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Sleep disorders seriously affect human health and life. Accurate classification of sleep stages is the key to detecting and treating sleep disorders. In recent years, methods based on deep learning have surpassed traditional machine learning methods and human experts. However, the internal structure of deep learning is complex and requires to be designed by expert who is familiar with the computer and medical fields. This paper aims to analyze the relational induction biases in the existing sleep staging model based on deep learning, and explores the basic principles of sleep staging model design. This paper analyzes relational induction biases such as translation invariance, time invariance and hierarchical processing. Firstly, the model is divided into three categories according to whether it contains convolution layer with translation invariance and recurrent layer with time invariance: convolutional neural network framework, recurrent neural network framework and hybrid neural network framework. Secondly, according to the hierarchical processing method of the frame, segment and sequence in the model, a more detailed classification is carried out. Thirdly, it analyzes the impact of different relational induction biases in the model on the performance of sleep staging. It is proposed that a relational inductive bias matched the task should be introduced when the automatic sleep staging model is designed. Finally, the advantages and limitations of sleep staging based on deep learning are discussed, and it may be necessary to use more advanced relationship induction bias to express knowledge more abstractly and combine it with other artificial intelligence technologies in the future.

Purpose/Objective(s) We hypothesize that radiomic features provide information for predicting early treatment response of lung cancer with definitive radiation therapy (RT). This study aims to develop and validate a radiomics-based model for predicting early treatment response of lung cancer with definitive radiation therapy (RT). Materials/Methods From January 2018 to March 2020, 128 lung cancer patients with definitive radiation therapy (RT) had enrolled retrospectively in the study and randomly divided into training set (n = 90) and test set(n = 38). Based on the Response Evaluation Criteria in Solid Tumors1.1 (RECIST1.1), response of lung cancer with definitive radiation therapy (RT) was dichotomized that treatment was effective if tumor volume decreased over 30༅ at the first follow-up CT after definitive radiation therapy (RT). Radiomic features were extracted using an open-source software development tool from the Gross Tumor Volume (GTV) of planning CT images. Specifically, a total of 107 radiomics features are extracted that include the first-order statistic features, the second-order texture features, and 2D-3D shape-based features. To reduce the feature dimensionality, we used the RFE (Recursive Feature Elimination) method to filter the features and obtained 13 out of 107 features that are most effective for final classification. By analyzing the data and comparing the experimental validation, we employed Random Forest classifier for the response prediction. Results All patients received definitive radiation therapy (56-70Gy) and no operation. 36 patients received Intensity-modulated radiation therapy (IMRT) and 92 patients received Volumetric Intensity Modulated Arc Therapy (VMAT) (P = 0.951). 103 patients are men and 25 patients are women (P = 0.969). In addition to the five-fold cross-validation, we evaluated the classification results using the independent test set. The AUC for five-fold cross validation is 0.798, and the AUC for the independent test set is 0.771. Conclusion This study demonstrated that radiomic model shows a good prediction value of early treatment response of lung cancer with definitive radiation therapy (RT). Radiomic features extracted from the Gross Tumor Volume (GTV) of planning CT images may predict response of radiation and might be helpful for individual treatments. The result still needs to be further validated by increasing the amount of data, especially prospective data.

// Huan-Huan Wang 1, * , Lei Deng 2, * , Qing-Lian Wen 3, * , Chun-Ze Zhang 4, * , Nicholas G. Zaorsky 5 , Bai-Lin Zhang 1 , Jie Chen 1 , Xian-Liang Zeng 1 , Yao-Li Cui 6 , Yang-Yang Shi 7 , Hai-Ling Hou 1 , Wei Wang 1 , Bo Jiang 1 , Jun Wang 1 , Qing-Song Pang 1 , Lu-Jun Zhao 1 , Zhi-Yong Yuan 1 , Ping Wang 1 and Mao-Bin Meng 1 1 Department of Radiation Oncology and CyberKnife Center, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China 2 Department of Thoracic Cancer, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu 610041, China 3 Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China 4 Department of Surgery, Nankai University Tianjin People’s Hospital, Tianjin People’s Hospital, Tianjin 300121, China 5 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 6 Department of Lymphoma, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China 7 Stanford University School of Medicine, Stanford, CA 94305, USA * These authors have contributed equally to this work Correspondence to: Mao-Bin Meng, email: doctormm991@hotmail.com Keywords: non-small cell lung cancer, postoperative radiotherapy, postoperative chemotherapy, multimodality therapy, overall survival Received: December 10, 2016 Accepted: April 24, 2017 Published: May 23, 2017 ABSTRACT Aims: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. Patients and Methods: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy (“early PORT”) or with PORT administered after two cycles of chemotherapy (“late PORT”) at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan–Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. Results: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. Conclusions: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Xian-Liang Zeng,* Huan-Huan Wang,* Mao-Bin Meng, Zhi-Qiang Wu, Yong-Chun Song, Hong-Qing Zhuang, Dong Qian, Feng-Tong Li, Lu-Jun Zhao, Zhi-Yong Yuan, Ping Wang Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China *These authors contributed equally to this work Background and aim: The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Patients and methods: Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results: Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8days (range, 1–14days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. Conclusion: SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely. Keywords: stereotactic body radiation therapy, pancreatic adenocarcinoma, recurrent disease, overall survival

