RESUMO
Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.
RESUMO
BACKGROUND: Ultrasonography is a well-established efficient diagnostic tool for ileocolic intussusceptions in children. It can also be used to control hydrostatic reduction by saline enemas. This reduction method presents the advantage of avoiding radiations. Parents can even stay with their children during the procedure, which is comforting for both. The purpose of this study was to present our 20 years' experience in intussusception reductions using saline enema under ultrasound control and to assess its efficiency and safety. MATERIAL AND METHODS: This retrospective single center study included patients with ileocolic intussusceptions diagnosed by ultrasound between June 1993 and July 2013. We excluded the data of patients with spontaneous reduction or who underwent primary surgery because of contraindications to hydrostatic reduction (peritonitis, medium or huge abdominal effusion, ischemia on Doppler, bowel perforation). A saline enema was infused into the colon until the reduction was sonographically confirmed. The procedure was repeated if not efficient. Light sedation was practiced in some children. RESULTS: Eighty-tree percent of the reductions were successful with a median of 1 attempt. Reduction success decreased with the number of attempts but was still by 16% after 4 attempts. The early recurrence rates were 14.5%, and 61.2% of those had a successful second complete reduction. Forty-six patients needed surgery (11 of them had a secondary intussusception). Sedation multiplies success by 10. In this period, only one complication is described. CONCLUSION: Ultrasound guided intussusception reduction by saline enema is an efficient and safe procedure. It prevents exposure of a young child to a significant amount of radiation, with similar success rate. We had very low complication rate (1/270 cases or 3). The success rate could be increased by standardized procedures including: systematic sedation, trained radiologists, accurate pressure measurement, and number and duration of attempts.
