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Xinwei Guo,1,* Han Zhang,2,* Liben Xu,3,* Shaobing Zhou,1 juying Zhou,4 yangchen Liu,1 Shengjun Ji5 1Department of Radiation Oncology, Affiliated Taixing People’s Hospital of Yangzhou University, Taixing, People’s Republic of China; 2School of Mathematical Science and Application, Nanjing Normal University, Taizhou College, Taizhou, People’s Republic of China; 3Department of Radiotherapy, Jiangsu University Affiliated People’s Hospital, Zhenjiang, People’s Republic of China; 4Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 5Department of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: yangchen LiuDepartment of Radiation Oncology, Affiliated Taixing People’s Hospital of Yangzhou University, Taixing, 225400, People’s Republic of ChinaTel +86 13961001669Email liuyctx@163.comShengjun JiDepartment of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaTel +86 18914087033Email drshengjunji@163.comBackground: The aim of this study was to explore the influence of preoperative tumor volume, length, maximum diameter and the number of postoperative pathologically lymph node metastasis (LNM) regions on survival prognosis of esophageal squamous cell carcinoma (ESCC) patients.Methods: A total of 296 patients with ESCC treated by standard curative esophagectomy were retrospectively analyzed. These patients were grouped for further analysis according to the optimal threshold of preoperative tumor volume, length, maximum diameter and the number of postoperative pathologically LNM regions. Kaplan–Meier method was used to calculate survival rate and survival comparison was performed by Log rank test. The Cox proportional hazards model was used to carry out univariate and multivariate analyses. Nomogram model was established by integrating statistically significant clinicopathological parameters, and the predictive value was further verified by calibration curve, concordance index (C-index) and decision curve.Results: The univariate and multivariate Cox regression analysis all showed that differentiation grade, TNM stage, adjuvant therapy, preoperative tumor volume and the number of post operative pathologically LNM regions were independent prognostic factors for PFS and OS (all P< 0.05). The C-indexes of PFS and OS by nomograms were predicted to be 0.747 (95% CI: 0.717– 0.777) and 0.732 (95% CI: 0.697– 0.767), respectively, which were significantly higher than the 7th AJCC TNM stage, the C-indexes 0.612 (95% CI: 0.574– 0.650) and 0.633 (95% CI: 0.595– 0.671), separately. In addition, the calibration curves of nomogram models were highly consistent with actual observation for the five-year PFS and OS rate, and the decision curve analysis also showed that nomogram models had higher clinical application potentials than TNM staging model in predicting survival prognosis of thoracic ESCC after surgery.Conclusion: The nomograms incorporated preoperative tumor volume and the number of postoperative pathologically LNM areas are of great value in predicting survival prognosis of patients with thoracic ESCC.Keywords: esophageal neoplasm/post-operation, tumor volume, the number of lymph node metastasis areas, nomograms, prognosis

Objective: The purpose of this study was to evaluate the efficacy of two radiotherapy techniques for breast cancer patients with post-mastectomy. The intensity-modulated radiotherapy for treating the chest wall and regional nodes contoured as a whole planning target volume was compared with the conventional segmented 3-dimensional conformal radiotherapy undergoing modified radical mastectomy. Materials and methods: Patients who received the two post-mastectomy radiation therapies were retrospectively analyzed. The chest wall and supra/infraclavicular region +/- internal mammary nodes were contoured as a whole planning target volume on the planning computed tomography. We evaluated differences in survival, recurrence, and late side effects between the integrated intensity-modulated radiotherapy group and the conventional segmented group. Results: A total of 223 patients were recruited. The mean follow-up was 104.3 months. Of these patients, 129 received integrated radiotherapy and 94 patients received segmented radiotherapy. The 8-year disease-free survival rates were 86.0% and 73.4% for patients treated with integrated radiotherapy and traditional segmented radiotherapy, respectively (P = 0.022). The 8-year overall survival rates were 91.4% and 86.2% for patients treated with integrated radiotherapy and traditional segmented radiotherapy, respectively (P = 0.530). Multivariate analysis demonstrated that radiotherapy was an independent prognostic factor for disease-free survival. No significant difference was observed in late side-effects between the two groups. Conclusion: Intensity-modulated radiotherapy for treating the chest wall and regional nodes contoured as a whole planning target volume reduces the recurrence rate for post-mastectomy breast cancer patients with tolerable toxicities.