Background Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. Material and methods Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. Results The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. Conclusions A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.

Background The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. Methods 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT + RT with ChT groups that matched on possible confounding variables. Results Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT + TRT, and 10.3% ( p 0.001 ), 4.6% ( p 0.001 ) and 6.3% for ChT only ( p 0.001 ), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED > 50 Gy) TRT and received low dose (tBED ≤ 50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% ( p p = 0.097) and 34.7% ( p = 0.029) for low dose radiotherapy. Conclusions TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC.

There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p

The aim of the paper is to evaluate the efficacy of CyberKnife® for the treatment of primary or metastatic retroperitoneal tumours. Twenty-eight patients were treated. The prescription isodose line (median, 78%; range, 70-84%) covered the planning target volume at a total dose of 2000-6000 cGy (median, 4500 cGy) and a biologically effective dose of 3750-10,080 cGy (median, 7680 cGy) in 2-10 fractions (median, five fractions). The results showed that the complete response, partial response, stable disease, and progressive disease rates were 43% (12/28), 36% (10/28), 18% (5/28), and 4% (1/28) respectively. The overall response rate was 96%. The 1-, 2- and 3-year local control rates were 92%, 86%, and 86% respectively. The 1-, 2- and 3-year overall survival rates were 60%, 49%, and 49% respectively. No significant difference was found between local progression-free survival and overall survival. Moreover, if a patient only had metastases in the retroperitoneum and local control was effective, there was no significant difference between local progression-free survival and overall progression-free survival. In conclusion, CyberKnife treatment for retroperitoneal tumours resulted in high response rates with minimal side effects. All radiation-induced side effects were well tolerated.

Background Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone. Methods We searched the Cochrane Library, MEDLINE, EMBASE, CENTRAL, CBMdisc, and CNKI, as well as employing manual searches. The primary end points were survival and local control. The second end point was toxicities. Results Based on search criteria, we found 29 trials involving 3187 patients. Our results showed that LCAHR, compared with CFR, improved the survival and local control, and was, thus, more therapeutically beneficial. Further analysis revealed that LCAHR plus CT proved to be better for patients' survival and local control compared to LCAHR alone. Acute toxicities were increased rather than late toxicities. Conclusions There was a significant survival and local control benefit of LCAHR over CFR, as well as LCAHR plus CT over LCAHR alone. Considering the strength of the evidence, the results of this study indicate that this regimen would be a new promising modality worth further investigation.

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell-survival rates were evaluated by colony-forming assays. Cell apoptosis and cell-cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl-2, Bax, Rad51 and phosphorylated DNA-PKcs (phospho-DNA-PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G(2)/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl-2, Bax, P21, Cdc25c, Rad51 and phospho-DNA-PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G(2)/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G(2)/M cell cycle arrest. Moreover, the pro-apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation.

Transforming growth factor-β (TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer progression. However, TGF-β can modulate cancer-related processes, such as cell invasion, distant metastasis, and microenvironment modification that may be used by cancer cells to their advantage in late stages. Corresponding mechanisms include angiogenesis promotion, anti-tumor immunity suppression, and epithelial-to-mesenchymal transition (EMT) induction. The correlation between TGF-β expression and cancer prognosis has also been extensively investigated. Results suggest that TGF-β pathway can be targeted to treat cancer; as such, the feasibility of this treatment is investigated in clinical trials.

