Reporting that manganese could protect from Ganoderic-acid-F Stx1-S mediated toxicity to HeLa cells in vitro and BALB/c mice in vivo. As these studies only investigated protection from the less potent Stx1-S, we investigated the potential of manganese to protect from both Stx1-S and the more potent Stx2a in experimental systems well-established for assessing Stx toxicity: in vitro, using Vero monkey kidney epithelial cells, and in vivo, using outbred CD-1 mice. Mukhopadhyay and Linstedt reported that manganese protects cells in vitro from Stx1-S. However, in our studies, we did not observe manganese protection from either Stx1-S or Stx2a using an experimental system that differed from those of Mukhopadhyay and Linstedt in several respects.Even though no objective responses were seen in that study, responses were observed when bevacizumab was used in combination with irinotecan in children with low and high-grade glioma. Anecdotal reports and case series of combination of bevacizumab, irinotecan and temozolomide have been published, but this combination has not been systematically studied in children. The maximum tolerated dose of irinotecan administered intravenously over five days in combination with temozolomide is yet to be defined. A previous study of irinotecan and temozolomide performed in neuroblastoma patients used a lower threshold for platelets. We conducted a phase I study of escalating doses of irinotecan together with standard doses of vincristine, temozolomide and bevacizumab in patients with relapsed or refractory solid tumors. Irinotecan has been administered using various schedules in both adults and children. Preclinical studies in Gomisin-D pediatric tumors by Houghton et al, showed that a protracted schedule of irinotecan given daily for 5 days per week for 2 consecutive weeks resulted in greater response rates when compared to the same dose administered over 5 days. Based on this, irinotecan was initially administered on a protracted schedule of 5 consecutive days for 2 weeks in pediatric studies. A subsequent randomized phase II study of protracted versus 5 day schedule of irinotecan did not show any difference in response rates in 
rhabdomyosarcoma patients. Another trial comparing the two regimens of oral irinotecan given with vincristine and temozolomide reported higher frequency of dose limiting toxicity in the protracted regimen. Since the 5 day schedule is more convenient for patients, we used this schedule in our trial. The MTD for irinotecan administered as a single agent in a 5 day regimen ranges from 39-50 mg/m2 depending on the number of previous treatment regimens received. Myelosuppression was dose limiting in heavily pretreated patients while diarrhea was dose limiting in less heavily pretreated patients. Irinotecan 50mg/m2 and temozolomide 150 mg/m2 administered over 5 days every 3-4 weeks has been studied in neuroblastoma patients, but this study used a lower platelet count threshold of 30,000/L for administering subsequent cycles. Therefore, we decided to study escalating dose levels of irinotecan. Overall this regimen was tolerated well. There was no delay in therapy due to hematological toxicity. Similar to other studies with this backbone, the number of patients requiring platelet or blood transfusions was low.