Congli Jia,1 Zhengquan Li,2 Dong Guo,1 Zhen Zhang,3 Jingming Yu,4 Guangdong Jiang,1 Xiaobo Xing,3 Shengjun Ji,5 Feng Jin3 1Weifang Medical University, Weifang, People’s Republic of China; 2Department of Laboratory Pathology, People’s Liberation Army 80th Group Military Hospital, Weifang, People’s Republic of China; 3Department of Radiotherapy & Oncology, Qingdao Center Hospital, Qingdao, People’s Republic of China; 4Department of Radiotherapy & Oncology, Shandong Hospital, Jinan, People’s Republic of China; 5Department of Radiotherapy & Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, People’s Republic of ChinaCorrespondence: Shengjun JiDepartment of Radiotherapy & Oncology, Nanjing Medical University Affiliated Suzhou Hospital, No. 16 Baita Road, Suzhou 215001, People’s Republic of ChinaEmail drshengjunji@163.comFeng JinDepartment of Radiotherapy & Oncology, Qingdao Center Hospital, No. 127 Siliu Road, Qingdao 266042, People’s Republic of ChinaEmail 1093910079@qq.comBackground: Brain metastases (BM) are severe incidents among patients with non-small cell lung cancer (NSCLC) and have been associated with significant morbidity and decreased survival; thus, new methods are required to improve clinical management. Magnetic resonance spectroscopy (MRS) allows noninvasive measurements of biochemical information from tumor tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to explore the application of MRS in the assessment of tumor prognosis after stereotactic radiotherapy in NSCLC patients with BM.Patients and Methods: MRS was performed on NSCLC patients attending Qingdao Center Hospital with suspected BM, and 68 patients were included in the survival analysis. The qualitative and quantitative parameters of MRS metabolites, such as choline (Cho), creatine (Cr), and N-acetyl-aspartate (NAA), were recorded. To select a cutoff for MRS metabolite parameters in the tumor and to distinguish patients who had recurrence, we performed an ROC curve analysis. Univariate and multivariate Cox regression analyses were used to assess the association between MRS metabolite parameters and clinical cancer prognosis.Results: The average age was 56 years. A total of 68 NSCLC patients underwent metabolic evaluation with single voxel proton MRS and were selected for retrospective analysis. According to the area under the curve (AUC) to predict recurrence, the MRS metabolite parameters were determined as Cho (AUC=0.550), Cr (AUC=0.415), NAA (AUC=0.524), NAA/Cr (AUC=0.600), Cho/Cr (AUC=0.723), and Cho/NAA (AUC=0.543). Cho and Cr predicted poor survival while Cho/Cr and NAA/Cr predicted improved survival (P< 0.05). In the multivariate model with adjustment to establish the potential role of MRS metabolite parameters, Cho/Cr showed a significant association with OS (P=0.009) and PFS (P=0.006) after stereotactic radiotherapy.Conclusion: The positive results of this study indicate the predictive value of metabolic characteristics of BM detected with MRS for the outcome after stereotactic radiotherapy.Keywords: brain metastases, magnetic resonance spectroscopy, stereotactic radiotherapy

