Clinical Implications of Immune Checkpoints and the RANK/RANK-L Signaling Pathway in High-Grade Canine Mast Cell Tumors.

Mast cell tumors (MCTs) are the most common malignant cutaneous tumors in dogs, and they present extremely variable biological behavior. The interaction between RANK, RANK-L, and immune checkpoints is frequently detected in the tumor microenvironment, and, together, they participate in every stage of cancer development. Thus, the aim of this study was to characterize the molecular profiles of PD-L1, CTLA-4, RANK/RANK-L signaling pathway, and IFN-γ in primary tumors and lymph node metastases. Formalin-fixed, paraffin-embedded slides of MCTs and metastatic lymph nodes of ten dogs were submitted to immunohistochemical investigations. The results demonstrated that the tumor microenvironment of the high-grade mast cell tumors showed moderate or intense immunolabeling of all proteins, and the lymph node metastases also showed moderate or intense immunolabeling of checkpoint proteins. In addition, MCTs larger than 3 cm were associated with intensified PD-L1 (p = 0.03) in metastatic lymph nodes and RANK-L (p = 0.049) immunoreactivity in the tumor. Furthermore, dogs with a survival time of less than 6 months showed higher PD-L1 immunoreactivity (p = 0.042). In conclusion, high-grade MCT is associated with an immunosuppressive microenvironment that exhibits elevated RANK/RANK-L signaling and enhanced immune checkpoint immunoreactivity, potentially facilitating intratumorally immune escape. These biomarkers show promise as clinical indicators of disease progression and might response to immunotherapy in dogs with high-grade MCTs, thus emphasizing their importance for guiding treatment decisions and improving outcomes.

Corioamnionitis histológica y neurodesarrollo en niños prematuros menores de 34 semanas, Lima-Perú

Para determinar los efectos de la corioamnionitis histológica en el neurodesarrollo de los prematuros menores de 34 semanas evaluados a los 2 años de edad corregida se realizó un estudio secundario de casos y controles. Fueron analizados los datos clínicos, hallazgos histológicos de la placenta e índices del desarrollo medidos por la Escala Bayley III de 38 niños expuestos y 53 niños no expuestos. Las infecciones genitourinarias de la madre y la sepsis precoz fueron más frecuentes en el grupo expuesto (p<0,005). Las dimensiones del desarrollo cognitivo, motor y lenguaje fueron normales en ambos grupos. Los expuestos al subtipo subcorionitis obtuvieron menor desempeño en las tres dimensiones. La corioamnionitis histológica no mostró influencia sobre el neurodesarrollo en prematuros menores de 34 semanas a los 2 años de edad. Se recomienda estudios longitudinales y multicéntricos para definir los efectos a largo plazo.

SUMMARY The objective of this study was to determine the effects of histologically diagnosed chorioamnionitis on neurodevelopment of premature babies born with less than 34-week gestational age who were assessed at two-year corrected age. A secondary case-control study was carried out. Clinical data, placental histological findings, and development indexes assessed using the Bayley III scale were analyzed in 38 exposed children and 53 non-exposed children. Genitourinary infections in mothers and early sepsis were more frequent in the exposed group (p<0.005). Cognitive development, motor development and language were normal in both groups. Those children exposed to the chorionitis subtype had lower scores in the aforementioned variables. Histologically diagnosed chorioamnionitis did not show any influence on neurodevelopment in premature babies born with less than 34-week gestational age when they were assessed at two years. Longitudinal and multicenter studies are advised in order to define the long-term effects.

Risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis Lima, Peru. / Riesgo de daño cerebral en prematuros menores de 34 semanas expuestos a corioamnionitis histológica, Lima, Perú.

OBJECTIVES: To assess the risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis (HCA). MATERIALS AND METHODS: A cohort study was conducted at the Hospital Cayetano Heredia, during 2015. Premature infants under 34 weeks of gestational age, who had histopathological examination of the placenta, were included. The types of HCA evaluated were sub-chorionitis, chorionitis, chorioamnionitis, with or without funisitis. Brain damage was evaluated in three age periods, between 0 and 7 days, between 7 and 30 days and at 40 weeks of corrected gestational age. A neurological follow-up and regular controls were performed with brain ultrasound. RESULTS: A total of 85 premature infants were included, 47.1% were women and the mean gestational age was 30.9 weeks. From the total, 42% (36/85) were born exposed to HCA. Premature rupture of membranes was the main cause of sepsis, which was related to neurological damage. HCA was associated with intraventricular hemorrhage (IVH) during the first week and with white matter lesions between 7 and 30 days of age (p = 0.035). The chorioamnionitis type of HCA was associated with neurological damage during the first week (RR = 2.11, 95% CI: 1.09-4.11) and between 7 and 30 days of age (RR = 2.72, 95% CI: 1.07-6.88). CONCLUSIONS: Chorioamnionitis was a risk factor for developing brain injuries in premature infants under 34 weeks of gestational age. It was also a risk factor for HIV during the first 7 days and for white matter injuries between 7 and 30 days of age. At 40 weeks of corrected gestational age, extreme premature infants with HCA had more extensive brain damage.

