SIRT1 activation promotes bone repair by enhancing the coupling of type H vessel formation and osteogenesis.

Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

Treatment of nasolabial fold rhabdomyosarcoma in children: A single-institution experience.

OBJECTIVES: To summarize the clinical characteristics and prognosis of children with nasolabial fold rhabdomyosarcoma (RMS). METHODS: Retrospective review of children treated for nasolabial fold RMS from January 2014 to September 2019. RESULTS: Of 21 patients with nasolabial fold RMS, 90.48% were alveolar subtype, in which PAX3/7-FOXO1 fusion positive accounted for 87.5%. Ten patients (47.62%) had nodals invasion. Almost all patients received comprehensive treatment (chemotherapy [100%], radiation therapy [100%], and surgery [95.24%]). The median follow-up time was 34.3 months. The 3-year overall survival (OS) and event-free survival (EFS) was 67.7% ± 14.1% and 42.1% ± 13.5%, respectively. Four patients had regional lymph node relapse (NR), all in the ipsilateral submandibular lymph node region. CONCLUSION: Majority of the patients with RMS in the nasolabial fold area were alveolar subtype and had positive PAX3/7-FOXO1 gene fusion. In addition, the nasolabial fold RMS had a high probability of regional lymph node metastasis in the submandibular area. To maintain the facial aesthetics and functions, the surgical area for nasolabial fold RMS is often very conservative and restricted. This could be one of the contributors for the poor prognosis of nasolabial fold RMS beside its worse pathological subtype and gene fusion.

Postoperative adjuvant radiotherapy for patients with upper tract urothelial carcinoma (UTUC) who underwent kidney-sparing surgery (KSS): a single-center study.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of postoperative adjuvant radiotherapy for patients with upper tract urothelial carcinoma (UTUC) who underwent kidney-sparing surgery (KSS). METHODS: We retrospectively reviewed the clinical records of 31 patients with primary UTUC who underwent kidney-sparing surgery (KSS) and who were treated with adjuvant radiotherapy at our center between October 1998 and May 2017. Statistical analyses were performed with SPSS 23.0. The primary endpoints of this study included overall survival (OS) and local recurrence-free survival (LRFS); the secondary endpoints were disease-free survival (DFS) and treatment-related toxicity. RESULTS: The median follow-up was 58.4 months (range, 12.7-185.3 months), and the median local recurrence time was 59.0 months (range, 7.0-185 months). All of the patients completed radiotherapy on schedule, and no grade 3-4 late-stage reaction was observed. The estimated 5-year and 10-year OS, DFS and LRFS rates of the patients were 64.0%, 61.1%, 69.6% and 48.0%, 40.9%, 64.6%, respectively. Univariate analysis showed that age (χ2 = 4.224, P = 0.040), R0 resection (χ2 = 3.949, P = 0.047), and early stage (I + II) (χ2 = 6.515, P = 0.011) were associated with good OS; DFS benefit in early stage patients (χ2 = 6.151, P = 0.013) and age<70 years old (χ2 = 5.091, P = 0.024). Patients with distal ureteral segments had better LRFS than patients with proximal ureteral cancer (χ2 = 5.248, P = 0.022). However, multivariate analysis showed that age was the only factor of OS (χ2 = 4.099, P = 0.043). CONCLUSION: Adjuvant radiotherapy is safe and tolerated, and LRFS was superior in middle and distal ureteral cancer than in proximal ureteral cancer.

[18F]MFBG PET/CT outperforming [123I]MIBG SPECT/CT in the evaluation of neuroblastoma.