Background. The systemic immune-inflammation index (SII) has an important role in predicting survival in some solid tumors. However, little information is available concerning the change of the SII (∆SII) in colorectal cancer (CRC) after curative resection. This study was designed to evaluate the role of ∆SII in CRC patients who received surgery. Methods. A total 206 patients were enrolled in this study. Clinicopathologic characteristics and survival were assessed. The relationships between overall survival (OS), disease-free survival (DFS), and ∆SII were analyzed with both univariate Kaplan-Meier and multivariate Cox regression methods. Results. Based on the patient data, the receiver operating characteristic (ROC) optimal cutoff value of ∆SII was 127.7 for OS prediction. The 3-year and 5-year OS rates, respectively, were 60.4% and 36.7% in the high-∆SII group (>127.7) and 87.6% and 79.8% in the low-∆SII group (≤127.7). The 3-year and 5-year DFS rates, respectively, were 54.1% and 34.1% in the high-∆SII group and 80.3% and 78.5% in the low-∆SII group. In the univariate analysis, smoking, pathological stages III-IV, high-middle degree of differentiation, lymphatic invasion, vascular invasion, and the high-ΔSII group were associated with poor OS. Adjuvant therapy, pathological stages III-IV, vascular invasion, and ΔSII were able to predict DFS. Multivariate analysis revealed that pathological stages III-IV ( HR = 0.442 , 95% CI = 0.236 -0.827, p = 0.011 ), vascular invasion ( HR = 2.182 , 95% CI = 1.243 -3.829, p = 0.007 ), and the high-ΔSII group ( HR = 4.301 , 95% CI = 2.517 -7.350, p < 0.001 ) were independent predictors for OS. Adjuvant therapy ( HR = 0.415 , 95% CI = 0.250 -0.687, p = 0.001 ), vascular invasion ( HR = 3.305 , 95% CI = 1.944 -5.620, p < 0.001 ), and the high-ΔSII group ( HR = 4.924 , 95% CI = 2.992 -8.102, p < 0.001 ) were significant prognostic factors for DFS. Conclusions. The present study demonstrated that ∆SII was associated with the clinical outcome in CRC patients undergoing curative resection, supporting the role of ∆SII as a prognostic biomarker.

Cognitive deficit is one of the most serious complications of cranial radiotherapy of head and neck cancers. However, the underlying mechanism of this cognitive impairment remains unclear. In the present study, the role of tropomyosin receptor kinase A (TrkA) and its ligand neurotrophin nerve growth factor (NGF) were investigated following whole‑brain irradiation (WBI). Young male Sprague‑Dawley rats underwent WBI at a single dose of 10 Gy. WBI was determined to result in notable memory decline and substantial neurogenesis impairment in the hippocampus 3 months post‑irradiation. Compared with the control group, TrkA protein expression was greater in irradiated rats 1 week after WBI, which then decreased significantly by the 3‑month time‑point. However, no difference in NGF expression was observed from 1 day to 3 months post‑WBI. Overexpression of hippocampal TrkA in rats using adeno‑associated virus ameliorated memory decline induced by irradiation. Additionally, upregulating TrkA expression rescued irradiation‑induced hippocampal precursor cell proliferation and promoted neurogenesis. PI3K, Akt and ERK1/2 phosphorylation were also revealed to be significantly inhibited by WBI, which was ameliorated by TrkA overexpression. Findings of the present study indicated that the TrkA‑dependent signaling pathway may serve a critical role in radiotherapy‑induced cognitive deficit and impairments in neurogenesis.

Background Pancreatic cancer (PC) is aggressive and with poor clinical prognosis. However, mechanisms underlying the aggressiveness of PC remain unclear. Increasing evidence indicates that cholesterol, a major source of bio-energy, is required for the progression of human cancers including PC. Therefore, this study aimed to investigate the anti-tumor effect of atorvastatin, a widely used lipid-lowering agent that blocks the production of cholesterol, on human PC. Methods We firstly assessed the impacts of atorvastatin on the proliferation, apoptosis, cell cycle distribution, migration and invasion of human PC cells PANC-1 and SW1990. Furthermore, we studied the effects of atorvastatin on neurotrophin receptor signaling, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and their downstream receptors tropomyosin receptor kinase (Trk) Trk A, Trk B and Trk C in human PC cells. Results Atorvastatin significantly inhibited the proliferation, migration and invasion, and induced G1-phase cell cycle arrest and apoptosis in both PANC-1 and SW1990 cells. Meanwhile, atorvastatin treatment remarkably suppressed the expression of NGF, BDNF, and NT-3 as well as that of their downstream receptors Trk A and Trk C. Conclusions These results provide evidence that atorvastatin inhibits the proliferation, migration and invasion ability of human PC cells, and atorvastatin may exert the anti-tumor effect in PC via the inhibition of neurotrophin signaling pathway.