Background Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. Methods In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. Results SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C–X–C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. Conclusion Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

// Huan-Huan Wang 1 , Nicholas G. Zaorsky 2 , Mao-Bin Meng 1 , Xian-Liang Zeng 1 , Lei Deng 3 , Yong-Chun Song 1 , Hong-Qing Zhuang 1 , Feng-Tong Li 1 , Lu-Jun Zhao 1 , Zhi-Yong Yuan 1 , Ping Wang 1 , Xi-Shan Hao 4 1 Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China 2 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 3 Department of Thoracic Cancer and Huaxi Student Society of Oncology Research, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China 4 Department of Gastrointestinal Surgery, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China Correspondence to: Mao-Bin Meng, email: // Keywords : stereotactic radiation therapy, mediastinal lymph node, neoplasm metastasis, oligometastasis, oligorecurrence Received : October 26, 2015 Accepted : February 11, 2016 Published : February 23, 2016 Abstract Aims: This study evaluated the safety and efficacy of stereotactic radiation therapy (SRT) for the treatment of patients with oligometastases or oligorecurrence within mediastinal lymph nodes (MLNs) originating from different tumors. Methods: Between October 2006 and May 2015, patients with MLN oligometastases or oligorecurrence were enrolled and treated with SRT at our hospital. The primary endpoint was MLN local control (LC). Secondary endpoints were time to symptom alleviation, overall survival (OS) after SRT, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Results: Eighty-five patients with 98 MLN oligometastases or oligorecurrences were treated with SRT. For the entire cohort, the 1-year and 5-year actuarial LC rates were 97% and 77%, respectively. Of 53 symptomatic patients, symptom alleviation was observed in 47 (89%) after a median of 5 days (range, 3-30 days). The median OS was 27.2 months for all patients. For patients with non-small cell lung cancer, univariate and multivariate analyses revealed that a shorter interval between diagnosis of primary tumors and SRT and larger MLN SRT volume were associated with worse OS. CTCAE v4.0 ≥ Grade 3 toxicities occurred in six patients (7%), with Grade 5 in three patients (all with RT history to MLN station 7). Conclusions: SRT is a safe and efficacious treatment modality for patients with oligometastases or oligorecurrence to MLNs originating from different tumors, except for patients who received radiotherapy to MLN station 7. Further investigation is warranted to identify the patients who benefit most from this treatment modality.

Objective: To compare the differences between contrast-enhanced (CE) fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET)/CT and CECT in target volume delineation and radiotherapy (RT) dose distribution, and to evaluate the sparing of organs at risk (OARs) in the treatment plan of locally advanced pancreatic cancer (LAPC). Methods: 21 consecutive patients with LAPC with histologically or cytologically confirmed adenocarcinoma underwent both non-CECT and 18F-FDG scans; 11 of whom also underwent CECT scans. Intensity-modulated RT plans (prescribed dose, 54 Gy) were constructed to cover the corresponding gross tumour volume (GTV). The differences among GTVCT, GTVPET, GTVPET-CT and OARs in these different image sets as well as the uniformity of target dose were analysed. Results: The mean non-CE GTVCT, GTVPET and GTVPET-CT were 76.9 ± 47.8, 47.0 ± 40.2 and 44.5 ± 34.7 cm3 (mean ± standard deviation), respectively. The non-CE GTVPET-CT was significantly smaller than the non-CE GTVCT (p

Background: To evaluate the safety and efficacy of combined chemoradiotherapy or radiotherapy alone in elderly patients with esophageal carcinoma to identify the best method of treatment. Materials and Methods: One hundred and sixteen patients with esophageal carcinoma aged 70 and older who received definitive radiotherapy or chemoradiotherapy entered the study. Overall survival (OS), disease-free survival (DFS) and treatment- related toxicities were assessed. Results: The median OS of the overall population was 17.9 months. For patients treated with cCRT, sCRT and radiotherapy alone, the median OS was 22.3 months, 18.0 months and 12.4 months respectively(P=0.044). Median OS for patients treated with radiotherapy dose ≥60Gy and

Objective Radiation-induced lung injury commonly follows radiotherapy (RT) for tumors within and near the thorax. Lung function is usually measured by pulmonary function tests (PFTs). But RT-induced regional changes of pulmonary function cannot be accurately evaluated by PFTs. Lung perfusion scintigraphy compared with other radiographic methods can assess well regional pulmonary physiological function, and a 3-dimensional conformai radiotherapy planning system can quantitatively calculate irradiation dosage. The purpose of this study is to assess, by lung perfusion scintigraphy, early changes in the pulmonary function of patients with lung cancer when receiving thoracic 3-dimensional conformaL radiotherapy (3D-CRT).