PURPOSE: Iodine 123 labeled meta-iodobenzylguanidine ([123I]MIBG) scan with SPECT/CT imaging is one of the most commonly used imaging modalities in the evaluation of neuroblastoma. [18F]-meta-fluorobenzylguanidine ([18F]MFBG) is a novel positron emission tomography (PET) tracer which was reported to have a similar biodistribution to [123I]MIBG. However, the experience of using [18F]MFBG PET/CT in the evaluation of patients with neuroblastoma is limited. This preliminary investigation aims to assess the efficacy of [18F]MFBG PET/CT in the evaluation of neuroblastomas in comparison to [123I]MIBG scans with SPECT/CT. MATERIALS AND METHODS: In this prospective, single-center study, 40 participants (mean age 6.0 ± 3.7 years) with history of neuroblastoma were enrolled. All children underwent both [123I]MIBG SPECT/CT and [18F]MFBG PET/CT studies. The number of lesions and the Curie scores revealed by each imaging method were recorded. RESULTS: Six patients had negative findings on both [123I]MIBG and [18F]MFBG studies. Four of the 34 patients (11.8%) were negative on [123I]MIBG but positive on [18F]MFBG, while 30 patients were positive on both [123I]MIBG and [18F]MFBG studies. In these 34 patients, [18F]MFBG PET/CT identified 784 lesions while [123I]MIBG SPECT/CT detected 532 lesions (p < 0.001). The Curie scores obtained from [18F]MFBG PET/CT (11.32 ± 8.18, range 1-27) were statistically higher (p < 0.001) than those from [123I]MIBG SPECT/CT (7.74 ± 7.52, range 0-26). 30 of 34 patients (88.2%) with active disease on imaging had higher Curie scores based on the [18F]MFBG study than on the [123I]MIBG imaging. CONCLUSION: [18F]MFBG PET/CT shows higher lesion detection rate than [123I]MIBG SPECT/CT in the evaluation of pediatric patients with neuroblastoma. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov : NCT05069220 (Registered: 25 September 2021, retrospectively registered); Institute Review Board of Peking Union Medical College Hospital: ZS-2514.

Prophylactic Extended-Field Irradiation Versus Pelvic Irradiation in Patients With Cervical Cancer With 2018 FIGO Stage IIIC1 Disease.

PURPOSE: The aim of this study was to compare the survival rates and toxicities of prophylactic extended-field radiation therapy (EFRT) and pelvic radiation therapy (PRT) among patients with cervical cancer with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 disease. METHODS AND MATERIALS: We retrospectively analyzed patients with 2018 FIGO stage IIIC1 disease who were treated with definitive concurrent chemoradiotherapy at our institute between 2011 and 2015. A dose of 50.4 Gy in 28 fractions was delivered to the pelvic region (by PRT) or the pelvic plus para-aortic lymph node region (by EFRT) with intensity modulated radiation therapy. The first-line regimen of concurrent chemotherapy was weekly cisplatin. RESULTS: A total of 280 patients were included, with 161 patients treated with PRT and 119 patients treated with EFRT. After propensity score matching (1:1), 71 pairs of patients were selected. The respective 5-year rates of the patients treated with PRT and EFRT were 61.9% and 85.0% for overall survival (P = .025) and 53.0% and 77.9% for disease-free survival (DFS) (P = .004), respectively, after matching. In the subgroup analysis, patients were grouped into a high-risk group (122 patients) and a low-risk group (158 patients) based on 3 factors: positive common iliac lymph nodes, ≥3 pelvic lymph nodes, and 2014 FIGO stage IIIB disease. In both the high-risk and low-risk groups, EFRT significantly improved DFS compared with PRT. The rates of grade ≥3 chronic toxicities were 1.2% and 5.9% in the PRT and EFRT groups, respectively (P = .067). CONCLUSIONS: In comparison to PRT, prophylactic EFRT was associated with improved overall survival, DFS, and para-aortic lymph node control in patients with cervical cancer with FIGO stage IIIC1 disease. The incidence of grade ≥3 toxicities was higher in the EFRT group than in the PRT group, although the difference was not significant.

Clinical Validation and Treatment Plan Evaluation Based on Autodelineation of the Clinical Target Volume for Prostate Cancer Radiotherapy.

PURPOSE: Clinical target volumes (CTVs) and organs at risk (OARs) could be autocontoured to save workload. This study aimed to assess a convolutional neural network for automatic and accurate CTV and OARs in prostate cancer, while comparing possible treatment plans based on autocontouring CTV to clinical treatment plans. METHODS: Computer tomography (CT) scans of 217 patients with locally advanced prostate cancer treated at our hospital were retrospectively collected and analyzed from January 2013 to January 2019. A deep learning-based method, CUNet, was used to delineate CTV and OARs. A training set of 195 CT scans and a test set of 28 CT scans were randomly chosen from the dataset. The mean Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (95HD), and subjective evaluation were used to evaluate the performance of this strategy. Predetermined evaluation criteria were used to grade treatment plans, and percentage errors for clinical doses to the planned target volume (PTV) and OARs were calculated. RESULTS: The mean DSC and 95HD values of the defined CTVs were (0.84 ± 0.05) and (5.04 ± 2.15) mm, respectively. The average delineation time was < 15 s for each patient's CT scan. The overall positive rates for clinicians A and B were 53.15% versus 46.85%, and 54.05% versus 45.95%, respectively (P > .05) when CTV outlines from CUNet were blindly chosen and compared with the ground truth (GT). Furthermore, 8 test patients were randomly chosen to design the predicted plan based on the autocontouring CTVs and OARs, demonstrating acceptable agreement with the clinical plan: average absolute dose differences in mean value of D2, D50, D98, Dmax, and Dmean for PTV were within 0.74%, and average absolute volume differences in mean value of V45 and V50 for OARs were within 3.4%. CONCLUSION: Our results revealed that the CTVs and OARs for prostate cancer defined by CUNet were close to the GT. CUNet could halve the time spent by radiation oncologists in contouring, demonstrating the potential of the novel autocontouring method.

