastic leukaemia (ANLL) and has rarely been detected in ALL. The blasts showed L2 morphology by the French American British (FAB) classification and pre B ALL immunophenotype.

Tandem triplication and quadruplication of chromosome 21 in childhood acute lymphoblastic leukemia.

A 5-year-old girl with ALL was shown to have a leukemic clone characterized by a triplication and quadruplication of chromosome 21, arranged in tandem, at diagnosis and relapse, respectively. To our knowledge, this is the second report of this chromosomal anomaly in ALL, which was confirmed by in situ staining. The karyotype evolution in the leukemic clone from triplication to quadruplication at relapse emphasizes the association of chromosome 21 with hematopoietic malignancies.

[Thoracic tuberculosis in adults. A comparative study of radiological findings of HIV seropositive and seronegative patients]. / Tuberculosis torácica en el adulto. Estudio comparativo de los hallazgos radiológicos entre enfermos VIH positivo y negativo.

We compare the radiologic manifestations of chest TB in three groups of patients: HIV patients (52 cases), HIV negative patients (85 cases and 100 cases). Initial radiologic findings were similar in the two seronegative groups, even though there is an eight-year interval between both series. However, seropositive patients have a higher risk of acquiring the infection (x 2.25), of extrathoracic disease (x 4.22), of coincidental infections (p < 0.0002) and of progression of the disease p < 0.0003) than the normal population. Lymphadenopathy and miliary TB are much more common in the HIV positive patients (x 6.23 and x 44 respectively). Cavitation, pulmonary scarring, volume loss and calcification are more frequent among the seronegative patients (p < 0.03), as well as pleural disease (p < 0.0001).

Regulation of amiloride-sensitive Na+ channels by endothelin-1 in distal nephron cells.

We used patch-clamp methods to investigate the effects of basolateral endothelin-1 (ET-1) on the amiloride-sensitive Na+ channel in A6 distal nephron cells. One hundred picomolar ET-1 decreased channel activity via an increase in mean time closed (P < 0.01, n = 10). Channel inhibition by pM ET-1 was mimicked by an ET-B receptor agonist (P < 0.05, n = 7) and was prevented by ET-B antagonists (P = 0.14, n = 10) but not by an ET-A antagonist (P < 0.05, n = 4). With the inhibitory ET-B receptor blocked, higher doses of ET-1 (10 nM) actually increased channel activity through an increase in mean time open (P < 0.001, n = 12). The current-voltage relationship and the number of channels were not changed by basolateral ET-1 exposure. We conclude that 1) basolateral ET-1 regulates amiloride-sensitive Na+ channels; 2) binding of picomolar ET-1 to ET-B receptors inhibits, whereas the binding of nanomolar ET-1 to a different ET receptor (likely ET-A) stimulates, channel activity; and 3) these dose-dependent, distal nephron responses provide a potential mechanism for the in vivo natriuresis and antinatriuresis observed in response to "subpressor" and "pressor" concentrations of ET-1, respectively.

New variant Ph translocation in chronic myeloid leukemia: t(Y;22)(p11;q11).

A 4-year-old boy with chronic myeloid leukemia (CML) was shown to have a variant Ph t(Y;22)(p11;q11). To our knowledge, this is the first report of a variant Ph translocation involving Y. Molecular analysis showed that the breakpoint on chromosome 22 is in the breakpoint cluster region (bcr), typical of CML with the classic t(9;22), suggesting that it might be a complex Ph translocation with the involvement of 9q34.

Safety and immunogenicity of an inactivated hepatitis A vaccine in children 2 to 5 years old.

The reactogenicity and immunogenicity of an inactivated hepatitis A vaccine were assessed. Seventy healthy children aged between 2 and 5 years old, who lacked antibodies against the hepatitis A virus, were enrolled in this study. With a 0-, 1-, and 6-month vaccination schedule, the children received three doses of 360 enzyme-linked immunosorbent assay (ELISA) units of hepatitis A vaccine intramuscularly (deltoid). Safety parameters were recorded in standardized diary cards by the parents on the day of injection and the three following days. Blood tests for liver enzymes and anti-hepatitis A virus antibody analyses were performed the day of screening and 1, 2, 6 and 7 months after the first dose. Anti-hepatitis A virus antibody was tested by ELISA. Titres < 20 mIU/ml were considered negative. For the three hepatitis A vaccine doses administered, 22% (46/210) of the diary cards reported any kinds of signs or symptoms. Soreness at the injection site (9%, 18/210) and malaise (6%, 12/210) were the most common local and systemic reactions reported, respectively. The seroconversion rates were 83, 99 and 100% one month after the 1st, 2nd, and 3rd doses, respectively. The corresponding geometric mean titres were 124, 352, and 2,778 mIU/ml. We conclude that this HAV vaccine is safe and immunogenic in healthy children. As the hepatitis A epidemiology pattern is rapidly changing in our country (and other regions), resulting in an increasing population of susceptible adolescents and young adults, we suggest that the routine vaccination against hepatitis A in pre-school children attending day-care centres should be seriously considered.

Primary adenocarcinoma of the terminal ileum simulating Crohn's disease.

An unusual case of histologically proven ileal adenocarcinoma mimicking regional enteritis in a 22-year-old man is reported. Although in 2 previous reports the patient's age was stressed as an important factor for the differential diagnosis, this was not of diagnostic help in our case. This report emphasizes the need to include other diagnostic possibilities when regional enteritis has an anomalous evolution and responds poorly to treatment.