Objective: To evaluate the prognostic value of conversion of high-risk human papillomavirus (HR-HPV) status after treatment for cervical cancer. Methods: A total of 112 cervical cancer patients with HR-HPV positivity without distant metastasis treated with surgery or radical concurrent radiochemotherapy were enrolled. HR-HPV status was analyzed before and after treatment and at the time point of recurrence or metastasis. Log-rank tests and Cox proportional hazard models were used to evaluate the association between conversion of HR-HPV status after treatment and survival. Results: Eighty-four (75%) patients had negative conversion HR-HPV (ncHR-HPV) after treatment and twenty-eight (25%) were persistent positive HR-HPV (ppHR-HPV). The negative conversion rate was 75.8% in patients who received surgical treatment and 71.4% in patients who received radical concurrent radiochemotherapy. There was no significant difference between the two groups (χ2=0.000, P=1.000). There was no significant correlation between HR-HPV conversion after treatment with age (χ2=0.616, P=0.252), FIGO stage (χ2=0.051, P=0.823) and pathological type (χ2=0.000, P=1.000). Univariate analysis showed that treatment regimen and ncHR-HPV was closely related to progression-free survival (PFS) and overall survival (OS) of cervical cancer patients. Multivariate COX regression model showed that treatment regimen (HR=3.57, 95% CI: 1.57-8.11, P=0.002) and ncHR-HPV (HR=5.14, 95% CI: 2.32-11.46, P

Dong Guo,1 Jiafeng Liu,2 Yanping Li,3 Chao Li,3 Quan Liu,3 Shengjun Ji,4 Shuchai Zhu1 1Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Radiotherapy, Rizhao Center Hospital, Rizhao, People’s Republic of China; 3Sunshine Union Hospital, Weifang, People’s Republic of China; 4Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, People’s Republic of ChinaCorrespondence: Shengjun Ji; Shuchai Zhu Email drshengjunji@163.com; 3562069484@qq.comBackground: Naples prognosis score (NPS) is a new prognostic score according to host inflammatory and nutritional state, and it could be useful for predicting tumor prognosis based on albumin level, total cholesterol level, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio. This study aimed to evaluate the clinical significance of Naples prognostic score (NPS) in stage III non-small cell lung cancer patients (NSCLC).Patients and Methods: In this study, 206 patients diagnosed with locally advanced NCCLC receiving chemoradiotherapy were retrospectively reviewed from January 2013 to January 2017. The included patients were divided into 3 groups according to NPS (group 0, group 1, and group 2), and the associations of the NPS with clinical characteristics and outcomes were evaluated among the groups. Survival curves for the NPS were analyzed using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to evaluate the prognostic value of overall survival (OS) and progression-free survival (PFS).Results: The median follow-up time of this study was 37.0 (range, 13– 59) months. The median OS was 27 months in group 0, 23 months in group 1, and 21 months in group 2, and median PFS was 15, 12 and 13 in group 0, group 1 and group 2, respectively. Age was significantly different among the 3 groups. The NPS was superior to other host inflammatory and nutritional indexes for prognostic risk stratification. In the multivariate analysis, NPS was identified as an independent prognostic indicator for OS and PFS (all P< 0.05).Conclusion: The NPS system is considered to be a useful predictor of outcomes in patients with stage III NSCLC.Keywords: Naples prognostic score, stage III NSCLC, predictive values

