Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments.

PurposeMultiple energy extraction (MEE) is a technology that was recently introduced by Hitachi for its spot-scanning proton treatment system, which allows multiple energies to be delivered in a single synchrotron spill. The purpose of this paper is to investigate how much beam delivery time (BDT) can be reduced with MEE compared with single energy extraction (SEE), in which one energy is delivered per spill.Methods and MaterialsA recently developed model based on BDT measurements of our synchrotron's delivery performance was used to compute BDT. The total BDT for 2694 beam deliveries in a cohort of 79 patients treated at our institution was computed in both SEE and 9 MEE configurations to determine BDT reduction. The cohort BDT reduction was also calculated for hypothetical accelerators with increased deliverable charge and compared with the results of our current delivery system.ResultsA vendor-provided MEE configuration with 4 energy layers per spill reduced the total BDT on average by 35% (41 seconds) compared with SEE, with up to 65% BDT reduction for individual fields. Adding an MEE layer reduced the total BDT by <1% of SEE BDT. However, improving charge recapture efficiency increased BDT savings by up to 42% of SEE BDT.ConclusionsThe MEE delivery technique reduced the total BDT by 35%. Increasing the charge per spill and charge recapture efficiency is necessary to further reduce BDT and thereby take full advantage of our MEE system's potential to improve treatment delivery efficiency and operational throughput.

Mice with miR-21 loss demonstrated delay in spontaneous tumor formation, decreased growth rate, and reduced macroscopic lung metastases compared to MMTV-PyMT mice with intact miR-21. When challenged with orthotopic tumor implantation, miR-21+/and miR-21-/-mice had increased delay in allograft tumor formation compared to wild-type mice, suggesting stromal changes in the mammary microenvironment modulated by miR-21. Conclusion: Modulation of miR-21 expression in a murine tumor model appears to play an important role in breast cancer tumorigenesis and progression. Expression of miR-21 may be linked to treatment resistance and development of an aggressive tumor phenotype. As modulation of miR-21 appears to delay de novo tumorigenesis as well as tumor allograft formation, multiple mechanisms of tumorigenesis may be implicated. Targeted inhibition of the miR-21 pathway may be an attractive therapeutic option to both sensitize tumors to cytotoxic treatment while modulating the peritumoral stroma.

Objectives:To report characteristics, treatment, and outcomes for an international cohort of patients with extraskeletal osteosarcoma (ESOS).Materials and Methods:Through the Rare Cancer Network, retrospective data on patients with ESOS were collected. Patient characteristics, multimodality treatment information, and survival status were analyzed.Results:Thirty-seven patients in 4 health care institutions were identified. Thirty-one (86%) patients had grade 3 or 4 tumors. Most patients (27 [73%]) had stage III disease. Fourteen (38%) received neoadjuvant chemotherapy or chemoradiation. Of 28 (85%) who underwent surgery, 21 (75%) had free margins achieved and 15 (41%) subsequently received adjuvant chemotherapy. At median follow-up of 45 months, 20 (55%) patients were alive, 13 (43%) of whom were disease free. Univariate analysis showed that poor overall survival was related to stage IV (P<0.001), no surgery (P<0.001), primary size >10 cm (P=0.002), and age (P=0.002). In multivariate analysis, primary size >10 cm (P=0.005) was prognostic for overall survival. For patients without metastases, univariate analysis showed disease-free survival (DFS) related to primary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and older age (P<0.001) were significant for worse outcome.Conclusions:Multimodality treatment remains standard for localized ESOS, with indications for neoadjuvant therapy less clear. Larger tumor size and older age were prognostic of poorer DFS.

Purpose Intensity‐modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient’s outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them. Methods We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient‐specific breathing pattern parameters as acquired during the four‐dimensional (4D)‐computed tomography (CT) simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients’ respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose‐volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application’s example, we compared plan robustness under both three‐dimensional (3D) and 4D robustly optimized IMPT plans for 10 nonrandomly selected patients with non‐small cell lung cancer. Results The developed comprehensive plan robustness tool had been successfully applied to compare the plan robustness between 3D and 4D robustly optimized IMPT plans for 10 lung cancer patients. In the presence of interplay effect with uncertainties considered simultaneously, 4D robustly optimized plans provided significantly better CTV coverage (D95%, P = 0.002), CTV homogeneity (D5%‐D95%, P = 0.002) with less target hot spots (D5%, P = 0.002), and target coverage robustness (CTV D95% bandwidth, P = 0.004) compared to 3D robustly optimized plans. Superior dose sparing of normal lung (lung Dmean, P = 0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4 ± 2.6 min. Conclusion A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation, highly practical and versatile nature, including possible real‐time intra‐fractional interplay effect evaluation as a potential application for future use.