Voice biomarkers， as an emerging smart medical technology， are now being used in applications such as assisting in the diagnosis and treatment of diseases， facilitating accurate and personalized medical services for patients. However， it also raises many ethical issues， including informed consent， privacy protection， accuracy and reliability， data security， legal risks， and other issues. This paper systematically sorted out the ethical issues in the applications of voice biomarkers in the medical field， summarized these issues， such as informed consent， privacy protection， accuracy and reliability， data security， and legal risks， as well as explored the corresponding coping strategies. These countermeasures encompassed utilizing new media platforms to raise public awareness of voice biomarkers， strengthening supervision and management to promote the privacy protection of voice biomarkers， reducing algorithm biases to promote the general benefits of voice biomarkers to the public， establishing multidisciplinary teams to protect the data security of voice biomarkers， and encouraging medical professionals and researchers to participate in policy research， with a view to providing references for promoting and regulating the applications of voice biomarkers in the medical field.

Objective: To analyze the failure patterns of locoregional recurrence (LRR) and investigate the range of radiotherapy in T_1-2N₁ breast cancer patients undergoing modified radical mastectomy. Methods: From September 1997 to April 2015, 2472 women with T_1-2N₁ breast cancer after modified radical mastectomy without neoadjuvant systemic therapy were treated in our hospital. 1898 patients who did not undergo adjuvant radiotherapy were included in this study. The distribution of accumulated LRR was analyzed. The LR and RR rates were estimated by the Kaplan-Meier method, and the prognostic factors were identified in univariate analyses with Log-rank test. Multivariate analysis was performed using Cox logistic regression analysis. Results: With a median follow-up of 71.3 months (range 1.1-194.6), 164 patients had LRR, including supraclavicular/infraclavicular lymph nodes in 106(65%), chest wall in 69(42%), axilla in 39(24%) and internal mammary lymph nodes (IMNs) in 19 patients (12%). In multivariate analysis, age (>45 years vs.≤45 years), tumor location (other quadrants vs. inner quadrant), T stage (T₁ vs. T₂), the number of positive axillary lymph nodes (1 vs. 2-3), hormone receptor status (positive vs. negative) were significant prognostic factors for both LR and RR. Conclusions In patients with T_1-2N₁ breast cancer after modified radical mastectomy, the most common LRR site is supraclavicular/infraclavicular nodal region, followed by chest wall. The axillary or IMN recurrence is rare. The prognostic factors for LR and RR are similar, which indicates that supraclavicular/infraclavicular and chest wall irradiation should be considered for postmastectomy radiotherapy.

Objective:To analyze the efficacy of chest wall boost radiotherapy in stage T 4 breast cancer patients after modified radical mastectomy. Methods:A retrospective analysis was performed on the data of 148 stage T 4 breast cancer patients who were admitted from 2000 to 2016 and received radiotherapy after modified radical mastectomy. There were 57 cases in the chest wall boost radiotherapy group and 91 cases in the conventional dose group. Radiotherapy was performed by conventional+ chest wall electron beam, three-dimensional conformal+ chest wall electron beam, intensity modulated radiotherapy+ chest wall electron beam irradiation. EQD 2 at the boost group was >50Gy. All patients received neoadjuvant chemotherapy. Kaplan-Meier method was used to analyze survival; Logrank was used to test differences; and Cox model was used to do multivariate prognostic analysis. Results:The median follow-up time was 67.2 months. The 5-year rates of chest wall recurrence (CWR), locoregional recurrence (LRR), disease-free survival (DFS), and overall survival (OS) were 9.9%, 16.2%, 58.0%, and 71.4%, respectively. The 5-year rates of CWR, LRR, DFS, and OS with and without chest wall boost radiotherapy were 14% vs. 7%, 18% vs. 15%, 57% vs. 58%, 82% vs. 65%( P>0.05), respectively. Multivariate analysis showed that chest wall boost radiotherapy had no significant effect on prognosis ( P>0.05). Among 45 patients in the recurrent high-risk group, boost radiotherapy seemed to have higher OS rate ( P=0.058), DFS rate ( P=0.084), and lower LRR rate ( P=0.059). Conclusions:Stage T 4 breast cancer patients had strong heterogeneity. Chest wall boost radiotherapy did not apparently benefit all patients. For patients with 2-3 high risk factors including positive vascular tumor embolus, pN 2-N 3, and hormone receptor negative, chest wall boost radiotherapy showed a trend of improving efficacy.