The isobaric vapor–liquid equilibrium (VLE) data for phenol–dimethyl carbonate (DMC) and phenol–methanol binary systems were measured at 101.3 kPa by using a modified Rose–Williams still. The experimental VLE data have been tested for thermodynamic consistency via Herington analysis and correlated with Wilson, NRTL and UNIQUAC equations.

Huan-Huan Wang,1,* Nicholas G Zaorsky,2,* Mao-Bin Meng,1 Zhi-Qiang Wu,1 Xian-Liang Zeng,1 Bo Jiang,1 Chao Jiang,1 Lu-Jun Zhao,1 Zhi-Yong Yuan,1 Ping Wang1 1Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention andTherapy, Tianjin Medical University Cancer Institute andHospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 2Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA *These authors contributed equally tothis work Background and aim: Limited-stage combined small cell esophageal carcinoma (LS-C-SCEC) is a rare, poorly understood, underdiagnosed disease, with components of both small cell esophageal cancer and non–small cell esophageal cancer. We investigated the optimal treatment strategy and prognostic factors in patients with LS-C-SCEC. Patients and methods: LS-C-SCEC patients included in the analysis (from our hospital and the literature) were treated between January 1966 and December 2013. Patient treatment strategies included surgery (S), chemotherapy (CT), and radiation therapy (RT). The primary end point was overall survival (OS); the secondary end points included tumor complete response rates, patterns of failure, and toxicity. Kaplan–Meier curves were compared with the log-rank test. Univariate and multivariate analyses were used to determine prognosticators for OS. Results: A total of 72 patients were included in the analysis: 24 (33%) from our hospital and 48 (67%) from the literature. The median OS of all patients was 15.0 months. Patients who received CT had a significantly longer median OS than did those who did not (OS 22.8monthsvs 10.0months) (P=0.03). Patients treated with multimodality therapy (including RT+CT [18%], S+CT [40%], or S+RT+CT [17%]) vs monotherapy (typically, S [18%]) had significantly improved OS (15.5 months vs 9.3 months) (P=0.02) and complete response rates. On multivariate analysis, tumor location (upper third of the esophagus) and type of treatment (monotherapy) were the only factors predictive of poor OS. Conclusion: Multimodality therapy (including RT+CT, S+CT, or S+RT+CT) improves OS for patients with LS-C-SCEC compared with monotherapy (typically, S). Additional studies are necessary to personalize multimodal treatment approaches to individual patients. Keywords: esophageal neoplasm, small cell, radiation therapy, surgery, chemotherapy

Purpose Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization. Methods A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis. Results The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET. Conclusions Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

ABSTRACT Pericytes, which envelope the vascular endothelium throughout the body, are often targeted to promote vascular normalization and restore normal function of blood vessels in cancer treatment. The goals of pericyte-targeted therapy tend to promote proper vascular normalization of the tumor. Tumor vascular normalization prevents metastasis, increases tumor oxygenation (making radiation more effective in killing tumor cells), optimizes Starling forces to increase delivery of cancer cell-directed therapies (e.g., chemotherapy or targeted agents), increases the efficacy of focal therapies (e.g., surgery or radiation), and increases recognition by the host immune system. We review how approaches in pericyte-targeted therapy aim to reach a balance between pro-angiogenic and anti-angiogenic function (i.e., by targeting platelet-derived growth factor beta receptors, vascular endothelial growth factor receptors and Tie-2) for tumor vascular normalization.

Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3β phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC.

