mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

Needle decompression to avoid tension pneumoperitoneum and hemodynamic compromise after pneumatic reduction of pediatric intussusception.

BACKGROUND: The contemporary management of children with ileocolic intussusception often includes pneumatic reduction. While failure of the procedure or recurrence after reduction can result in the need for surgical treatment, more serious adverse sequelae can occur including perforation and, rarely, tension pneumoperitoneum. During the last year, four cases of perforation during attempted pneumatic reductions complicated by tense pneumoperitoneum have occurred in our center. OBJECTIVE: We have elected to report our patient experience, describe methods of management and review available literature on this uncommon but serious complication. MATERIALS AND METHODS: Using ICD-9 diagnosis codes, we reviewed the records of children with intussusception during 2011. Demographic and therapeutic clinical data were collected and summarized. RESULTS: During the study period, 101 children with intussusception were treated at our institution, with 19% (19/101) of them requiring surgical intervention. Four children (4%) experienced a tense pneumoperitoneum during air enema reduction, prompting urgent needle decompression in the fluoroscopy suite. These children required bowel resection during subsequent laparotomy. No deaths occurred. CONCLUSION: Pneumoperitoneum is a real and life-threatening complication of pneumatic enemas. It requires immediate intervention and definitive surgical management. Caution should be exercised by practitioners performing this procedure at institutions where pediatric radiology experience is limited and immediate pediatric surgical support is not available.