Objective:To compare the setup errors between deep inspiration breath hold (DIBH) and free breathing (FB) for breast cancer patients who were treated with whole breast irradiation (WBI) after breast conserving surgery (BCS).Methods:In this retrospective analysis, 30 breast cancer patients receiving WBI following BCS using DIBH in National Cancer Center/ Chinese Academy of Medical Sciences, an 30 patients treated with WBI using FB were enrolled as comparator.The kilovoltage cone-beam computed tomography (CBCT) was performed to evaluate and reduce setup errors. The optimal margins from clinical target volume (CTV) to planning target volume (PTV) for DIBH were estimated. The differences of setup errors between two techniques were compared using independent two-sample t-test. Results:A total of 318 sets of CBCT images were acquired, with (5.1±1.1) sets per patient on average. The setup errors along the three translational directions (laternal, longitudinal and vertical) were (2.1±1.6) mm, (2.6±1.7) mm and (2.5±2.1) mm for DIBH, and (2.2±1.7) mm, (3.1±2.5) mm and (3.3±2.3) mm for FB, respectively. Compared with FB, DIBH significantly reduced setup errors in the longitudinal ( P=0.015) and vertical ( P=0.004) directions, whereas the setup errors in the lateral direction did not significantly differ ( P=0.294). The optimal margins from CTV to PTV using DIBH were 6.2 mm, 7.3 mm and 7.8 mm, respectively. In the DIBH group, treatment fractions at the beginning and higher body mass index (BMI) did not associate with larger set-up deviation. Conclusions:DIBH technique yields less setup errors than FB for breast cancer patients treated with WBI after BCS. The CTV-PTV margins of 6-8 mm are recommended for DIBH.

Objective:To evaluate the incidence of early cardiac injury in patients with left-sided breast cancer receiving hypofractionated radiotherapy after breast conserving surgery, and to investigate the correlation between cardiac injury and hypofractionated radiotherapy dose.Methods:We prospectively enrolled 103 breast cancer patients who received whole breast with or without regional nodal irradiation after breast conserving surgery using either deep inspiration breath-hold (DIBH) or free breathing (FB) radiotherapy technique. Cardiac examinations that included N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiogram, and myocardial perfusion imaging were performed routinely before and after radiotherapy. The effects of heart dose, systemic therapy and individual factors (Framingham score) on the incidence of cardiac events were analyzed.Results:The median age was 48 years. The mean dose (Dmean) of the heart, left anterior descending coronary artery (LAD), left ventricular (LV), and right ventricular (RV) were 4.0, 16.9, 6.3, and 4.4 Gy, respectively. With a median follow-up of 13.4 months, no patient had clinical cardiac abnormalities. The incidence rates of subclinical cardiac events at 1- 6- and 12-month were 23.5%, 31.6%, and 41.3%, respectively. The DIBH group had a lower mean dose, maximum dose, and V5-V40 in the heart, LAD, LV, and RV than the FB group ( P<0.001). Univariate analysis showed an increased incidence of subclinical cardiac events with heart Dmean >4 Gy, LAD V40 > 20%, LV Dmean >6 Gy, RV Dmean >7 Gy, or cumulative doses of anthracycline or taxane > 300 mg/m 2 (All P<0.05). Anti-HER2 targeted therapy, endocrine therapy and Framingham score were not associated with the incidence of subclinical cardiac events (all P>0.05). Multivariate analysis demonstrated that Dmean of LV and RV were independently associated with the increased incidence of subclinical cardiac events. Conclusions:Early subclinical heart injury are found in patients with left-sided breast cancer after hypofractionated radiotherapy. The increased incidence of subclinical cardiac events after radiotherapy is positively associated with the cardiac radiation doses.