Artificial Intelligence Splint in Orthognathic Surgery for Skeletal Class III Malocclusion: Design and Application.

BACKGROUND: Digital splints are indispensable in orthognathic surgery. However, the present design process of splints is time-consuming and has low reproducibility. To solve these problems, an algorithm for artificial intelligent splints has been developed in this study, making the automatic design of splints accessible. METHODS: Firstly, the algorithm and program of the artificial intelligence splint were created. Then a total of 54 patients with skeletal class III malocclusion were included in this study from 2018 to 2020. Pre and postoperative radiographic examinations were performed. The cephalometric measurements were recorded and the difference between virtual simulation and postoperative images was measured. The time cost and differences between artificial intelligent splints and digital splints were analyzed through both model surgery and radiographic images. RESULTS: The results showed that the efficiency of designing splints is significantly improved. And the mean difference between artificial intelligent splints and digital splints was <0.15 mm in model surgery. Meanwhile, there was no significant difference between the artificial intelligent splints and digital splints in radiological image analysis. CONCLUSIONS: In conclusion, compared with digital splints, artificial intelligent splints could save time for preoperative design while ensuring accuracy. The authors believed that it is conducive to the presurgical design of orthognathic surgery.

A novel X-Ray and γ-Ray combination strategy for potential dose escalation in patients with locally advanced pancreatic cancer.

BACKGROUND: Treatment of locally advanced pancreatic cancer (LAPC) has long been calling for advances in technology of radiotherapy. Patients who received radiotherapy still had high risks of local recurrence, while suffering from gastrointestinal side effects. Based on the inherent characteristics of the x-ray and γ-Ray radiation techniques, here we proposed and investigated an unexplored radiation therapy. PURPOSE: To investigate the potential clinical benefit of a novel x-ray and γ-Ray combination radiation technique in patients with LAPC. METHODS: Retrospective intensity-modulated radiotherapy (IMRT) treatment plans of 10 LAPC patients were randomly selected to compare with dual-modality plans. The prescribed dose to PGTV was 60.2 Gy. The PGTV dose was further escalated in dual-modality plan while maintaining clinically tolerable dose to organs at risk (OARs). Dosimetric comparisons were made and analyzed for three treatment plans (tomotherapy, standard dual-modality plan, escalated dual-modality plan) to assess the ability to increase dose to target volume while minimizing dose in adjacent OARs. Finally, radiobiological models were utilized for comparison. RESULTS: All strategies resulted in dosimetrically acceptable plans. Dual-modality plans were present with similar conformity index (CI) and significantly lower gradient index (GI) compared with tomotherapy (3.64 ± 0.37 vs. 4.14 ± 0.61, p = 0.002; 3.64 ± 0.42 vs. 4.14 ± 0.61, p = 0.003). Dmean of PGTV (65.46 ± 3.13 vs. 61.56 ± 1.00, p = 0.009; 77.98 ± 5.86 vs. 61.56 ± 1.00, p < 0.001) and PCTV (55.04 ± 2.14 vs. 53.93 ± 1.67, p = 0.016; 58.24 ± 3.24 vs. 53.93 ± 1.67, p = 0.001) were significantly higher, while Dmean of the stomach was reduced in both dual-modality plans (17.98 ± 10.23 vs. 19.34 ± 9.75, p = 0.024; 17.62 ± 9.92 vs. 19.34 ± 9.75, p = 0.040). The lower V30Gy in the liver (4.83 ± 5.87 vs. 6.23 ± 6.68, p = 0.015; 4.90 ± 5.93 vs. 6.23 ± 6.68, p = 0.016) and lower V45Gy of the small intestine (3.35 ± 3.30 vs. 4.06 ± 3.87, p = 0.052) were found in dual-modality plans. Meanwhile, radiobiological models demonstrated higher probability of tumor control (29.27% ± 9.61% vs. 18.34% ± 4.70%, p < 0.001; 44.67% ± 18.16% vs. 18.34% ± 4.70%, p = 0.001) and lower probability of small intestine complication (2.16% ± 2.30% vs. 1.25% ± 2.72%, p = 0.048) in favor of dual-modality strategy. CONCLUSIONS: A novel dual-modality strategy of x-ray and γ-Ray combination radiation appears reliable for target dose escalation and normal tissue dose reduction. This strategy might be beneficial for local tumor control and the protection of normal organs in patients with LAPC.

