Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations.

Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant" for this intriguing group.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

Evaluación de los parámetros de patología en el pronóstico de pacientes con retinoblastoma / Assessing pathology parameters in the prognosis of patients with retinoblastoma

Existe la necesidad de identificar los factores de riesgo de anatomía patológica (compromiso de humor vítreo, nervio óptico en sus diversas extensiones, esclera, cámara anterior y coroides) en globos oculares enucleados de pacientes con retinoblastoma sin tratamiento previo, para así saber en que pacientes indicar o no un tratamiento de quimioterapia. Por este motivo se llevó a cabo un estudio retrospectivo de dichos pacientes durante el período 1997-2006, en el Departamento de Pediatría del INEN. Se tuvieron 305 pacientes nuevos con retinoblastoma, de los cuales 85 ingresaron al presente estudio. Del análisis efectuado se evidenció que el compromiso aislado del humor vítreo y de nervio óptico prelaminar no constituyen factores de riesgo por los cuales haya que indicarse tratamiento de quimioterapia adicional, a diferencia de los pacientes con compromiso de nervio óptico post laminar y en aquellos con compromiso del borde quirúrgico. Así mismo se confirma el pronóstico desfavorable de la combinación de compromiso de nervio óptico son coroides, resaltando la necesidad de tratamiento de quimioterapia en este grupo.

There is a need to identify the pathologic risk factors in enucleated eyes with retinoblastoma (involvement of the vitreous, optic nerve in its different extensions, sclera, anterior chamber and choroids) in previously untreated patients to decide which patients should or should not receive adjuvant therapy. This is a retrospective analysis of 305 new patients with retinoblastoma seen in the Pediatric Department of INEN during the period of January 1997 and December 2006, 85 of these patients have been included in the present study. We found that isolated involvement of the vitreous and prelaminar optic nerve were no risk factors for giving additional chemotherapy treatment. Those with postlaminar optic nerve involvement and those with disease at the cut end of the optic nerve should receive treatment. We also found that the combination of involvement of the optic nerve and choroids carries a ban prognosis in these patients, requiring the need of additional chemotherapy treatment for this group.

Pubertad precoz transitoria en la niña / Transient precocious puberty in the girl

Objetivo: Presentar cinco casos de pubertad precoz transitoria o regresiva en la niña, forma poco usual de presentación de la pubertad precoz. Material y métodos: se revisaron las historias clínicas de pacientes de sexo femenino con pubertad precoz vistas en el Servicio de Endocrinología del Instituto Nacional de Salud del Niño entre el año 1982 y 2003. Se hallaron 5 historias de pacientes que presentaron pubertad transitoria o regresiva. Los datos de historia clinica y exámenes auxiliares se recolectaron en una ficha elaborada para este propósito. Resultados: La edad promedio al momento del diagnóstico fue de 29 meses (rango: 5 meses a 7 años). Los caracteres sexuales secundarios remitieron en todos los casos, en un período promedio de 11,4 meses (rango: 3 a 20 meses). Por lo general, estos casos se presentan a edades tempranas y los caracteres sexuales regresionaron alrededor del año del inicio de su presentación. No existió progresión rápida de la edad ósea ni de la velocidad de crecimiento. La prueba de GnRH, así como el desarrollo de genitales internos detectados ecográficamente, retornaron a sus valores prepuberales en todos los casos. Conclusiones: Estas formas clínicas deben tenerse en cuenta a fin de evitar tratamientos innecesaios con frenadores de la pubertad.

Objetive: To report five cases of transient or regressive precocious puberty in girls, as an unusual form of precocious puberty. Patients and methods: The medical records of girls with precocious puberty were reviewed. Five cases of transient or regressive precocious puberty were found. They all attended the Endocrinology Unit at Instituto Nacional de Salud del Niño between the years 1982 and 2003. The clinical data and the results of the exams were recorded in a form designed for this study. Results: The mean age at time of diagnosis was 29 month (range: 5 months-7 years). The pubertal signs disappeared in a mean time of 11,4 months (range: 3-20 months). Generally, these cases appear at early ages and the puertal signs last for one year. There was no increase in the bone age maturation or growth rates. The GnRH test and the ultrasonography changes in the internal genitalia, return to a pre puberty state in all the cases. Conclusions: These clinical form must be considered in order to avoid unnecessary treatment as puberty delayers.