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Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotransposition events, was shown to be deregulated in multiple tumors but not yet in leukemia. We hypothesized that treatment with hypomethylating agents, commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased retroelement activity and somatic retrotranspositions, thus contributing to disease progression. To address this hypothesis, we induced the expression of ORF1p protein with hypomethylating agents in DAMI and HL‐60 myeloid cell lines. To study whether long‐term hypomethylating agent therapy induces somatic retrotranspositions, we analyzed (i) both cell lines treated for 4 weeks, and (ii) sequential samples from 17 patients with myelodysplastic syndrome treated with hypomethylating agents. Using a sensitive next‐generation sequencing (NGS)‐based method, no retroelement events were identified. To conclude, we show that although hypomethylating agents induce the expression of LINE‐1‐encoded proteins in myeloid cell lines, de novo somatic retrotransposition events do not arise during the long‐term exposure to these agents. We investigated whether hypomethylating agents (HMAs) used in myeloid malignancies induce somatic retrotransposition. Our findings indicate that HMA treatment increases L1‐encoded protein expression but does not lead to detectable de novo retrotransposition events in either patient samples or cell lines. This suggests HMAs do not promote new insertional mutagenesis.

Retroelements (RE) present in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potentially mutagenic effect. RE activity, demonstrated by their expression and somatic retrotransposition events, is deregulated in multiple tumor types but not in leukemia. We hypothesized that treatment with hypomethylating agents (HMA), commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased RE activity and somatic retrotranspositions, and contribute to disease progression. We induced expression of ORF1p protein encoded by long interspersed nuclear element-1 (L1) after 72h treatment with HMA in DAMI and HL-60 cell lines. ORF1p was predominantly localized in the cytoplasm, as evidenced by fluorescent microscopy of the DAMI cell line. To study whether long-term HMA therapy may induce somatic retrotranspositions, we (i) treated both cell lines for four weeks, (ii) analyzed a cohort of 17 MDS patients before and on treatment with HMA. Using a previously established sensitive NGS-based method, no RE events were identified. To conclude, we show that although HMA induces the expression of L1-encoded proteins in tumor myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term treatment of MDS patients and myeloid cell lines with these agents.

Purpose The aim of this study was to verify the possibility of summing the dose distributions of combined radiotherapeutic treatment of cervical cancer using the extended Lucas‐Kanade algorithm for deformable image registration. Materials and methods First, a deformable registration of planning computed tomography images for the external radiotherapy and brachytherapy treatment of 10 patients with different parameter settings of the Lucas‐Kanade algorithm was performed. By evaluating the registered data using landmarks distance, root mean square error of Hounsfield units and 2D gamma analysis, the optimal parameter values were found. Next, with another group of 10 patients, the accuracy of the dose mapping of the optimized Lucas‐Kanade algorithm was assessed and compared with Horn‐Schunck and modified Demons algorithms using dose differences at landmarks. Results The best results of the Lucas‐Kanade deformable registration were achieved for two pyramid levels in combination with a window size of 3 voxels. With this registration setting, the average landmarks distance was 2.35 mm, the RMSE was the smallest and the average gamma score reached a value of 86.7%. The mean dose difference at the landmarks after mapping the external radiotherapy and brachytherapy dose distributions was 1.33 Gy. A statistically significant difference was observed on comparing the Lucas‐Kanade method with the Horn‐Schunck and Demons algorithms, where after the deformable registration, the average difference in dose was 1.60 Gy (P‐value: 0.0055) and 1.69 Gy (P‐value: 0.0012), respectively. Conclusion Lucas‐Kanade deformable registration can lead to a more accurate model of dose accumulation and provide a more realistic idea of the dose distribution.

The purpose of this study was to evaluate the influence of 3D brachytherapy planning time on the real dose distribution. 10 patients with cervical cancer were evaluated using 2 computed tomography (CT) scans brachytherapy. The first scan was performed after the insertion of UVAG applicators, and the second was done after creating the treatment plan, just before the irradiation of first and third fraction. Both plans were compared in terms of changes of volumes and differences in the dose for high-risk organs using GEC-ESTRO Working Group parameters. The median planning time was 54 minutes (36-64 minutes). The absolute median change of volume for bladder, rectum, and sigmoid was 32.1 cm (1.6-108.6 cm ), 5.6 cm (0.4-61.8 cm ), and 8.4 cm (0.2-74.1 cm ), respectively. This difference led to an increased dose for bladder and sigmoid for D by 46.7 cGy and 25.7 cGy, for D by 59.2 cGy and 11.8 cGy, and for D by 44.7 cGy and 10 cGy, respectively, per each fraction. Measured volume change in case of rectum led to a decreased dose per each fraction for D with 7.1 cGy, for D with 3.5 cGy, and for D with 4.8 cGy. We observed that statistically significant dependency between the planning time and the dose was proved for rectum. The longer time for planning, the higher dose for rectum. The correlation coefficient for D was 0.6715 ( = 0.0061), for D was 0.6404 ( = 0.011), and for D was 0.5891 ( = 0.0197). Extended treatment planning time for brachytherapy due to the changes in topography of small pelvis can lead to different dose in high-risk organs than previously planned. It seems that the most significant changes are related to rectum.