Clinical target volume automatic segmentation based on lymph node stations for lung cancer with bulky lump lymph nodes.

BACKGROUND: The lack of standardized delineation of lymph node station in lung cancer radiotherapy leads to nonstandard clinical target volume (CTV) contouring, especially in patients with bulky lump gross target volume lymph nodes (GTVnd). This study defines lymph node region boundaries in radiotherapy for lung cancer and automatically contours lymph node stations based on the International Association for the Study of Lung Cancer (IASLC) lymph node map. METHODS: Computed tomography (CT) scans of 200 patients with small cell lung cancer were collected. The lymph node zone boundaries were defined based on the IASLC lymph node map, with adjustments to meet radiotherapy requirements. Contours of lymph node stations were confirmed by two experienced oncologists. A model (DiUNet) was constructed by incorporating the contours of GTVnd to precisely contour the boundaries. Quantitative evaluation metrics and clinical evaluations were conducted. RESULTS: The mean 3D Dice similarity coefficient (Dice similarity coefficient) values of DiUNet in most lymph node stations was greater than 0.7, 98.87% of the lymph node station slices are accepted. The mean DiUNet score was not significantly different from that of the man contoured in the evaluation of lymph node stations and CTV. CONCLUSION: This is the first study to propose a method that automatically contours lymph node regions station by station based on the IASLC lymph node map with bulky lump GTVnd. Delineation of lymph node stations based on the DiUNet model is a promising strategy to obtain accuracy and efficiency for CTV delineation in lung cancer patients, especially for bulky lump GTVnd.

Clinical performance evaluation of O-Ring Halcyon Linac: A real-world study.

BACKGROUND: Radiation therapy, especially the development of linear accelerators, plays a key role in cancer management. The fast-rotating coplanar O-ring Halcyon Linac has demonstrated many advantages. The previous literature has mainly focused on the machine parameters and plan quality of Halcyon, with a lack of relevant research on its clinical application. AIM: To evaluate the clinical performance of the O-ring Halcyon treatment system in a real-world application setting. METHODS: Data from sixty-one patients who were treated with the Halcyon system throughout the entire radiotherapy process in Peking Union Medical College Hospital between August 2019 and September 2020 were retrospectively reviewed. We evaluated the target tumour response to radiotherapy and irradiation toxicity from 1 to 3 mo after treatment. Dosimetric verification of Halcyon plans was performed using a quality assurance procedure, including portal dosimetry, ArcCHECK and point dose measurements for verification of the system delivery accuracy. RESULTS: Of the 61 patients in the five groups, 16, 12, 7 and 26 patients had complete response, partial response, progressive disease and stable disease, respectively. No increase in the irradiated target tumour volume was observed when separately evaluating the local response. Regarding irradiation toxicity, no radiation-induced deaths were observed. Thirty-eight percent (23/61 patients) had no radiation toxicity after radiotherapy, 56% (34/61 patients) experienced radiation toxicity that resolved after treatment, and 6% (4/61 patients) had irreversible adverse reactions. The average gamma passing rates with a 2% dose difference and 2-mm distance to agreement for IMRT/VMAT/SRT plans were ArcCHECK at 96.4% and portal dosimetry at 96.7%, respectively. All of the validated clinical plans were within 3% for point dose measurements, and Halcyon's ArcCHECK demonstrated a high pass rate of 99.1% ± 1.1% for clinical gamma passing criteria of 3%/3 mm. CONCLUSION: The O-ring Halcyon Linac could achieve a better therapeutic effect on the target volume by providing accurate treatment delivery plans with tolerable irradiation toxicity.

Clinical application of radiotherapy in patients with oligometastatic ovarian cancer: a sharp tool to prolong the interval of systemic treatment.

