Development and Clinical Implementation of an Automated Virtual Integrative Planner for Radiation Therapy of Head and Neck Cancer.

Purpose: Head and neck (HN) radiation (RT) treatment planning is complex and resource intensive. Deviations and inconsistent plan quality significantly affect clinical outcomes. We sought to develop a novel automated virtual integrative (AVI) knowledge-based planning application to reduce planning time, increase consistency, and improve baseline quality. Methods and Materials: An in-house write-enabled script was developed from a library of 668 previously treated HN RT plans. Prospective hazard analysis was performed, and mitigation strategies were implemented before clinical release. The AVI-planner software was retrospectively validated in a cohort of 52 recent HN cases. A physician panel evaluated planning limitations during initial deployment, and feedback was enacted via software refinements. A final second set of plans was generated and evaluated. Kolmogorov-Smirnov test in addition to generalized evaluation metric and weighted experience score were used to compare normal tissue sparing between final AVI planner versus respective clinically treated and historically accepted plans. A t test was used to compare the interactive time, complexity, and monitor units for AVI planner versus manual optimization. Results: Initially, 86% of plans were acceptable to treat, with 10% minor and 4% major revisions or rejection recommended. Variability was noted in plan quality among HN subsites, with high initial quality for oropharynx and oral cavity plans. Plans needing revisions were comprised of sinonasal, nasopharynx, P-16 negative squamous cell carcinoma unknown primary, or cutaneous primary sites. Normal tissue sparing varied within subsites, but AVI planner significantly lowered mean larynx dose (median, 18.5 vs 19.7 Gy; P < .01) compared with clinical plans. AVI planner significantly reduced interactive optimization time (mean, 2 vs 85 minutes; P < .01). Conclusions: AVI planner reliably generated clinically acceptable RT plans for oral cavity, salivary, oropharynx, larynx, and hypopharynx cancers. Physician-driven iterative learning processes resulted in favorable evolution in HN RT plan quality with significant time savings and improved consistency using AVI planner.

Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity.

Human topoisomerase IIα (TOP2A) is a vital nuclear enzyme involved in resolving knots and tangles in DNA during replication and cell division. TOP2A is a homodimer with a symmetrical, multidomain structure. While the N-terminal and core regions of the protein are well-studied, the C-terminal domain is poorly understood but is involved in enzyme regulation and is predicted to be intrinsically disordered. In addition, it appears to be a major region of post-translational modification and includes several Ser and Thr residues, many of which have not been studied for biochemical effects. Therefore, we generated a series of human TOP2A mutants where we changed specific Ser and Thr residues in the C-terminal domain to Ala, Gly, or Ile residues. We designed, purified, and examined 11 mutant TOP2A enzymes. The amino acid changes were made between positions 1272 and 1525 with 1-7 residues changed per mutant. Several mutants displayed increased levels of DNA cleavage without displaying any change in plasmid DNA relaxation or DNA binding. For example, mutations in the regions 1272-1279, 1324-1343, 1351-1365, and 1374-1377 produced 2-3 times more DNA cleavage in the presence of etoposide than wild-type TOP2A. Further, several mutants displayed changes in relaxation and/or decatenation activity. Together, these results support previous findings that the C-terminal domain of TOP2A influences catalytic activity and interacts with the substrate DNA. Furthermore, we hypothesize that it may be possible to regulate the enzyme by targeting positions in the C-terminal domain. Because the C-terminal domain differs between the two human TOP2 isoforms, this strategy may provide a means for selectively targeting TOP2A for therapeutic inhibition. Additional studies are warranted to explore these results in more detail.

Cognitive Effects of Adding Caloric Restriction to Aerobic Exercise Training in Older Adults with Obesity.

OBJECTIVE: This study examined the short- and long-term effects of adding caloric restriction to 5 months of aerobic exercise training on executive function in sedentary older adults with obesity. METHODS: Sedentary adults with obesity aged 65 to 79 years completed a randomized trial investigating the cardiorespiratory benefits of adding moderate (~ 250 kcal) or high (~ 600 kcal) caloric restriction to a 20-week aerobic exercise program. Approximately half (n = 88) completed a cognitive assessment battery at baseline, post intervention, and 18 to 24 months after intervention completion. The primary outcome was an executive function composite score. RESULTS: In the overall sample, the executive function composite increased 0.114 from baseline to postintervention (P = 0.01). Randomization to caloric restriction did not significantly alter executive function over aerobic exercise alone, nor were there between-group differences on any individual executive function test following the intervention or at long-term follow-up. Adding caloric restriction to exercise was associated with a modest increase in Mini-Mental State Examination score (P = 0.04). In the overall sample, increases from baseline at long-term follow-up were noted in digit symbol and word list recall performance as well. CONCLUSIONS: Adding caloric restriction to a 20-week aerobic exercise program does not worsen or improve executive function more than exercise alone assessed up to 24 months post randomization.

Reasons probably won't change your mind: The role of reasons in revising moral decisions.

Although many philosophers argue that making and revising moral decisions ought to be a matter of deliberating over reasons, the extent to which the consideration of reasons informs people's moral decisions and prompts them to change their decisions remains unclear. Here, after making an initial decision in 2-option moral dilemmas, participants examined reasons for only the option initially chosen (affirming reasons), reasons for only the option not initially chosen (opposing reasons), or reasons for both options. Although participants were more likely to change their initial decisions when presented with only opposing reasons compared with only affirming reasons, these effect sizes were consistently small. After evaluating reasons, participants were significantly more likely not to change their initial decisions than to change them, regardless of the set of reasons they considered. The initial decision accounted for most of the variance in predicting the final decision, whereas the reasons evaluated accounted for a relatively small proportion of the variance in predicting the final decision. This resistance to changing moral decisions is at least partly attributable to a biased, motivated evaluation of the available reasons: participants rated the reasons supporting their initial decisions more favorably than the reasons opposing their initial decisions, regardless of the reported strategy used to make the initial decision. Overall, our results suggest that the consideration of reasons rarely induces people to change their initial decisions in moral dilemmas. (PsycINFO Database Record

Improving treatment plan evaluation with automation.

The goal of this work is to evaluate the effectiveness of Plan-Checker Tool (PCT) which was created to improve first-time plan quality, reduce patient delays, increase the efficiency of our electronic workflow, and standardize and automate the phys-ics plan review in the treatment planning system (TPS). PCT uses an application programming interface to check and compare data from the TPS and treatment management system (TMS). PCT includes a comprehensive checklist of automated and manual checks that are documented when performed by the user as part of a plan readiness check for treatment. Prior to and during PCT development, errors identified during the physics review and causes of patient treatment start delays were tracked to prioritize which checks should be automated. Nineteen of 33checklist items were automated, with data extracted with PCT. There was a 60% reduction in the number of patient delays in the six months after PCT release. PCT was suc-cessfully implemented for use on all external beam treatment plans in our clinic. While the number of errors found during the physics check did not decrease, automation of checks increased visibility of errors during the physics check, which led to decreased patient delays. The methods used here can be applied to any TMS and TPS that allows queries of the database.