Evaluation of dopamine D₂/₃ specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: implications for measuring cortical dopamine release

In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine‐induced dopamine (DA) release in the human cortex with the DA D_2/3 radioligand [¹¹C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [¹¹C]FLB 457 signal in the cerebellum represents specific binding to D_2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [¹¹C]FLB 457 binding potential (BP) (BP_ND) would bias cortical DA release measurements. Thus, we evaluated the fractional contribution of specific binding to D_2/3 receptors in the human cerebellum for [¹¹C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [¹¹C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D_2/3 partial agonist. [¹¹C]FLB 457 distribution volume (V_T) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [¹¹C]FLB 457 V_T following aripiprazole ranged from ?33 to ?42% in the cortical regions of interest (ROIs). The aripiprazole‐induced change in [¹¹C]FLB 457 V_T in three potential reference regions suggests significant specific binding the cerebellum (CER, –17 ± 12%), but not pons (PON, –10 ± 10%) and centrum semiovale (CESVL, –3 ± 12%). Nevertheless, a reanalysis of the published [¹¹C]FLB 457 test–retest and amphetamine studies suggests that the use of the PON V_T and CESVL V_T as an estimate of nonspecific binding to derive [¹¹C]FLB 457 BP_ND in DA release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure DA release in the cortex. D_2/3 blocking studies with aripiprazole and [¹¹C]FLB 457 suggest specific binding to D_2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D_2/3 receptors in the cerebellum is lower than that in the cortical ROIs and that CER V_T is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [¹¹C]FLB 457 BP_ND. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

Ion channels in pediatric CNS Atypical Teratoid/Rhabdoid Tumor (AT/RT) cells: potential targets for novel therapeutic agents

The purpose of the current study was to quantify the reduction in T2 signal abnormality accompanying administration of the anti-angiogenic drug bevacizumab in recurrent glioblastoma (GBM) patients using a voxel-wise differential quantitative T2 (DQT2) mapping technique. Twenty-six patients with recurrent GBM treated with bevacizumab were scanned before and 4–6 weeks after treatment on a 1.5T clinical MR scanner. Quantitative T2 maps were created from proton density and T2-weighted images acquired using a standard multi-echo fast-spin echo sequence. T2 maps after treatment were co-registered with T2 maps prior to treatment in the same patient, and then voxel-wise subtraction was performed to create DQT2 maps for each patient. Results suggest DQT2 maps allow visualization and quantification of voxel-wise T2 changes resulting from anti-VEGF therapy. Results demonstrated a significant decrease in T2 within pre-treatment T2 abnormal regions (mean reduction = 49.4 ms at 1.5T) following anti-VEGF treatment (Wilcoxon signed rank test, P < 0.0001). An elevated residual, post-treatment, median T2 was predictive of both progression-free (Log-rank, P = 0.0074) and overall survival (Log-rank, P = 0.0393).     

Combination therapy of low-fluence photodynamic therapy and intravitreal ranibizumab for choroidal neovascular membrane in choroidal osteoma

Choroidal osteoma is an unusual form of intraocular calcification seen in otherwise healthy eyes. It is a benign idiopathic osseous tumor of the choroid, typically seen in young females. Choroidal neovascular membrane (CNVM) is a complication seen in one-third of these patients and carries a poor visual outcome. We report a case of a 25-year-old hyperthyroid female with choroidal osteoma and subfoveal CNVM in her left eye which was successfully treated using low-fluence photodynamic therapy (PDT) with verteporfin followed by a single injection of intravitreal ranibizumab.     

Technical aspects of laser treatment for acute retinopathy of prematurity under topical anesthesia

Retinopathy of prematurity (ROP) is a significant cause of childhood blindness. The criteria for laser therapy have been revised from threshold ROP to include the earlier stage of high-risk prethreshold ROP. Laser photocoagulation is an established technique for the treatment of ROP. However, the detailed procedure and techniques for laser photocoagulation have not yet been published. Adequate and appropriate laser photocoagulation for ROP is different from the application of lasers in adult retinal vascular diseases, and many ophthalmologists need to be trained in this technique if the outreach of ROP treatment programs is to improve. Laser under topical anesthesia has been practiced in India as a preferred modality especially due to logistics and risks of general anesthesia in these pre-term babies. We discuss the details of the technique as practiced at tertiary care ophthalmic hospitals in India, so that the nuances in treatment parameters and clinical decision-making can be usefully applied to ophthalmic practice. This will ultimately lead to safe and effective treatment delivery in ROP.     

Characterization of Bone Marrow Stromal Abnormalities in a Patient with Constitutional Trisomy 8 Mosaicism and Myelodysplastic Syndrome

The development of myeloid leukemias and myelodysplastic syndrome (MDS) is common in children with trisomy 8 mosaicism. However, the mechanisms by which the presence of an additional chromosome 8 translates to an increased risk of leukemias and MDS is currently unknown. The authors describe the analysis of stromal cells from a pediatric MDS patient with constitutional trisomy 8. Patient and control marrow stromal cells were analyzed for alterations in cytokine production. Clonogenic assays were used to examine stromal support for hematopoiesis. The interplay between leukemia cells and stroma was studied by co-culture experiments. The results indicate that stromal cell function in this patient was seriously altered in favor of progenitor cell proliferation and expansion. This indicates that constitutional trisomy 8 in stromal cells plays a critical role in the pathogenesis of MDS.     

Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors

BackgroundPrevious studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure.MethodsCell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed.ResultsvvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors.ConclusionsOncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.