BACKGROUND: With the advances of radiation technology, treatment of oligometastatic disease, with limited metastatic burden, have more chances to achieve long-term local control. Here we aim to evaluate the efficacy and safety of radiotherapy (RT) in oligometastatic ovarian cancer patients. METHODS: A retrospective analysis collecting 142 patients (189 lesions) with oligometastatic ovarian cancer were included in the study. All pateints received radiotherapy and the curative effect and response rate were evaluated by diagnostic imaging after 1-3 months of radiotherapy with RECIST. Endpoints were the rate of complete response (CR), chemotherapy-free interval (CFI), local control (LC) rate and overall survival (OS) rate. Toxicity was evaluated by the Radiation Therapy Oncology Group (RTOG). Logistic and Cox regression were used for the uni- and multivariate analysis of factors influencing survival outcomes. RESULTS: From 2013.1.1 to 2020.12.30, a total of 142 ovarian cancer patients (189 oligometastasis lesions) were included in the analysis. Prescribed doses to an average GTV of 3.10 cm were 1.8-8 Gy/fraction, median BED (28-115, a/b = 10 Gy), 5-28 fractions. For 179 evaluable lesions, the cases of CR, partial response (PR), stable disease (SD) and progressive disease (PD) after radiotherapy were 22,39,38 and 80 respectively. The disease control rate (DCR): CR + PR + SD was 55.31%, and the objective response rate (ORR): CR + PR was 34.08%. No patient developed grade 3 or higher side effect. The median CFI was 14 months (1-99 months), and the LC rate was 69.7%, 54.3% and 40.9% in 1 year, 2 years and 5 years respectively. GTV < 3 cm before treatment, platinum sensitivity, time from the last treatment ≥ 6 months, single lesion and BED(a/b = 10 Gy) ≥ 60 are the factors of good LC (p < 0.05). The total OS of 1 year, 2 years and 5 years were 67.1%, 52.6% and 30.3%, respectively. Single lesion (HR 0.598, 95%CI 0.405-0.884), DCR (HR 0.640, 95% CI 0.448-0.918) and ORR(HR 0.466, 95% CI 0.308-0.707) were the significant factors influencing 5-year OS. CONCLUSION: For patients with oligometastatic ovarian cancer, radiotherapy has high LC, long chemotherapy-free interval, and survival benefits. Subgroup analysis shows that patients with single lesion and good local treatment results have higher overall survival rate, suggesting that active treatment is also beneficial for oligometastatic ovarian cancer patients.

Risk of second primary malignancies associated with radiotherapy in prostate cancer patients: competing risk analysis.

Background: The effect of radiotherapy (RT) for second primary malignancies (SPMs) among prostate cancer survivors is controversial. Methods: Applying logistic regression, competing risk analysis and propensity score matching method, this study analyzed clinical data from the Surveillance, Epidemiology, and End Results program to compare the risk for SPMs between patients receiving RT and non-RT. Results: In this study, prostate cancer patients treated with RT developed more SPMs in the anus, bladder, rectum, liver, lung and bronchus and lymphoma than non-RT groups. Conclusion: More intensive surveillance should be adopted for these cancers among prostate cancer survivors.

Plain language summary Patients with prostate cancer have the highest 5-year survival rate, which increases the risk for developing second primary malignancies (SPMs). The effect of radiotherapy (RT) for SPMs is controversial among prostate cancer survivors. This study analyzed a mass of prostate cancer patients from a public database to compare risk for SPMs between RT and non-RT groups. RT indeed increased certain categories of SPM and intensive surveillance should be considered.

A blind randomized validated convolutional neural network for auto-segmentation of clinical target volume in rectal cancer patients receiving neoadjuvant radiotherapy.

BACKGROUND: Delineation of clinical target volume (CTV) for radiotherapy is a time-consuming and labor-intensive work. This study aims to propose a novel convolutional neural network (CNN)-based model for fast auto-segmentation of CTV. To evaluate its performance and clinical utility, a blind randomized validation method was used. METHODS: Our proposed model was based on the generally accepted U-Net architecture using computed tomography slices with CTV contours delineated by experienced radiation clinicians from 135 rectal patients receiving neoadjuvant radiotherapy. The Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) were used to measure segmentation performance. The validated dataset of additional 20 patients for clinical evaluation by 10 experienced oncology clinicians from 7 centers was randomly and blindly divided into two groups for clinicians' scoring and Turing test, respectively. Second evaluation was performed with different randomization after 2 weeks. RESULTS: The mean DSC and 95HD values of the proposed model were 0.90 ± 0.02 and 8.11 ± 1.93 mm for CTV of rectal cancer patients, respectively. The average time for automatic segmentation in the validation groups was 15 s per patient. By clinicians' scoring, the AI model performed better than manually delineating, though the differences were not significant (Week 0: 2.59 vs. 2.52, p = 0.086; Week 2: 2.55 vs. 2.47, p = 0.115). Additionally, the mean positive rates in the Turing test were 40.5% in Week 0 and 45.2% in Week 2, which demonstrated the great intelligence of our model. CONCLUSIONS: Our proposed model can be used clinically for assisting contouring of CTVs in rectal cancer patients receiving neoadjuvant radiotherapy, which improves the efficiency and consistency of radiation clinicians' work.