To evaluate the clinical efficacy and safety of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with locally advanced non-small-cell lung cancer (LANSCLC).48 patients with LANSCLC treated with SIB-IMRT from January 2010 to April 2012 were retrospectively analysed. A radiation dose of 45-63 Gy (median dose, 51.58 Gy) was delivered to the planning target volume (1.8-2.0 Gy daily fractions) simultaneously with 55.0-74.2 Gy (median dose, 63 Gy) to the planning gross tumour volume (2.00-2.25 Gy daily fractions). 45 patients received concurrent/sequential chemotherapy. The overall survival (OS), locoregional recurrence-free survival (LRFS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Treatment-related pneumonitis and oesophagitis were graded according to the Common Terminology Criteria for Adverse Events v. 4.0.By 1 July 2013, 29 of the 48 patients were dead. The median follow-up time for the survivors was 28 months (19-44 months). The median OS and PFS were 21 and 14 months, respectively. The median LRFS time was not reached. The 2-year LRFS, OS and PFS were 62.5%, 45.1% and 28.0%, respectively. Two patients experienced Grade 3 treatment-related pneumonitis, two patients experienced Grade 5 treatment-related pneumonitis and two patients had ≥Grade 3 oesophagitis.SIB-IMRT appears to be an effective therapeutic option in patients with LANSCLC and warrants further evaluation with increased number of patients in prospective clinical trials.This study explores the feasibility of delivering tumoricidal doses of radiation to primary lesions in non-small-cell lung cancer.

Aim The purpose of this study is to evaluate the role of postoperative radiotherapy (PORT) in resected small-cell lung cancer (SCLC). Methods: This study retrospectively analyzed 143 patients with completely resected SCLC in our institution between 1996 and 2011. The primary endpoint was overall survival (OS). The log-rank test and Cox regression model were used to evaluate the factors influencing local-regional recurrence (LRR) and OS. Results The median OS for the entire population was 34 months, and the 5-year OS rate was 34.6%. In multivariate analysis, age, surgical procedure, pathology stage, adjuvant chemotherapy and distant relapse were significant factors for survival. For the whole population, PORT had no effect on OS, with a median OS of 40 months in the PORT group versus 27 months in the non-PORT group (p = 0.260). However, in patients with N1 disease, the median OS were 40 months in the PORT group versus 14 months in the non-PORT group (p = 0.032). The corresponding OS in N2 patients were 35 months versus 17 months, respectively (p = 0.040). Similarly, PORT significantly reduced the LRR in patients with positive lymph node. For patients with N1 disease, the 3-year LRR rate was 0.0% in the PORT group versus 14.3% in the non-PORT group (p = 0.037). The corresponding LLR rate in N2 patients was 4.2% versus 56.6% (p Conclusion PORT significantly reduced LRR and improved OS in patients with regional metastasis SCLC. We suggest supplementing PORT in the multimodality treatment of resected SCLC with lymph node metastasis.

To explore the reasonable radiotherapy range by analyzing the characteristics of supraclavicular lymph node metastasis in limited-stage small cell lung cancer (LS-SCLC).From January 2005 to December 2011, patients of LS-SCLC were reviewed. Supraclavicular zone was further divided into five subgroups including para-recurrent laryngeal nerve (region I and region II ), para-internal jugular vein (region III ), supraclavicular region (region IV), as well as the other regions except for the mentioned above (region V). The characteristics of the lymph nodes in each region were analyzed.The supraclavicular lymph node metastasis was found in 60 patients, with a positive rate of 34.5%. In multivariate Logistic regression analysis,intra-thoracic lymph node metastasis in the lymph node stations of level 2 and 3 were found to be the risk factors of supraclavicular lymph node metastasis (P = 0.006,P = 0.000). Our data suggests that the frequencies of metastasis in region I and III were much higher than those in the other areas.Among the sixty patients with supraclavicular lymph node metastasis, 95.0% were found at region I or III while the incidence of skip metastasis was only 5.0%.It is advisable to contain the bilateral supraclavicular nodes in patients with mediastinal lymph nodes metastasis to the level 2 or 3 for elective radiation target volume.The clinical target volume (CTV) exterior margin containing the outer margin of internal jugular vein may be suitable.