OBJETIVOS: Evaluar el riesgo de daño cerebral en prematuros menores de 34 semanas expuestos a corioamnionitis histológica (CAH). MATERIALES Y MÉTODOS: Se realizó un estudio de cohortes en el Hospital Cayetano Heredia, durante el 2015. Fueron incluidos prematuros menores de 34 semanas que tuvieran examen histopatológico de la placenta. Los tipos de CAH evaluados fueron subcorionitis, corionitis, corioamnionitis, con o sin funisitis. El daño cerebral se evaluó en tres periodos de edad, entre 0 y 7 días, entre 7 y 30 días y a las 40 semanas gestacionales corregidas. Se realizó un seguimiento neurológico y controles con ecografía cerebral. RESULTADOS: Se estudiaron 85 prematuros, 47,1% eran mujeres y la media de la edad gestacional fue de 30,9 semanas. El 42% (36/85) nacieron expuestos a CAH. La ruptura prematura de membrana fue la principal generatriz de sepsis, y la sepsis se relacionó con daño neurológico. La CAH estuvo asociada con hemorragia intraventricular (HIV) durante la primera semana y con lesiones de la sustancia blanca entre los 7 y 30 días de edad (p = 0,035). El tipo corioamnionitis de CAH se asoció al daño neurológico durante la primera semana (RR = 2,11; IC 95%: 1,09-4,11) y entre los 7 y 30 días de vida (RR = 2,72; IC 95%: 1,07-6,88). CONCLUSIONES: La corioamnionitis fue un factor de riesgo para desarrollar lesiones cerebrales en prematuros menores de 34 semanas, para HIV durante los primeros 7 días y lesiones de sustancia blanca entre los 7 y los 30 días de edad. A las 40 semanas de edad corregida, los prematuros extremos con CAH tuvieron lesiones cerebrales más extensas.

Riesgo de daño cerebral en prematuros menores de 34 semanas expuestos a corioamnionitis histológica, Lima, Perú / Risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis Lima, Peru

RESUMEN Objetivos: Evaluar el riesgo de daño cerebral en prematuros menores de 34 semanas expuestos a corioamnionitis histológica (CAH). Materiales y métodos: Se realizó un estudio de cohortes en el Hospital Cayetano Heredia, durante el 2015. Fueron incluidos prematuros menores de 34 semanas que tuvieran examen histopatológico de la placenta. Los tipos de CAH evaluados fueron subcorionitis, corionitis, corioamnionitis, con o sin funisitis. El daño cerebral se evaluó en tres periodos de edad, entre 0 y 7 días, entre 7 y 30 días y a las 40 semanas gestacionales corregidas. Se realizó un seguimiento neurológico y controles con ecografía cerebral. Resultados: Se estudiaron 85 prematuros, 47,1% eran mujeres y la media de la edad gestacional fue de 30,9 semanas. El 42% (36/85) nacieron expuestos a CAH. La ruptura prematura de membrana fue la principal generatriz de sepsis, y la sepsis se relacionó con daño neurológico. La CAH estuvo asociada con hemorragia intraventricular (HIV) durante la primera semana y con lesiones de la sustancia blanca entre los 7 y 30 días de edad (p = 0,035). El tipo corioamnionitis de CAH se asoció al daño neurológico durante la primera semana (RR = 2,11; IC 95%: 1,09-4,11) y entre los 7 y 30 días de vida (RR = 2,72; IC 95%: 1,07-6,88). Conclusiones: La corioamnionitis fue un factor de riesgo para desarrollar lesiones cerebrales en prematuros menores de 34 semanas, para HIV durante los primeros 7 días y lesiones de sustancia blanca entre los 7 y los 30 días de edad. A las 40 semanas de edad corregida, los prematuros extremos con CAH tuvieron lesiones cerebrales más extensas.

ABSTRACT Objectives: To assess the risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis (HCA). Materials and methods: A cohort study was conducted at the Hospital Cayetano Heredia, during 2015. Premature infants under 34 weeks of gestational age, who had histopathological examination of the placenta, were included. The types of HCA evaluated were sub-chorionitis, chorionitis, chorioamnionitis, with or without funisitis. Brain damage was evaluated in three age periods, between 0 and 7 days, between 7 and 30 days and at 40 weeks of corrected gestational age. A neurological follow-up and regular controls were performed with brain ultrasound. Results: A total of 85 premature infants were included, 47.1% were women and the mean gestational age was 30.9 weeks. From the total, 42% (36/85) were born exposed to HCA. Premature rupture of membranes was the main cause of sepsis, which was related to neurological damage. HCA was associated with intraventricular hemorrhage (IVH) during the first week and with white matter lesions between 7 and 30 days of age (p = 0.035). The chorioamnionitis type of HCA was associated with neurological damage during the first week (RR = 2.11, 95% CI: 1.09-4.11) and between 7 and 30 days of age (RR = 2.72, 95% CI: 1.07-6.88). Conclusions: Chorioamnionitis was a risk factor for developing brain injuries in premature infants under 34 weeks of gestational age. It was also a risk factor for HIV during the first 7 days and for white matter injuries between 7 and 30 days of age. At 40 weeks of corrected gestational age, extreme premature infants with HCA had more extensive brain damage.