A Population-Based Systematic Clinical Analysis With a Single-Center Case Series of Patients With Pulmonary Large Cell Neuroendocrine Carcinoma.

Background and Objectives: This study aims to conduct an updated systematic analysis of patients with pulmonary large cell neuroendocrine carcinoma (PLCNC) in recent decades, concerning incidence and mortality trends, demographics, treatments, survival and death causes. Methods: Patients who were diagnosed with PLCNC at the Peking Union Medical College Hospital (PUMCH) between 2000 to 2020 were retrospectively analyzed. The population-based Surveillance, Epidemiology, and End Results (SEER) database were also retrieved. Frequencies and average annual age-adjusted rates (AAR) of PLCNC patients were calculated and analyzed by Joint-point regression. Univariate and multivariate Cox regression were used for identifying prognostic factors. Predictive nomograms for overall survival (OS) and cancer-specific survival (CSS) were developed and then validated by calculating C-index values and drawing calibration curves. Survival curves were plotted using the Kaplan-Meier method and compared by log-rank test. Causes of death were also analyzed by time latency. Results: A total of 56 PLCNC patients of the PUMCH cohort were included. Additionally, the PLCNC patients in the SEER database were also identified from different subsets. The AAR from 2001 to 2017 were 3.21 (95%CI: 3.12-3.30) per million. Its incidence and mortality rates in PLCNC patients increased at first but seemed to decline in recent years. Besides TNM stage and treatments, older age and male gender were independently associated with poorer survival, while marital status only affected CSS other than OS. The nomograms for OS and CSS presented great predictive ability and calibration performance. Surgery gave significantly more survival benefits to PLCNC patients, and chemotherapy might add survival benefits to stage II-IV. However, radiation therapy seemed to only improve stage III patients' survival. Conclusions: This study supported some previous studies in terms of incidence, survival, and treatment options. The mortality rates seemed to decline recently, after an earlier increase. Among PLCNC patients, most of the deaths occurred within the first five years, while other non-PLCNC diseases increased after that. Thus, careful management and follow-up of other comorbidities are of equal importance. Our study may partly solve the dilemma caused by PLCNC's rarity and inspire more insights in future researches.

Second Malignant Neoplasms in Patients With Rhabdomyosarcoma.

OBJECTIVE: Rhabdomyosarcoma (RMS) is a rare malignant tumor. The main treatment modality is comprehensive with chemotherapy, radiotherapy, and surgery. With the advancement in recent decades, patient survival has been prolonged, and long-term complications are attracting increasing attention among both physicians and patients. This study aimed to present the survival of patients with RMS and analyze the risk factors for the development of a second malignant neoplasm (SMN). METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program 18 registry database from 1973 to 2015 of the National Cancer Institute of the United States was used for the survival analyses, and the SEER 9 for the SMN analysis. RESULTS: The 5-, 10-, and 20-year overall survival rates of the patients with RMS were 45%, 43%, and 33%, respectively. The risk of SMN was significantly higher in patients with RMS compared to the general population (SIR=1.95, 95% CI: 1.44 - 2.57, p < 0.001). The risk of developing SMN was increased in multiple locations, including the bones and joints (SIR = 35.25) soft tissues including the heart (SIR = 22.5), breasts (SIR = 2.10), male genital organs (SIR = 118.14), urinary system (SIR = 2.36), brain (SIR = 9.21), and all nervous system organs (SIR = 8.59). The multivariate analysis indicated that RMS in the limbs and earlier diagnosis time were independent risk factors for the development of SMN. Patients with head and neck (OR = 0.546, 95% CI: 0.313 - 0.952, p = 0.033) and trunk RMS (OR = 0.322, 95% CI: 0.184 - 0.564. p < 0.001) and a later diagnosis time were less likely to develop SMN (OR = 0.496, 95% CI: 0.421 - 0.585, p < 0.001). CONCLUSION: This study describes the risk factors associated with the development of SMN in patients with RMS, which is helpful for the personalized screening of high-risk patients with RMS.

Second primary malignancies associated with radiation therapy in cervical cancer patients diagnosed between 1975 and 2011: a population-based competing-risk study.

