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Purpose To evaluate two deformable image registration (DIR) algorithms for the purpose of contour mapping to support image guided adaptive radiotherapy with four-dimensional cone beam computed tomography (4DCBCT). Methods and Materials One planning 4D fan-beam CT (4DFBCT) and 7 weekly 4DCBCT scans were acquired for 10 locally advanced non-small cell lung cancer patients. The gross tumor volume (GTV) was delineated by a physician in all 4D images. End-of-inspiration phase planning 4DFBCT was registered to the corresponding phase in weekly 4DCBCT images for day-to-day registrations. For phase-to-phase registration, the end-of-inspiration phase from each 4D image was registered to the end-of-expiration phase. Two DIR algorithms—small deformation inverse consistent linear elastic (SICLE) and Insight Toolkit diffeomorphic demons (DEMONS)—were evaluated. Physician-delineated contours were compared to the warped contours by using the Dice similarity coefficient (DSC), average symmetric distance (ASD), false positive and false negative indices. The DIR results are compared to rigid registration of tumor. Results For day-to-day registrations, the mean DSC was 0.75 ± 0.09 with SICLE, 0.70 ± 0.12 with DEMONS, 0.66 ± 0.12 with rigid-tumor registration and 0.60 ± 0.14 with rigid-bone registration. Results were comparable to intra-observer variability calculated from phase-to-phase registrations as well as measured inter-observer variation for one patient. SICLE and DEMONS, when compared to rigid-bone (4.1 mm) and rigid-tumor (3.6 mm) registration, respectively reduced the ASD to 2.6 and 3.3 mm. On average, SICLE and DEMONS increased the DSC to 0.80 and 0.79 respectively, compared to rigid-tumor (0.78) registrations for 4DCBCT phase-to-phase registrations. Conclusions DIR achieved comparable accuracy to reported inter-observer delineation variability and higher accuracy than rigid-tumor registration. DIR performance varied with the algorithm and the patient.

Cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP) are the most common types of orofacial clefts in dogs. Orofacial clefts in dogs are clinically relevant because of the associated morbidity and high newborn mortality rate and are of interest as comparative models of disease. However, the incidence of CL, CP and CLP has not been investigated in purebred dogs, and the financial impact on breeders is unknown. The aims of this study were to document the incidence patterns of CL, CP and CLP in different breeds of dogs, determine whether defect phenotype is associated with skull type, genetic cluster and geographic location, and estimate the financial impact in breeding programs in the United States by means of an anonymous online survey. A total of 228 orofacial clefts were reported among 7,429 puppies whelped in the 12 preceding months. Breeds in the mastiff/terrier genetic cluster and brachycephalic breeds were predisposed to orofacial clefts. Certain breeds in the ancient genetic cluster were at increased odds of orofacial clefts. Male purebred dogs were at increased odds of CPs. Results confirm that brachycephalic breeds are overrepresented among cases of orofacial clefts. Furthermore, geographic region appeared to be a relevant risk factor and orofacial clefts represented a considerable financial loss to breeders. Improved understanding of the epidemiology of orofacial clefts (frequency, causes, predictors and risk factors) may help in identifying ways to minimize their occurrence. Information gained may potentially help veterinarians and researchers to diagnose, treat and prevent orofacial clefts.

Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) microM for a 48 h exposure with a range of 64-358 microM. Cell killing was schedule-dependent, favoring exposure times > or =48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations < or =200 microM for 48 h. When concentrations were increased to 300 microM for > or =48 h, the MiaPaCa-2 cells arrested in G2 phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of > or =400 microM were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards. The levels of imexon that are cytotoxic in human PCC's are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G2 arrest, accumulation of ROS, and the induction of apoptosis.

Purpose-Gemcitabine (GEM) is currently the standard first line treatment for pancreatic cancer; however, the overall survival of patients with this disease remains poor. Imexon is a prooxidant small molecule which produced a high response rate in combination with GEM in a phase I trial in pancreatic cancer. In this study, we investigate the combination of GEM with a novel redox-active agent, imexon, in vitro and in vivo.Methods-Median effect analysis was used for in vitro combination cytotoxicity. The effect of imexon on GEM metabolism and uptake into cells and into DNA and effects on ribonucleotide reductase (RNR) were examined in vitro. The pharmacokinetics and antitumor efficacy of the imexon/GEM combination was evaluated in mouse models.Results-In three human pancreatic cancer lines, there was additivity for the imexon/GEM combination. There was significantly greater efficacy for the drug combination in Panc-1 xenograft tumors. A pharmacokinetic study in mice showed a near doubling in the AUC of imexon when GEM was co-administered, with no effect of imexon on GEM's pharmacokinetic disposition. In vitro, imexon did not alter GEM's metabolism or uptake into DNA, but significantly inhibited RNR, and this effect was greater when combined with GEM.Conclusions-These results suggest that the interaction between imexon and GEM may be due to complimentary inhibition of RNR plus an enhanced exposure to imexon when the GEM is administered in vivo. This combination is currently being tested in a randomized phase II trial in pancreatic cancer.