Citations

159 Background: Intensity-modulated proton therapy (IMPT) with small spot size has the potential to reduce dose to normal tissues but also introduces new confounding factors such as setup uncertainty, range uncertainty, and interplay effects due to breathing motion. We investigated plan quality and robustness of IMPT with small spot size for distal esophageal adenocarcinoma (DEA). Methods: 19 patients with DEA treated by IMPT were retrospectively evaluated. Spot sizes ranged from 2 to 6mm, with spot spacing of 5mm. All plans were generated using a commercial treatment planning system. In-house-developed dose-evaluation software modeled time-dependent spot delivery to incorporate interplay effects. Dose-volume-histogram (DVH) indices were used to evaluate plan quality and robustness was evaluated using the DVH band method. Results: For plan quality, median values of clinical target volume D95% and D5%-D95% (normalized to the prescribed doses), total lung mean dose, heart mean dose, and cord Dmax were 1.014, 0.035, 3.82Gy[RBE], 7.73Gy[RBE], 39.16Gy[RBE], respectively. For plan robustness, median band widths of the aforementioned DVH indices were 0.018, 0.048, 0.60Gy[RBE], 4.17Gy[RBE], and 2.36Gy[RBE], respectively. For interplay effects, median values of the aforementioned DVH indices were 0.99, 0.061, 4.07Gy[RBE], 7.87Gy[RBE], and 39.66Gy[RBE], respectively. Seven patients underwent esophagectomy after neoadjuvant chemoradiation, and five, three, and one of them achieved downstaging, near complete response, and pathologic complete response, respectively; R0 resection was achieved in all cases. For all patients, acute side effects were mostly limited to grades 1-2 only. The only grade 3 adverse events were related to feeding tube placement (8 patients); there were no RT-induced pneumonitis or other lung-related toxicities. Conclusions: IMPT plans with small spot size for DEA have good target dose coverage, homogeneity and normal tissue protection. Treatment plans are also robust to uncertainties and interplay effects. Early clinical results demonstrate low acute toxicity and encouraging clinical and pathologic response.

Objective Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis. Design DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo. Results We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates. Conclusion Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.