RESUMEN
The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.
Asunto(s)
Pronóstico , Sarcoma de Ewing/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adolescente , Animales , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Xenoinjertos/efectos de los fármacos , Humanos , Irinotecán/farmacología , Irinotecán/uso terapéutico , Masculino , Ratones , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND/PURPOSE: Although the pathogenesis of necrotizing enterocolitis (NEC) is not completely defined, ischemia appears to be one of the most important causative factors. Trefoil factor family peptide 3 (TFF3) is a peptide normally expressed in the small bowel and colon and is involved in the maintenance and repair of mucosal integrity. The authors hypothesized that monomeric (TFF3 Ser57) and dimeric (TFF3 Cys57) recombinant TFF3 may prevent the development and accelerate healing of intestinal ischemia-reperfusion injury in weanling rats. METHODS: Intestinal injury was induced in 18-day-old rats by occlusion of the superior mesenteric vessels for 60 minutes. To examine the protective effect, rats were given 3 microg/g of TFF3 Ser57 or TFF3 Cys57 by subcutaneous or enteral administration 30 minutes before the vascular occlusion. To examine the healing effect, rats were given 3 microg/g of TFF3 Ser57 or TFF3 Cys57 by subcutaneous or enteral administration 60 minutes after the beginning of reperfusion. Samples from small bowel and colon were collected for morphometric analysis after 3 hours of reperfusion. Mucosal damage was assessed by the Chiu score. RESULTS: Both forms of TFF3 reduced the amount of damage when administered before the ischemia. Administration of TFF3 Ser57 and TFF3 Cys57 after the beginning of reperfusion significantly increased the villous height and decreased the Chiu score in the small intestine and colon. CONCLUSIONS: TFF3 Ser57 monomer and TFF3 Cys57 dimer prevent the development and promote healing of ischemia-reperfusion injury in weanling rats. There are no differences between the routes of administration of TFF3.
