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Buenos Aires, Argentina

Francis J.H.,Sloan Kettering Cancer Center | Schaiquevich P.,CONICET | Del Sole M.J.,CONICET | Zapata G.,University of Buenos Aires | And 6 more authors.

Purpose Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. Design Clinical and preclinical, prospective, cohort study. Participants In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye. Methods Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. Main Outcome Measures For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. Results By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. Conclusions Weekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected. © 2014 by the American Academy of Ophthalmology. Source

Danielian S.,Servicio de Inmunologia y Reumatologia | Basile N.,Servicio de Inmunologia y Reumatologia | Rocco C.,Laboratorio Of Biologia Celular Y Retrovirus | Prieto E.,Servicio de Inmunologia y Reumatologia | And 7 more authors.
Journal of Clinical Immunology

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease with major diagnostic and therapeutic difficulties, basically comprising two different conditions: primary and secondary forms. Recent advances regarding molecular diagnosis may be useful to distinguish from one another, especially in sporadic cases starting in early infancy. Materials and Methods In this report, we evaluated three Argentinean patients with clinical suspicion of HLH, but without family history. We excluded mutations in the perforin gene but identified in the three patients a novel homozygous deletion (c. 581-584delTGCC; p.Leu194- ProfsX2) in the gene-encoding syntaxin 11 (STX11), causing a premature termination codon. Results and Conclusion Each parent from the three unrelated families resulted heterozygous for this deletion confirming the diagnosis of familial hemophagocytic lymphohistiocytosis type 4. Patients shared the same single-nucleotide polymorphism profile in STX11 gene, and genotyping at ten microsatellites surrounding this gene support the presence of a single-haplotype block carrying the novel mutation. © Springer Science+Business Media, LLC 2010. Source

Chaves A.,Servicio de Hematologia Oncologia | Eberle S.E.,Servicio de Hematologia Oncologia | Defelipe L.,University of Buenos Aires | Pepe C.,Servicio de Hematologia Oncologia | And 5 more authors.
Clinical Biochemistry

Objective: The enzyme glucose-6-phosphate dehydrogenase (G6PD) catalyses the first step in the pentose phosphate pathway, producing nicotinamide adenine dinucleotide phosphate (NADPH). NADPH plays a crucial role in preventing oxidative damage to proteins and other molecules in cells, mostly red blood cells. G6PD deficiency has an x-linked pattern of inheritance in which hemizygous males are deficient, while females may or may not be deficient depending on the number of affected alleles. We report two novel DNA variants in the G6PD gene detected in two male probands with chronic nonspherocytic hemolytic anemia (CNSHA), who were referred for hematological evaluation. Method: Probands and their relatives underwent clinical, biochemical, and molecular assessment. Results: Two novel DNA variants, c.995C. >. T and c.1226C. >. A, were found in this study. At the protein level, they produce the substitution of Ser332Phe and Pro409Gln, respectively. These DNA variants were analyzed in the female relatives of probands for genetic counseling. Conclusions: The novel DNA variants were classified as class I based on the clinical, biochemical, and molecular evaluations performed. © 2016. Source

Mansini A.P.,Servicio de Hematologia Oncologia | Fernandez D.A.,Servicio de Hematologia Oncologia | Aguirre F.M.,Servicio de Hematologia Oncologia | Pepe C.,Servicio de Hematologia Oncologia | And 4 more authors.
Medicina (Argentina)

The co-inheritance of erythrocyte defects, hemoglobinopathies, enzymopathies, and membranopathies is not an unusual event. For the diagnosis, a laboratory strategy, including screening and confirmatory tests, additional to molecular characterization, was designed. As the result of this approach, a 24-year-old man carrying a hemoglobinopathy (Hemoglobin Woodville) and an enzymopathy (glucose-6-phosphate dehydrogenase deficiency) was identified. In the heterozygous state hemoglobin Woodville, is asymptomatic, and homozygous or double heterozygous individuals have not been reported thus far. On the other hand, previously described double point mutation in the gene for glucose-6-phosphate dehydrogenase c. [202G>A; 376A>G], p. [Val 68Met; Asn126Asp], causes hemolysis of varying severity after food or drug intake or infections. This case highlights the importance of the methodology carried out for the diagnosis, treatment, and proper genetic counseling. © 2015, Instituto de Investigaciones Medicas. All rights reserved. Source

Eberle S.E.,Servicio de Hematologia Oncologia | Rosolen N.G.,Servicio de Hematologia Oncologia | Urtasun C.,Servicio de Hematologia Oncologia | Sciuccati G.,Servicio de Hematologia Oncologia | And 7 more authors.
Archivos Argentinos de Pediatria

We describe the laboratory and clinical characteristics of 50 patients with glucose 6 phosphate dehydrogenase deficiency (G6PD). G6PD deficiency represented 1.1% of all the diagnosis made. Coexistence of G6PD with other erythropathy was detected as follow: G6PG/HbS 2 patients and G6PG/hereditary spherocytosis 1 patient. A positive Brewer's test was found in 100% of males but in only 56% of women. Males had a mean enzymatic activity (MEA) of 0.85 ± 0.52 U/g Hb. Women, with positive Brewer's test, showed a MEA of 3.82 ± 1.26 U/g Hb, while the MEA of women with negative Brewer's test was 5.65 ± 2.84 U/g Hb. Genetic counseling and the list of food and drugs potentially harmful was given to all patients. The inclusion of simple screening tests, such as Brewer's test, in the study of anemia, enables us to detect asymptomatic males and carriers in whom this enzymopathy was co-inherited with another erythropathy. Source

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