Objective:To evaluate the incidence of early cardiac injury in patients with left-sided breast cancer receiving hypofractionated radiotherapy after breast conserving surgery, and to investigate the correlation between cardiac injury and hypofractionated radiotherapy dose.Methods:We prospectively enrolled 103 breast cancer patients who received whole breast with or without regional nodal irradiation after breast conserving surgery using either deep inspiration breath-hold (DIBH) or free breathing (FB) radiotherapy technique. Cardiac examinations that included N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiogram, and myocardial perfusion imaging were performed routinely before and after radiotherapy. The effects of heart dose, systemic therapy and individual factors (Framingham score) on the incidence of cardiac events were analyzed.Results:The median age was 48 years. The mean dose (Dmean) of the heart, left anterior descending coronary artery (LAD), left ventricular (LV), and right ventricular (RV) were 4.0, 16.9, 6.3, and 4.4 Gy, respectively. With a median follow-up of 13.4 months, no patient had clinical cardiac abnormalities. The incidence rates of subclinical cardiac events at 1- 6- and 12-month were 23.5%, 31.6%, and 41.3%, respectively. The DIBH group had a lower mean dose, maximum dose, and V5-V40 in the heart, LAD, LV, and RV than the FB group ( P<0.001). Univariate analysis showed an increased incidence of subclinical cardiac events with heart Dmean >4 Gy, LAD V40 > 20%, LV Dmean >6 Gy, RV Dmean >7 Gy, or cumulative doses of anthracycline or taxane > 300 mg/m 2 (All P<0.05). Anti-HER2 targeted therapy, endocrine therapy and Framingham score were not associated with the incidence of subclinical cardiac events (all P>0.05). Multivariate analysis demonstrated that Dmean of LV and RV were independently associated with the increased incidence of subclinical cardiac events. Conclusions:Early subclinical heart injury are found in patients with left-sided breast cancer after hypofractionated radiotherapy. The increased incidence of subclinical cardiac events after radiotherapy is positively associated with the cardiac radiation doses.

Objective To investigate the setup errors and influencing factors of the whole breast intensity-modulated radiotherapy (IMRT) after breast-conserving surgery,and to identify the margins from clinical target volume (CTV) to planning target volume (PTV).Methods Thirty patients with left-sided (n=15) or right-sided breast cancer (n=15) receiving whole breast hypofractionated IMRT with breast board immobilization after breast-conserving surgery in Cancer Hospital from 2016 to 2017 were enrolled.The kilo-voltage cone-beam computed tomography (CBCT) was used to compare the errors of planning CT and treatment unit and determine the setup errors.The margins from CTV to PTV were calculated.The setup errors under different conditions were statistically compared by t-test.Results A total of 151 sets of CBCT images were taken in the whole cohort,(5.0± 1.3) sets per patient on average.The setup errors in the x-axis (left-right direction),y-axis (cranial-caudal direction) and z-axis (anterior-posterior direction) were (2.2± 1.7) mm,(3.1±2.5) mm and (3.3±2.3) mm,respectively.The margins from CTV to PTV were 6.39 mm,10.00 mm and 8.57 mm,respectively.The setup error in anterior-posterior direction in the first week was (3.7±2.5) mm,significantly larger than (2.6±1.6) mm in the following week (P=0.002).The setup error of the patients with overweight or obesity was (3.9±2.6) mm,significantly higher than (2.9±2.0) mm in those with normal weight in the z-axis direction (P=0.033).Conclusion The margins from CTV to PTV are recommended to be ranged from 6 to 10 mm during hypofractionated whole breast IMRT with breast board immobilization after breast-conserving surgery.More frequent imaging verification should be applied in the first week of IMRT.

Objective: To investigate the dose characteristics and outcomes of a single isocenter bilateral tangential fields (IBTF) combined with intensity-modulated radiotherapy (IMRT) in bilateral breast radiotherapy (BBR). Methods: Fourteen female patients with synchronous bilateral breast cancer (SBBC) after breast-conserving surgery (BCS) were enrolled in this study. All patients received BBR using IBTF combined with IMRT at a conventional (50 Gy/25f) or hypofractionated (43.5 Gy/15f) dose. For patients with invasive cancer, the additional tumor bed boost was given with sequential electron radiation or simultaneously photon IMRT. The coverage, uniformity and short-term clinical efficacy were evaluated. Results: The number of the irradiation field was 8-11, including 4-7 intensity-modulated fields. The bilateral breast PTV dose coverage reached 95% in all plans. For the tumor bed, the mean dose coverage was (95.54±1.33)%(left) and (94.19±1.03)%(right) using photon, and (90.25±8.79)%(left) and (85.28±8.35)%(right) using electron. The average V₂₀ of bilateral lungs was (16.69±3.90)%. The cardiac D_mean was 5.48 Gy. Three patients presented with grade Ⅱ acute skin toxicities. No ≥ grade Ⅱ pneumonitis was observed. No recurrence occurred with the median follow-up time of 30.1 months. Eleven patients showed excellent cosmetic results. Conclusion BBR using IBTF combined with IMRT is efficacious and safe for patients with SBBC after BCS.

