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Background This study set out to evaluate the effect of dose rate on normal tissues (the lung, in particular) and the variation in the treatment efficiency as determined by the monitor unit (MU) and energy applied in Linac-based volumetric arc therapy (VMAT) total marrow irradiation (TMI). Methods Linac-based VMAT plans were generated for the TMI for six patients. The planning target volume (PTV) was divided into six sub-volumes, each of which had their own isocenter. To examine the effect of the dose rate and energy, a range of MU rates (40, 60, 80, 100, 300, and 600 MU/min) were selected for 6, 10, and 15 MV. All the plans were verified by portal dosimetry. Results The dosimetric parameters for the target and normal tissue were consistent in terms of the energy and MU rate. The beam-on time was changed from 59.6 to 6 min for 40 and 600 MU/min. When 40 MU/min was set for the lung, the dose rate delivered to the lung was less than 6 cGy/min (that is, 90%), while the beam-on time was approximately 10 min. The percentage volume of the lung receiving 20 cGy/min was 1.47, 3.94, and 6.22% at 6, 10, and 15 MV, respectively. However, for 600 MU/min, the total lung volume received over 6 cGy/min regardless of the energy, and over 20 cGy/min for 10 and 15 MV (i.e., 54.4% for 6 MV). Conclusions In TMI treatment, reducing the dose rate administered to the lung can decrease the incidence of pulmonary toxicity. To reduce the probability of normal tissue complications, the selection of the lowest MU rate is recommended for fields including the lung. To minimize the total treatment time, the maximum MU rate can be applied to other fields. ; This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (no. 2017M2A2A7A02020641) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (no. HA 16C0025).

INTRODUCTION: China has the world's largest diabetes epidemic and has been facing a serious shortage of primary care providers for chronic diseases including diabetes. To help primary care physicians follow guidelines and mitigate the workload in primary care communities in China, we developed a guideline-based decision tree. This study aimed to validate it at 3 months with real-world data. METHODS: The decision tree was developed based on the 2017 Chinese Type 2 Diabetes (T2DM) guideline and 2018 guideline for primary care. It was validated with the data from two registry studies: the NEW2D and ORBIT studies. Patients' data were divided into two groups: the compliance and non-compliance group, depending on whether the physician's prescription was consistent with the decision tree or not. The primary outcome was the difference of change in HbA1c from baseline to 3 months between the two groups. The secondary outcomes included the difference in the proportion of patients achieving HbA1c < 7% at 3 months between the two groups, the incidence of self-reported hypoglycemia at 3 months, and the proportion of patients (baseline HbA1c ≥ 7%) with a HbA1c reduction ≥ 0.3%. The statistical analysis was performed using linear or logistic regression with inverse probability of treatment weighting with adjustments of confounding factors. RESULTS: There was a 0.9% reduction of HbA1c in the compliance group and a 0.8% reduction in the non-compliance group (P < 0.001); 61.1% of the participants in the compliance group and 44.3% of the participants in the non-compliance group achieved a HbA1c level < 7% at 3 months (P < 0.001). The hypoglycemic events occurred in 7.1% of patients in the compliance group vs. 9.4% in the non-compliance group (P < 0.001). CONCLUSION: The decision tree can help physicians to treat their patients so that they achieve their glycemic targets with fewer hypoglycemic risks. (http://www.clinicaltrials.gov NCT01525693 & NCT01859598). SUPPLEMENTARY INFORMATION: The online version contains ...

Ya-Lan Zhou,1 Qiu-Mei Yao,1 Jiao Zhou,1 Yan Chang,1 Jin-Lan Li,1 Ya-Zhe Wang,1 Hong-Ping Wu,2 Yu-Hong Chen,1 Yan-Rong Liu,1 Xiao-Jun Huang,1 Guo-Rui Ruan1 1Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, Beijing, China; 2Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China Background: Daunorubicin is a traditional chemotherapeutic agent that plays a pivotal role in leukemia therapy. However, the dose-related toxicity remains a considerable challenge. The apoptosis-regulating gene, PDCD5, is downregulated in various tumors, including leukemias, and may provide a potential target for the diagnosis and treatment of leukemia. The purpose of this study was to construct a triple-regulated oncolytic adenovirus carrying a PDCD5 gene expression cassette (SG611-PDCD5) and explore the combined antitumor efficacy of SG611-PDCD5 in combination with low dose daunorubicin on leukemic cells. Materials and methods: A variety of leukemic cell lines, including K562, MEG-01, KG-1a, HL-60, SUP-B15, and BV-173, were cultured according to the providers' instructions. The insertion and orientation of all recombined plasmids were confirmed by restriction enzyme digestion and PCR. The tumor-selective replication of the constructed conditionally replicating SG611-PDCD5 and its antitumor efficacy in combination with daunorubicin were characterized in leukemic cell lines in vitro and in a nude mouse xenograft model. Cell viability was detected using cell-counting kit-8. Apoptosis was detected in whole living cells using flow cytometry and in paraffin-embedded tumor tissues using a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results: The triple-regulated CRAd carrying SG611-PDCD5 and nude mouse xenograft models of K562 cells were successfully constructed. In vitro treatment with SG611-PDCD5 in combination with low-dose daunorubicin elicited more potent anti-proliferative and proapoptotic effects in leukemic cells in a dose-dependent manner. The Chou-Talalay analysis revealed synergistic anti-proliferative effects in all of the above cell lines. In the nude mice xenograft model, the tumor size in the control, daunorubicin, SG611-PDCD5, and combined treatment groups on day 10 were 170.1±47.8, 111.9±81.1, 60.7±12.3, and 33.2±17.5 mm3, respectively (all P<0.05). The results of the TUNEL assay showed significantly more apoptotic cells in the SG611-PDCD5 plus daunorubicin group than in the SG611-PDCD5 or daunorubicin groups alone (25±0.82, 12.5±2.27, and 7.8±2.67 apoptotic cells/field, respectively) (P<0.05). Conclusion: The findings suggest that combined treatment with SG611-PDCD5 and daunorubicin may be a promising strategy for enhancing chemosensitivity and thus lowering the dose-related toxicity of daunorubicin in leukemia therapy. Keywords: PDCD5 gene, oncolytic adenovirus, leukemia, gene therapy