Mutaciones somáticas raras en un paciente con retinoblastoma unilateral

Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Somatic inactivation of both alleles of the RB1 tumor suppressor gene in a developing retina is a crucial event in the initiation of tumorigenesis in most cases of isolated unilateral retinoblastoma. We analyzed the DNA from tumor tissue and peripheral blood of a unilateral retinoblastoma patient to determine the RB1 mutation status and to provide an accurate genetic counseling. A comprehensive approach, based on our previous experience, was used to identify the causative RB1 mutations. Screening for RB1 mutations was performed by PCR direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and Real Time-PCR analyses. Three different mutations were identified in the tumor DNA, which were absent in blood DNA. The somatic origin of these mutations was vital to rule out the heritable condition in this patient.El retinoblastoma (RB) es el cáncer ocular más común de la niñez. La inactivación somática de ambos alelos del gen supresor de tumores RB1 en la retina en desarrollo es un evento crucial en la iniciación de la tumorigénesis en la mayoría de los casos de retinoblastoma unilateral. Nosotros analizamos el ADN de tumor y de sangre periférica de un paciente con retinoblastoma unilateral para identificar las mutaciones y así proveer un asesoramiento genético a la familia. Para ello utilizamos un protocolo basado en nuestra previa experiencia para identificar todas las mutaciones en el gen RB1 que causaron el RB. El rastreo de mutaciones se realizó por medio de los siguientes análisis: PCR-secuenciación, amplificación multiplex de sondas ligadas (MLPA) y PCR-Tiempo Real. Se encontraron tres mutaciones diferentes en el ADN del tumor, las cuales estaban ausentes en el ADN de la sangre. El origen somático de estas mutaciones es importante para indicar que la enfermedad no es hereditaria.Fil: Ottaviani, Daniela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Alonso, Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Szijan, Irena. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Mutations in the RB1 Gene in Argentine Retinoblastoma Patients and Uncommon Clinical Presentations

Background: Retinoblastoma, the most common ocular cancer of childhood, is caused by inactivation of the RB1 tumor suppressor gene in the developing retina. It may occur as unilateral, bilateral or rarely as multicentric retinoblastoma, including pineal or suprasellar tumors. Being the retinoblastoma a hereditary cancer, identification of the causative mutation is important for risk prediction in the family members. An early detection of tumor is critical for survival and eye preservation. Screening for RB1 mutations is important for early tumor detection, critical for survival and eye preservation. Purpose: To identify causative RB1 mutations in retinoblastoma patients with different clinical presentations, some of them with a rare multicentric retinoblastoma or with a second non ocular malignancy, as well as the rare association with down syndrome. A comprehensive approach was used to identify the mutations and to detect children with a hereditary condition. Methods: A cohort of 20 patients with unilateral, bilateral and multicentric retinoblastoma was studied. Blood and tumor DNA was analyzed by sequencing, segregation of polymorphisms and MLPA analyses. Some of the rare mutations were validated by cloning or by Real-Time PCR. Results: Six germline and seven somatic mutations were identified; they include nonsense, frameshift, splice mutations and gross rearrangements, four of them novel. Three out of four nonsense/ frameshift germline mutations were associated with severe phenotype: bilateral and multicentric retinoblastomas. The at-riskhaplotype was identified in a familial case including one patient with osteosarcoma; it was useful for detection of mutation carriers. Conclusions: This study allowed us to identify causative RB1 mutations, including several novels. Some patients showed uncommon clinical presentations of retinoblastoma. These data are significant for genetic counseling. Our results support the relevance of carrying out complete genetic screening for RB1 mutations in both constitutional and tumor tissues.Fil: Ottaviani, Daniela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Parma, Diana Lidia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Ferrer, Marcela Maria. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Florencia Giliberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Luce, Leonela Natalia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Alonso, Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Servicio de Hemato-Oncología; ArgentinaFil: Szijan, Irena. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Cuando las infancias cuentan: encuentros entre la universidad y escuelas primarias

En este trabajo compartiremos la experiencia de trabajo en el marco del proyecto de extensión universitaria denominado “Las infancias cuentan en la escuela. El derecho a la educación: aprendizajes desde los vínculos y el reconocimiento de diversidades y desigualdades.”, de la Facultad de Trabajo Social de la UNLP. Desde este proyecto se aborda el espacio escolar en vistas a resignificarlo, recrearlo, haciendo partícipe a toda la comunidad educativa. Pretendemos desde una mirada interdisciplinaria dar vida a un nosotros inclusivo que sea capaz de mirar, contener y desplegar las diversas formas que existen de habitar la escuela desde las múltiples infancias; nos proponemos al decir de Skliar (2018) "dar infancia a la niñez" en la escuela, y, en ese sentido profundizar el derecho a la educación de lxs niñxs. Al respecto, pensamos que la universidad constituye un elemento clave desde la extensión universitaria para repensar y fundamentar intervenciones críticas en otras instituciones, en este caso las escuelas públicas. En ese sentido, sostenemos que la articulación universidad-escuelas puede fortalecer lo democrático y la perspectiva de derechos, a través de un juego de mutuo enriquecimiento.Eje temático 1: Neoliberalismo y desigualdades sociales. Precariedades de la vida cotidiana y de la trama institucional.Grupo de trabajo 2: Educación escolar e intervención social: experiencias, interrogantes y desafíos.Facultad de Trabajo Socia

Oral Problems in Oncology Patients Undergoing Chemotherapy for Solid Tumors: A Prospective Observational Study