Objective: To validate whether the prognostic stage groups by the 8th edition of the American Joint Committee on Cancer (AJCC) staging system provides improved prognostic accuracy in T1-2N1M0 postmastectomy breast cancer patients compared to 7th edition. Methods: a total of 1 823 female patients with T1-2N1M0 breast cancer who underwent mastectomy and axillary lymph node dissection without neoadjuvant chemotherapy were analyzed and restaged according to 8th edition. Univariate analysis of prognostic factors was evaluated by using log-rank test. Multivariate analysis was estimated by using the Cox proportional hazards model. The prognostic accuracy of the two staging systems was compared using receiver operating characteristic (ROC) analyses and the concordance index (C-index). Results: 5-year locoregional recurrence rate (LRR) for the whole group was 6.0%, 5-year distant metastasis (DM) rate was 11.5%, 5-year disease-free survival (DFS) was 85.0%, and 5-year overall survival (OS) was 93.1%. Cox analysis showed that 7th edition of the AJCC staging system and progesterone receptor status were independent risk factors for LRR, DM, DFS and OS (P<0.05). Compared with stage by 7th edition, 1 278(70.1%) were assigned to a different prognostic stage group: 1 088 (85.1%) to a lower stage and 190 (14.9%) to a higher stage. LRR, DM, DFS and OS were significantly different between prognostic stage ⅠA, ⅠB, ⅡA, ⅡB and ⅢA according to 8th edition of the AJCC staging system(P<0.001). Prognostic stage had significantly higher C-indexes and provided better estimation of prognosis compared to stage by 7th edition of the AJCC staging system (P<0.001). Conclusion The prognostic stage groups of 8th edition AJCC staging system has superior prognostic accuracy compared to 7th edition in T1-2N1M0 breast cancer, and has better clinical therapeutic guidance value.

Objective To quantify the setup errors measured with kV cone-beam CT (CBCT) using breast board with or without a thermoplastic head mask in breast cancer patients who received whole breast and supraclavicular nodal region irradiation.Clinical target volume (CTV) to planning target volume (PTV) in 3 directions were also calculated.Methods The study included thirty patient receiving both whole breast and supraclavicular nodal region irradiation on Elekta Versa HD linear accelerators (Elekta Oncology Systems,Crawley,UK) between June 2016 and January 2018.The setup error data were retrospectively analyzed.All the patients were immobilized in the supine position on a breast board system (Carbon fibre breast board,Civco,Iowa,USA) with both arms raised.Twenty of the patients added an extra thermoplastic head mask to immobilize the neck.A CBCT scan was taken before treatment at the first 3 to 5 fractions and then once every week.Registration with the planning CT was performed and adjusted to match the target volume of the supraclavicular nodal region and the cervical vertebra by experienced medical staff,the position of the arms and the breast were also considered.For all patients the couch shifts in left-right (x),superior-inferior (y),anterior-posterior (z) were recorded.Statistical analysis included two-tails significance tests (t-Student and Manne-Whitney test for means,x2 test for variances).Population of the two groups was compared in terms of distribution of the mean shift (systematic error) and their standard deviations (random error).Van Herk's setup margin defined as MPTV =2.5Σ + 0.7δ was calculated in patients with or without mask immobilization.Results Altogether,56 images and 109 images were acquired in breast board only group and head mask group,respectively.Shifts of the breast board only group and the head mask group in x,y,z were 0.212±0.174 cm vs.0.272±0.242 cm (P=0.070);0.364±0.246 cm vs.0.242±0.171 cm (P=0.001);0.423±0.302 cm vs.0.364±0.269 cm (P=0.204).Proportion of the shift less than 5 mm in the breast board only group and the head mask group were 91.07％ vs.85.32％ (P=0.294);67.86％ vs.89.91％ (P=0.001);67.86％ vs.74.31％ (P=0.381).The CTV to PTV margin in x,y,z were 0.645 cm,0.981 cm,1.317 cm in breast board only group and 0.873 cm,0.709 cm,0.961 cm in head mask group,respectively.Setup error in the x direction was significantly correlated with BMI (P=0.001).Conclusions For the alignment and immobilization of patients who received whole breast and supraclavicular nodal region irradiation,using a breast board in combination of a thermoplastic head mask may significantly help to reduce the shift variance in superior-inferior direction compared to using breast board only.The anterior-posterior error is relatively large,other immobilization device or patient alignment methods are needed to be further explored to improve the accuracy.