The purpose of this study was to evaluate the association between epidermal growth factor receptor (EGFR) mutations and prognosis in patients with completely resected lung adenocarcinoma. A total of 131 patients were included in this study. EGFR mutation status in exons 18–21 of the tyrosine kinase-binding domain was detected using nested PCR amplification of individual exon. The χ 2 test was used to analyze the associations between EGFR mutations and the different variables. The log-rank test and Cox regression model were used to evaluate the factors influencing disease-free survival (DFS) and overall survival (OS). EGFR mutations in 18–21 exons were detected in 58 of the 131 patients (44.3 %). Smoking status (P = 0.029), N stage (P = 0.021), and pathologic stage (P = 0.048) were significantly associated with EGFR mutations. The median DFS in mutant EGFR and wild-type EGFR groups was 36.6 and 25.7 months, respectively (P = 0.533). No significant correlation was observed between EGFR mutations and OS (P = 0.564). However, patients with exon 19 mutation tended to have longer DFS than those with exon 21 mutation (46.2 vs. 21.9 months, P = 0.056), and the 1-, 2-, and 3-year OS rates were significantly higher in patients with exon 19 mutation compared to patients with exon 21 mutation (100, 96.7, 93.3 vs. 91.3, 82.6, 60.9 %, respectively, P = 0.01). Our data demonstrated that EGFR mutations do not have significant prognostic value in primary resected lung adenocarcinomas, but patients with exon 19 mutation tended to have better prognostic value compared to patients with exon 21 mutation.

Thoracic radiotherapy provides a survival benefit in patients with limited-stage disease of small cell lung cancer (LS-SCLC), but inclusion and exclusion of prophylactic irradiation of the supraclavicular area are still controversial. This study analyses the risk factors and characteristics of lymph node metastases in the supraclavicular area of LS-SCLC patients, which could help in developing a better radiotherapy for the patients. A total of 239 patients with LS-SCLC were included in this retrospective analysis. Clinical characteristics and mediastinal lymph node metastasis were analyzed for association with SCM, and the SCM pattern was further analyzed based on the treatment planning CT scans. The SCM incidence was 34.7 % (83 of 239). The multivariate analysis showed that only the mediastinal level 2 (OR = 16.101, P = 0.000) and level 3 (OR = 5.597, P = 0.000) lymph node metastases were significantly associated with SCM. As the most frequently involved region, supraclavicular level I lymph node metastases were identified in 61 of 83 patients (73.5 %), followed by level III, level IV, level V, and level II lymph node metastases, accounting a total of 95.2 % for level I and/or III lymph node metastases, whereas the incidence of skip metastasis was only 4.8 %. SCLC patients with mediastinal level 2 and level 3 lymph node metastasis were at high risk of SCM. If prophylactic irradiation therapy is considered, the nodal clinical target volume of irradiation should include bilateral lower para-recurrent laryngeal neural region (level I) and the para-internal jugular venous region (level III).

Background: This retrospective study evaluates the efficacy and safety of surgery and chemotherapy (S + CT) vs. radiotherapy and CT (RT + CT) in patients with limited stage small cell esophageal cancer (LSSCEC). Patients and methods: Patients included in analysis (from our hospital and the literature) were treated with S + CT or RT + CT between 1989 and 2012. The primary end point was overall survival (OS); secondary end points included tumor response and toxicity. Kaplan–Meier OS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS. Results: A total of 127 patients were included: 14 from our hospital and 113 from the literature. Fifty-four (43%) and 73 (57%) patients received S + CT or RT + CT, respectively. The median OS of all patients was 21.0 months. OS was longer for those who received RT + CT rather than S + CT (33.0 vs. 17.5 months, p = 0.02), especially those with N1 disease. Uni- and multi-variate analyses showed tumor location (upper 1/3rd of esophagus) and type of treatment (S + CT) were poor prognostic factors of OS. Conclusion: LS-SCEC patients treated with RT + CT had an improved OS compared to those treated with S + RT. Thus, RT + CT should be considered as a primary approach for these patients.

Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone.We searched the Cochrane Library, MEDLINE, EMBASE, CENTRAL, CBMdisc, and CNKI, as well as employing manual searches. The primary end points were survival and local control. The second end point was toxicities.Based on search criteria, we found 29 trials involving 3187 patients. Our results showed that LCAHR, compared with CFR, improved the survival and local control, and was, thus, more therapeutically beneficial. Further analysis revealed that LCAHR plus CT proved to be better for patients' survival and local control compared to LCAHR alone. Acute toxicities were increased rather than late toxicities.There was a significant survival and local control benefit of LCAHR over CFR, as well as LCAHR plus CT over LCAHR alone. Considering the strength of the evidence, the results of this study indicate that this regimen would be a new promising modality worth further investigation.