BACKGROUND: Cervical cancer is a major health threat for women. Radiotherapy plays an important role in the treatment of cervical cancer. However, its overall benefit has been questioned due to the risk of second primary malignancies. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to search for cervical cancer patients diagnosed between January 1975 and November 2011. Factors that could possibly affect the occurrence of second primary malignancies included the year of diagnosis, gender, ethnicity, histologic type, SEER cancer stage, histology, grade, and whether surgery, chemotherapy, or radiotherapy were used. Age-adjusted and propensity scoring matching (PSM)-adjusted competing-risk analysis was applied for analysis. RESULTS: Of the 23,112 patients identified through SEER, 14,800 (64.0%) received radiotherapy. Second malignancies were diagnosed in 2,545 (11.0%) cases. PSM-adjusted competing analysis revealed that patients receiving radiotherapy had a significantly higher risk of developing a second cancer in the colon, rectum and anus [hazard ratio (HR): 1.43; 95% confidence interval (CI): 1.09-1.87; P=0.01], lung and bronchus (HR: 1.41; 95% CI: 1.13-1.76; P=0.002), corpus uteri (HR: 3.71; 95% CI: 1.71-8.06; P<0.001), ovary (HR: 2.79; 95% CI: 1.38-5.64; P=0.004), and urinary bladder (HR: 2.18; 95% CI: 1.35-3.54; P=0.002). However, radiotherapy significantly lowered the risk of second cancers in the female breast (HR: 0.67; 95% CI: 0.52-0.86; P=0.002). Age-adjusted competing-risk analysis showed generally consistent results. CONCLUSIONS: Radiotherapy increased the risk of second cancers among cervical cancer patients. Those who underwent radiotherapy had a significantly higher risk of developing a second cancer in the colon, rectum and anus, lung and bronchus, corpus uteri, ovary, and urinary bladder.

Automatic Segmentation of Clinical Target Volume and Organs-at-Risk for Breast Conservative Radiotherapy Using a Convolutional Neural Network.

OBJECTIVE: Delineation of clinical target volume (CTV) and organs at risk (OARs) is important for radiotherapy but is time-consuming. We trained and evaluated a U-ResNet model to provide fast and consistent auto-segmentation. METHODS: We collected 160 patients' CT scans with breast cancer who underwent breast-conserving surgery (BCS) and were treated with radiotherapy. CTV and OARs were delineated manually and were used for model training. The dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) were used to assess the performance of our model. CTV and OARs were randomly selected as ground truth (GT) masks, and artificial intelligence (AI) masks were generated by the proposed model. Two clinicians randomly compared CTV score differences of the contour. The consistency between two clinicians was tested. Time cost for auto-delineation was evaluated. RESULTS: The mean DSC values of the proposed method were 0.94, 0.95, 0.94, 0.96, 0.96 and 0.93 for breast CTV, contralateral breast, heart, right lung, left lung and spinal cord, respectively. The mean 95HD values were 4.31mm, 3.59mm, 4.86mm, 3.18mm, 2.79mm and 4.37mm for the above structures, respectively. The average CTV scores for AI and GT were 2.89 versus 2.92 when evaluated by oncologist A (P=0.612), and 2.75 versus 2.83 by oncologist B (P=0.213), with no statistically significant differences. The consistency between two clinicians was poor (kappa=0.282). The time for auto-segmentation of CTV and OARs was 10.03 s. CONCLUSION: Our proposed model (U-ResNet) can improve the efficiency and accuracy of delineation compared with U-Net, performing equally well with the segmentation generated by oncologists.

Risk of developing second malignant neoplasms in patients with neuroblastoma: a population study of the US SEER database.

