Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

We thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, for funding, who received an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103639 for the use of the Histology and Immunohistochemistry Core for providing immunohistochemistry and photographic services. This work was also supported by Oklahoma State University, Center of Veterinary Health Science (Support Grant AE-1-50060 to P.C.S.), the Musella Foundation (R.A.T.), and the Childhood Brain Tumor Foundation (R.A.T.).Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals (Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05), as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients.Yeshttp://www.plosone.org/static/editorial#pee

Remote arterial vasculitis as a possible complication of Phosphorus-32 Radiosynovectomy

Patients with hemophilia suffer from repeated episodes of hemarthrosis leading to chronic inflammation and synovitis. Radiosynovectomy is an effective nonsurgical modality that can reduce inflammation, pain, and hemarthrosis in such cases. We describe an adolescent male with severe Hemophilia A, who developed arterial vasculitis and perivasculitis targeting the brachiocephalic, right common carotid, and right subclabvian arteries occurring within few days after difficult Phosphorus-32 radiosynovectomy, possibly as a complication of the procedure. Despite prophylaxis with recombinant FVIII therapy, he developed chronic synovitis and underwent radionuclide synovectomy with P-32 injection to the left ankle and right knee. Five days later, he developed pain in the lower right neck and right upper chest. Computed tomography and magnetic resonance imaging and angiography demonstrated inflammation involving the arteries of the right thoracic inlet. Geiger-Mueller meter indicated increased radioactivity not only in the left ankle and right knee but also in the right upper chest. Detection of radioisotope at the right thoracic inlet corresponding to the area of vasculitis was indicative of likely deposition of the P-32 isotope in an area exposed to maximum cardiac output and increased blood flow, leading to subclavian, carotid, and innominate arteritis with surrounding edema. Keywords: Radiosynovectomy, Complication, Vasculitis, Phosphorous-32, Arterial, Extravasatio

Management Challenges in a Child with Chronic Hyponatremia: Use of V2 Receptor Antagonist

Chronic hyponatremia is very rare in children and is often seen in the setting of congestive heart failure or liver failure in adults. Here, we report an 8-year-old child with hypothalamic glioma who presented with severe hyponatremia. Initial management consisted of fluid restriction. This was very difficult for the child to follow and the child developed bizarre drinking habits requiring intervention from child psychiatry. So therapy was initiated with low dose V2 receptor antagonist under close inpatient monitoring. While initial response was reassuring, her sodium levels tended to drift down with longer duration of treatment requiring us to increase the dose frequently. Her response to therapy and her stable clinical situation off therapy suggest that she may have reset osmostat

Effect of OKN-007 on perfusion rates measured as rCBF in IC3752 pGBM tumor bearing mice.

<p>T2-images (top) and perfusion maps (bottom) of normal mouse brain (A-B), untreated IC3752 pGBM (C-D), and OKN-007-R treated animal (E-F). (G) The untreated group (n = 9) showed significantly lower rCBF values for the tumor regions when compared to the normal mice brains (n = 9). The OKN-007–R treated group (n = 4) showed significantly higher rCBF values compared to the untreated group, and was significantly lower than normal brain. Values are represented as means ± SD. Asterisks indicate statistically significant difference (*<i>p</i> < 0.05; ***p<0.01; ***p<0.001; ****p<0.0001). n.s.: not statistically significant. Group comparisons: (1) Normal vs. UT; (2) UT vs. OKN-007 (R); (3) OKN-007 (R) vs. OKN-007 (NR); (4) Normal vs. OKN-007 (R); (5) UT vs. OKN-007 (NR); and (6) Normal vs. OKN-007 (NR).</p

Effect of OKN-007 on the immunoexpression of SULF2 in IC3752 pGBM tumor bearing mice.

<p>(Ai-Ci) Immunohistochemistry expression of SULF2 in normal mouse brain, IC3752 pGBM UT, and OKN-007 treated animals, respectively. (Aii-Cii) Make up images for the immunoexpression of SULF2 in normal mouse brain, IC3752 pGBM UT, and OKN-007 treated animals, respectively. (D) OKN-007 significantly decreased the immunoexpression of SULF2 (%) in the treated responsive group (n = 4) when compared to the untreated animals (n = 3). There was no significant difference between the immunoexpression of SULF2 of the OKN-007–NR (n = 2) and the untreated groups. % SULF-2 levels in high-expression areas within the normal brain tissue were significantly lower than those in UT or OKN-007-treated mice. Values are represented as means ± SD. Asterisks indicate statistically significant difference (*<i>p</i> < 0.05; **<i>p</i> < 0.01). n.s.: not statistically significant. Red = positive, blue = negative, white = neutral, background. Scale bar = 200 μm. Group comparisons: (1) Normal vs. UT; (2) UT vs. OKN-007 (R); (3) OKN-007 (R) vs. OKN-007 (NR); (4) Normal vs. OKN-007 (R); (5) UT vs. OKN-007 (NR); and (6) Normal vs. OKN-007 (NR).</p

Effect of OKN-007 on microvessel density in IC3752 pGBM tumor bearing mice.

<p>Microvessel density (MVD) was measured via the immuno-expression of CD31. Immunohistochemistry images of CD31 levels in untreated (A) and OKN-007-treated (B) IC3752 pGBM tumors. (C) The MVD was significantly lower in the OKN-007–R treated group (n = 3) than in the untreated group (n = 7). There was no significant difference between the MVD for the OKN-007–NR (n = 4) and the untreated groups. The MVA was significantly lower in the OKN-007–R treated group (n = 3) than in the untreated group (n = 9). There was no significant difference between the MVA of the OKN-007–NR (n = 3) and the untreated groups. Values are represented as means ± SD. Asterisks indicate statistically significant difference (*<i>p</i> < 0.05). n.s.: not statistically significant. Scale bar = 200 μm. Group comparisons: (1) UT vs. OKN-007 (R); (2) OKN-007 (R) vs. OKN-007 (NR); and (3) UT vs. OKN-007 (NR).</p