To explore the expressions of CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) and examine their correlations with metastasis and prognosis in small cell lung cancer (SCLC).Immunohistochemistry was employed to detect the expressions of CXCR4 and MMP-9 in the tissue samples from 65 SCLC patients treated in Cancer Institute and Hospital Attached to Tianjin Medical University from January 2003 to October 2009. And their correlations with metastasis and prognosis were analyzed by Chi-square test and Kaplan-Meier method and Cox regression.The positive expression rates of CXCR4 and MMP-9 were 100.0% (65/65) and 87.7% (57/65) in SCLC tissues respectively. Significant difference of the expression rate of CXCR4 was found between patients undergoing bone metastasis or not (P = 0.004). But the differences were not significant between brain metastasis or not (P = 0.068) and lymph node metastasis or not (P = 0.085). A high expression rate of MMP-9 was significantly associated with pathological staging (P = 0.048). But the difference between lymph node metastasis or not was not significant (P = 0.085). Univariate analysis suggested that a high expression rate of CXCR4 was significantly correlated with the disease-free survival (DFS) of SCLC patients (P = 0.005). But a high expression rate of MMP-9 was not associated with DFS (P = 0.341). Multivariate analysis suggested that a high expression rate of CXCR4 was an independent prognostic factor for DFS in SCLC.The elevated levels of CXCR4 and MMP-9 are found in SCLC tissues. And the expression rate of CXCR4 may be correlated with bone metastasis, but the correlation is not notable for MMP-9. The expression rate of CXCR4 is an independent prognostic factor for DFS in SCLC.

Recently, we reported the identification of a previously uncharacterized and evolutionarily conserved gene, fragile-site associated tumor suppressor (FATS), at a frequently deleted region in irradiation (IR)-induced tumors. However, the role of FATS in breast cancer development and its clinical significance has not been defined. The aim of this study was to determine the role of FATS in breast cancer development and to evaluate its clinical significance in breast cancer.The expression level of FATS mRNA was determined in 106 breast carcinomas and 23 paired normal breast tissues using quantitative real time reverse transcription-polymerase chain reaction (RT-PCR). The relationship between FATS expression and clinicopathological parameters were also analyzed.The mRNA level of FATS was down-regulated in breast cancer compared with paired normal tissues. Low expression of FATS was correlated with high nuclear grade. There was a tendency to a favorable outcome for patients with high expression of FATS (P = 0.346). However, low expression of FATS was associated with poor outcome of breast cancer patients with node positive (P = 0.011). Furthermore, the mRNA level of FATS showed an independent value in predicting the outcome of breast cancer patients with positive lymph nodes.FATS is involved in the carcinogenesis and development of breast cancer and could be a potential biomarker and prognostic factor for breast cancer therapy.

Background Despite of the recent success of EGFR inhibitory agents, the primary drug-resistant becomes a major challenge for EGFR inhibitor therapies. PTEN gene is an important positive regulatory factor for response to EGFR inhibitor therapy. Low-expression of PTEN is clearly one of the important reasons why tumor cells resisted to tyrosine kinase inhibitors. Methods To investigate the drug-resistance reversal to gefitinb and the mechanism in PTEN low expression cells which radiated with X-rays in vitro, We demonstrated that H-157 lung cancer cells (low-expression of PTEN but phospho-EGFR overexpressed tumor cells) exposed to X-rays. The PTEN expressions and radiosensitizing effects of tyrosine kinase inhibitor before and after irradiation were observed. The cell-survival rates were evaluated by colony-forming assays. The cell apoptosis was investigated using FCM. The expressions of phospho-EGFR and PTEN were determined by Western blot analysis. Results The results showed that the PTEN expressions were significantly enhanced by X-rays. Moreover, the cell growth curve and survival curve were down-regulated in the gefitinib-treated groups after irradiation. Meanwhile, the radiation-induced apoptosis of tumor cells was increased by inhibition of the EGFR through up-regulation of PTEN. Conclusion These results suggested that PTEN gene is an important regulator on TKI inhibition, and the resistance to tyrosine kinase inhibitors might be reversed by irradiation in PTEN low expression cancer cells.