BACKGROUND: Neuroblastoma is a common extracranial malignant tumor in children. Its main treatment modality is a combination of chemotherapy, radiotherapy, and surgery. Given the advances in chemotherapy regimens and the widespread use of bone marrow transplantation over the decades, there has been improvement in treatment efficacy, which has led to prolonged patient survival. Accordingly, long-term complications have become a growing concern among physicians and patients. This study aimed to analyze the survival rate of patients with neuroblastoma and the risk factors for developing second malignant neoplasms (SMNs). METHODS: The SEER 18 Regs (1973-2015) and SEER 9 Regs (1973-2015) data of the surveillance, epidemiology, and end results (SEER) database of the US National Cancer Institute were adopted for survival and SMN analysis. RESULTS: The 5-, 10-, and 20-year overall survival rates of patients with neuroblastoma were 67%, 65%, and 62%, respectively. Among 38 patients with neuroblastoma who presented with SMNs, those with abdomen as the primary site accounted for the majority (63.2%), followed by those with thorax (26.3%) and other sites (10.5%). SMNs occurred more commonly in non-specific neuroblastoma (incidence: 0.87%) than ganglioneuroblastoma (incidence: 0.3%). Compared with the general population, the risk of SMN is significantly higher (SIR = 4.36). The risk of developing SMNs was significantly higher in the digestive system (SIR = 7.29), bones and joints (SIR = 12.91), urinary system (SIR = 23.48), brain and other nervous systems (SIR = 5.70), and endocrine system (SIR = 5.84). Multivariate analysis revealed that the year of diagnosis (OR = 2.138, 95% CI = 1.634-2.797, p < 0.001) was the only independent risk factor for developing SMNs. CONCLUSION: This study identifies the risk factor for developing SMNs in patients with neuroblastoma, which could facilitate individualized screening for high-risk patients, to allow early diagnosis and treatment of SMNs.

Long-term radiation therapy-related risk of second primary malignancies in patients with lung cancer.

BACKGROUND: With the improvement of cancer therapy, a second primary malignancy (SPM) occurs more commonly among cancer survivors. At present, it remains unclear whether the radiation therapy for the initial lung cancer will increase the risk of developing a SPM. This study aims to investigate the long-term risk of a SPM attributable to the radiation therapy in patients with the initial lung cancer. METHODS: Patients initially diagnosed with lung cancer between January 1975 and November 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. SPM was defined as the occurrence of a second cancer at least five years after the diagnosis of the initial lung cancer. Age- and propensity score matching (PSM)-adjusted competing risk analyses were performed to compare the risk of SPM. RESULTS: Of 47,911 patients, 9,162 (19.1%) underwent radiotherapy for the initial lung cancer. The PSM-adjusted competing risk analyses showed that radiation therapy was associated with a lower overall risk of SPM (HR: 0.89, 95% CI: 0.84-0.94, P<0.001). Specifically, the risk of second primary melanoma (HR: 0.49, 95% CI: 0.29-0.81, P=0.006), second primary female breast cancer (HR: 0.65, 95% CI: 0.50-0.85, P=0.001), second primary prostate cancer (HR: 0.69, 95% CI: 0.58-0.84, P<0.001) and second primary thyroid cancer (HR: 0.23, 95% CI: 0.07-0.77, P=0.017) was found to decrease, while the risk for second primary esophageal cancer dramatically increased (HR: 1.76, 95% CI: 1.26-2.45, P<0.001). CONCLUSIONS: In patients who received radiotherapy for the initial lung cancer, the risk decreased for second primary melanoma as well as for second primary cancers of female breast, prostate and thyroid gland but increased for second primary cancer of esophagus. On the whole, radiation therapy for initial lung cancer may not increase the overall risk of SPM.

An Adversarial Deep-Learning-Based Model for Cervical Cancer CTV Segmentation With Multicenter Blinded Randomized Controlled Validation.

PURPOSE: To propose a novel deep-learning-based auto-segmentation model for CTV delineation in cervical cancer and to evaluate whether it can perform comparably well to manual delineation by a three-stage multicenter evaluation framework. METHODS: An adversarial deep-learning-based auto-segmentation model was trained and configured for cervical cancer CTV contouring using CT data from 237 patients. Then CT scans of additional 20 consecutive patients with locally advanced cervical cancer were collected to perform a three-stage multicenter randomized controlled evaluation involving nine oncologists from six medical centers. This evaluation system is a combination of objective performance metrics, radiation oncologist assessment, and finally the head-to-head Turing imitation test. Accuracy and effectiveness were evaluated step by step. The intra-observer consistency of each oncologist was also tested. RESULTS: In stage-1 evaluation, the mean DSC and the 95HD value of the proposed model were 0.88 and 3.46 mm, respectively. In stage-2, the oncologist grading evaluation showed the majority of AI contours were comparable to the GT contours. The average CTV scores for AI and GT were 2.68 vs. 2.71 in week 0 (P = .206), and 2.62 vs. 2.63 in week 2 (P = .552), with no significant statistical differences. In stage-3, the Turing imitation test showed that the percentage of AI contours, which were judged to be better than GT contours by ≥5 oncologists, was 60.0% in week 0 and 42.5% in week 2. Most oncologists demonstrated good consistency between the 2 weeks (P > 0.05). CONCLUSIONS: The tested AI model was demonstrated to be accurate and comparable to the manual CTV segmentation in cervical cancer patients when assessed by our three-stage evaluation framework.