PURPOSE: Oral problems in a group of oncological patients undergoing chemotherapy (CT) for solid tumors have been examined. Incidence and severity of patients’ self-reported oral problems have been evaluated along their interaction with age, gender, tumor diagnosis and stage, presence of mestastasis, CT agent type, and number of CT cycle. We also analyzed the presence of paraesthesia and anaesthesia and their predisposing factors associated with clinical and treatment-related variables. METHODS: Patients were asked to fill in a questionnaire to evaluate the onset and the intensity of oral and perioral pain, oral mucositis, salivary gland hypofunction, dysgeusia, dysphagia, dysphonia, and sensitivity neuropathy (paraesthesia or dysaesthesia) since the last CT infusion. We also investigated which types of medications have possibly been used and who recommended it, as well as patients’ degree of awareness about the possibility of oral problems arising during CT. RESULTS: We recruited 194 patients and obtained 491 questionnaires. We found that a metastatic disease was a risk factor for OM (OR 2.02, p = 0.026) and salivary gland hypofunction (OR 1.66, p = 0.042) and that platinum agents, compared to mitotic inhibitors, increased the risk of developing salivary gland hypofunction (OR 2.16, p = 0.013), dysphagia (OR 3.26, p = 0.001), and anaesthesia (OR 5.16, p = 0.041). Young age was a slight protective factor for most symptoms. The 80% of enrolled patients were informed by the oncologist about possible oral problems arising during CT. CONCLUSIONS: Our study highlighted the importance of collecting observational data from the patients’ perspective on oral problems arising during the routine oncology practice, across a range of solid tumors and CT regimens. The relevance of these findings focused on the key role of the multidisciplinary team in advising the patients on the possible occurrence of oral problems, also by recommending their management

Advancements in Understanding and Classifying Chronic Orofacial Pain: Key Insights from Biopsychosocial Models and International Classifications (ICHD-3, ICD-11, ICOP)

In exploring chronic orofacial pain (COFP), this review highlights its global impact on life quality and critiques current diagnostic systems, including the ICD-11, ICOP, and ICHD-3, for their limitations in addressing COFP's complexity. Firstly, this study outlines the global burden of chronic pain and the importance of distinguishing between different pain types for effective treatment. It then delves into the specific challenges of diagnosing COFP, emphasizing the need for a more nuanced approach that incorporates the biopsychosocial model. This review critically examines existing classification systems, highlighting their limitations in fully capturing COFP's multifaceted nature. It advocates for the integration of these systems with the DSM-5's Somatic Symptom Disorder code, proposing a unified, multidisciplinary diagnostic approach. This recommendation aims to improve chronic pain coding standardization and acknowledge the complex interplay of biological, psychological, and social factors in COFP. In conclusion, here, we highlight the need for a comprehensive, universally applicable classification system for COFP. Such a system would enable accurate diagnosis, streamline treatment strategies, and enhance communication among healthcare professionals. This advancement holds potential for significant contributions to research and patient care in this challenging field, offering a broader perspective for scientists across disciplines

Late-term fetuses with reduced umbilical vein blood flow volume: An under-recognized population at increased risk of growth restriction

Objectives: To investigate the umbilical vein and uterine arteries blood flow volume (UV-Q, UtA-Q) in late-term pregnancies.& nbsp;Study design: This was a prospective observational cohort study of singleton pregnancies > 40 + 0 weeks in which UV-Q and UtA-Q, both absolute and normalized for estimated fetal weight (EFW) values, were evaluated in relation to AC drop of > 20 percentiles from 20 weeks to term, Doppler signs of fetal cerebral blood flow redistribution and composite adverse perinatal outcome. The presence of neonatal hypoglycaemia and the need of formula milk supplementation were also examined.& nbsp;Results: The study population comprised 200 women. Fetuses with AC drop (n = 34) had a significantly lower UV-Q and UV-Q/EFW than fetuses without AC drop (n = 166): median UV-Q 184 ml/min (IQR 143-225) vs 233 ml/min (IQR 181-277), p = 0.0006; median UV-Q/EFW 55 ml/min/kg (IQR 42-66) vs 63 ml/min/kg (IQR 48-74), p = 0.03. Fetuses with cerebral blood flow redistribution (n = 48) had a significantly lower UV-Q and UV-Q/EFW than those without (n = 134): median UV-Q 210 ml/min (IQR 155-263) vs 236 ml/min (IQR 184-278), p = 0.04; median UV-Q/EFV 58 ml/min/kg (IQR 45-70) vs 65 ml/min/kg (IQR 50-76), p = 0.04. There was a significant moderate correlation between middle cerebral artery pulsatility index (MCA-PI) and UV -Q and UV-Q/EFW (Spearman Rho-0.20 and-0.20; p = 0.008 and p = 0.006).& nbsp;Conclusions: The umbilical vein blood flow volume might have a potential role to identify fetuses with stunted growth in late-term pregnancies

Recurrent somatic chromosomal abnormalities in relapsed extraocular retinoblastoma

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.Fil: Aschero, María del Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Francis, Jasmine H.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Ganiewich, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Gomez Gonzalez, Soledad. Hospital Sant Joan de Deu Barcelona; EspañaFil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ottaviani, Daniela. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lemelle, Lauriane. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Mena, Marcela Daniela C. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Correa Llano, Genoveva. Hospital Sant Joan de Deu Barcelona; EspañaFil: Lamas, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Szijan, Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; EspañaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Doz, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Radvanyi, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; EspañaFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study

BACKGROUND AND OBJECTIVES: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate. DESIGN AND METHODS: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily. RESULTS: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months. INTERPRETATION AND CONCLUSIONS: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses