Comparison of Optic Disc Ovality Index and Rotation Angle Measurements in Myopic Eyes Using Photography and OCT Based Techniques.

Purpose: To compare optic nerve head (ONH) ovality index and rotation angle measurements based on semi-automated delineation of the clinical ONH margin derived from photographs and automated BMO configuration derived from optical coherence tomography (OCT) images in healthy and glaucomatous eyes with high-, mild- and no axial myopia. Methods: One hundred seventy-five healthy and glaucomatous eyes of 146 study participants enrolled in the Diagnostic Innovations in Glaucoma Study (DIGS) with optic disc photographs and Spectralis OCT ONH scans acquired on the same day were stratified by level of axial myopia (non-myopic [n = 56, axial length (AL) <24 mm], mild-myopic [n = 58, AL 24-26 mm] and high-myopic [n = 32, AL >26 mm]. The clinical disc margin of each photograph was manually annotated, and semi-automated measurements were recorded of the ovality index and rotation angle based on a best-fit ellipse generated using ImageJ software. These semi-automated photograph-based measurements were compared to ovality index and rotation angle generated from custom automated BMO-based analysis using segmented OCT ONH volumes. R 2 values from linear mixed effects models were used to describe the associations between semi-automated, photograph-based and automated OCT-based measurements. Results: Average (95% CI) axial length was 23.3 (23.0, 23.3) mm, 24.8 (24.7, 25.0) mm and 26.8 (26.6, 27.0) mm in non-myopic, mild-myopic and high-myopic eyes, respectively (ANOVA, p ≤ 0.001 for all). The R 2 association (95% CI) between semi-automated photograph-based and automated OCT-based assessment of ONH OI for all eyes was [0.26 (0.16, 0.36); p < 0.001]. This association was weakest in non-myopic eyes [0.09 (0.01, 0.26); p = 0.02], followed by mild-myopic eyes [0.13 (0.02, 0.29); p = 0.004] and strongest in high-myopic eyes [0.40 (0.19, 0.60); p < 0.001]. No significant associations were found between photography- and OCT-based assessment of rotation angle with R 2 values ranging from 0.00 (0.00, 0.08) in non-myopic eyes to 0.03 (0.00, 0.21) in high-myopic eyes (all associations p ≥ 0.33). Conclusions: Agreement between photograph-based and automated OCT-based ONH morphology measurements is limited, suggesting that these methods cannot be used interchangeably for characterizing myopic changes in the ONH.

Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway.

PURPOSE: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo. METHODS: PET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times. RESULTS: Renal excretion was common to all three probes. Bone marrow had higher uptake for L: -(18)F-FAC and L: -(18)F-FMAC than (18)F-FAC. Prominent liver uptake was seen in L: -(18)F-FMAC and L: -(18)F-FAC, whereas splenic activity was highest for (18)F-FAC. Muscle uptake was also highest for (18)F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, respectively. CONCLUSION: The biodistribution of (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe affinities for nucleoside transporters, dCK, and catabolic enzymes such as cytidine deaminase (CDA). Dosimetry demonstrates that all three probes can be used safely to image the deoxyribonucleoside salvage pathway in humans.

Novel PET probes specific for deoxycytidine kinase.

UNLABELLED: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in the deoxyribonucleoside salvage pathway and a critical determinant of therapeutic activity for several nucleoside analog prodrugs. We have previously reported the development of 1-(2'-deoxy-2'-(18)F-fluoro-beta-D-arabinofuranosyl)cytosine ((18)F-FAC), a new probe for PET of dCK activity in immune disorders and certain cancers. The objective of the current study was to develop PET probes with improved metabolic stability and specificity for dCK. Toward this goal, several candidate PET probes were synthesized and evaluated in vitro and in vivo. METHODS: High-pressure liquid chromatography was used to analyze the metabolic stability of (18)F-FAC and several newly synthesized analogs with the natural D-enantiomeric sugar configuration or the corresponding unnatural L-configuration. In vitro kinase and uptake assays were used to determine the affinity of the (18)F-FAC L-nucleoside analogs for dCK. The biodistribution of selected L-analogs in mice was determined by small-animal PET/CT. RESULTS: Candidate PET probes were selected using the following criteria: low susceptibility to deamination, high affinity for purified recombinant dCK, high uptake in dCK-expressing cell lines, and biodistribution in mice reflective of the tissue-expression pattern of dCK. Among the 10 newly developed candidate probes, 1-(2'-deoxy-2'-(18)F-fluoro-beta-L-arabinofuranosyl)cytosine (L-(18)F-FAC) and 1-(2'-deoxy-2'-(18)F-fluoro-beta-L-arabinofuranosyl)-5-methylcytosine (L-(18)F-FMAC) most closely matched the selection criteria. The selection of L-(18)F-FAC and L-(18)F-FMAC was validated by showing that these two PET probes could be used to image animal models of leukemia and autoimmunity. CONCLUSION: Promising in vitro and in vivo data warrant biodistribution and dosimetry studies of L-(18)F-FAC and L-(18)F-FMAC in humans.