Hyperbilirubinemia has been AbMole 12-O-Tiglylphorbol-13-isobutyrate reported with the use of irinotecan in both single agent and combination pediatric studies. Known serious adverse effects of bevacizumab including severe hemorrhage, gastrointestinal perforation, arterial thromboembolism, posterior leukoencephalopathy and cardiac side effects were not seen. The number of cycles administered in this study may have been too few to detect these rare side effects that are reported in adult studies. Central nervous system hemorrhage, and transient leukoencephalopathy have been reported in children who received bevacizumab. The patient who developed hypertension requiring antihypertensive treatment in our study, had a history of bilateral nephron sparing surgery, which may have contributed to developing hypertension. Due to reversible physeal dysplasia seen in juvenile monkeys following bevacizumab administration, we performed serial imaging of growth plates in seven patients who had open growth plates. We did not detect any growth plate expansion. Even though this study was performed primarily to study toxicity, the antitumor activity of this combination is encouraging. Five of the 12 patients had objective responses. Two other patients had stable disease through 12 cycles. All three patients were heavily pretreated and had a history of previous autologous bone marrow transplant and lung irradiation. This was unexpected as 17 patients with Wilms tumor who had received either single agent irinotecan or irinotecan and temozolomide in previous studies did not show a response. Blockade of vascular endothelial growth factor has been shown to cause regression of Wilms tumor in preclinical studies. Addition of bevacizumab to the chemotherapy backbone may explain the activity observed in Wilms tumor in our study. The MTD was irinotecan 50 mg/m2 on days 1-5 administered with vincristine 1.5 mg/m2 on days 1 and 8, temozolomide 100 mg/m2 and, bevacizumab 15mg/kg on day 1 every 21 days. This combination was tolerable and showed significant antitumor activity. This study supports additional investigation of this combination, particularly in patients with Wilms tumor. Our 
study can also serve as a template for adding other targeted therapies to the vincristine, irinotecan and temozolomide chemotherapy backbone. Despite advances in diagnostic and therapeutic techniques, the prognosis for most glioma patients remains dismal. Histomorphological criteria alone are not sufficient to predict the clinical outcome of gliomas. Thus, new avenues must be taken to integrate the molecular advances with the histological assessment of gliomas. The IDH1 mutations occur in the highly conserved residue R132, which is in the catalytic domain, where it binds to its substrate. The mutations in IDH2 consistently occur at the analogous amino acid R172, which is functionally equivalent to amino acid 132 of IDH1.