Background: The aim of this study was to evaluate the significance of combination of the magnetic resonance spectroscopy (MRS) parameters and systemic immune-inflammation (SII) in patients with brain metastases (BM) from non-small-cell lung cancer (NSCLC) treated with stereotactic radiotherapy. Methods: 118 NSCLC patients with BM who treated with stereotactic radiotherapy were retrospectively enrolled into this study. All patients underwent MRS and blood samples test for SII analysis before the initiation of stereotactic radiotherapy. The correlation between the parameters of MRS and SII level were assessed using the spearman correlation coefficient. The cut-off values for the parameters of MRS, SII and clinical laboratory variables were defined by the receiver operating characteristic (ROC) curve analysis to quantify these predictive value. The prognostic factors of overall survival (OS) and progression-free survival (PFS) curves were assessed using Kaplan-Meier and Cox proportional hazards models.Results: The median follow-up time was 25 months (range, 12-49months). The optimal cutoff point for the cho/cr and SII were 1.50 and 480, respectively. The cho/cr was negatively correlated with SII (rs = 0.164, P = 0.075), but there was a trend. C-SII score was established by combining cho/cr and SII. Patients with both an elevated cho/cr (> 1.50) and an elevated SII (> 480) were given a C-SII score of 2, and patients with one or neither were given a C-SII score of 1 or 0, respectively. Kaplan–Meier analysis showed that the C-SII score of 2 was significantly linked with poor OS and PFS (P < 0.001, P < 0.001). In the Cox proportional hazards model, the C-SII score independently predicted OS [hazard ratio (HR), 1.749; 95% CI, 1.176-2.601; P = 0.006] and PFS (HR, 2.472; 95% CI, 1.624-3.763; P < 0.001). Conclusion: C-SII score was more accurate for predicting the clinical outcomes of NSCLC patients with BM who undergo stereotactic radiotherapy. The C-SII score, which was superior to either score alone, which could be used to identify for BM from NSCLC patients with poor outcomes.

Background: Although the systemic immune-inflammation index (SII) has been used to predict recurrence and survival in non-small-cell lung cancer (NSCLC) patients, the prognostic significance of change in SII (ΔSII) is unclear for stage III NSCLC patients treated with concurrent chemoradiotherapy (CCRT). In the present study we aimed to explore the association between ΔSII and the clinical outcomes of 142 patients with stage III NSCLC treated with CCRT. Methods: A total of 142 patients were included in this retrospective study. The SII values were calculated based on laboratory data regarding platelet, neutrophil and lymphocyte counts, and ΔSII was calculated using data acquired before and approximately 2 weeks after CCRT. The receiver operating characteristic curve was used to determine the optimal cut-off value for the peripheral blood inflammation index. Kaplan–Meier analysis and Cox proportional regression were used to analyze the prognostic value of ΔSII for overall survival (OS) and progression-free survival (PFS). Results: The area under the receiver operating characteristic curve for ΔSII (0.708) was larger than those for pre-CCRT SII (0.578) and post-CCRT SII (0.610). The optimal cut-off point for ΔSII was defined as 43. OS and PFS were better in patients with low ΔSII and in multivariate analysis, the ΔSII was an independent predictor of OS and PFS (p = 0.006 and p = 0.017, respectively). Conclusions: ΔSII is related to progression and death in patients with stage III NSCLC. The ΔSII can provide a detailed prognostic prediction for stage III NSCLC.

Background. As a parameter integrating platelet (P), neutrophil (N), and lymphocyte (L) levels, the systemic immune-inflammation index (SII) has been used as a prognostic marker for patient survival in various types of solid malignant tumors. However, there is no in-depth study in non-small-cell lung cancer (NSCLC) patients with brain metastases after stereotactic radiotherapy. Therefore, we performed a retrospective analysis to determine the clinical and prognostic value of the SII in NSCLC patients with brain metastases who underwent stereotactic radiotherapy. Materials and Methods. We enrolled 124 NSCLC patients with brain metastases treated with stereotactic radiotherapy in our hospital between May 2015 and June 2018. We obtained all baseline blood samples within one week prior to stereotactic radiotherapy. The SII was calculated by the following formula: neutrophil counts × platelet counts / lymphocyte counts . The optimal cutoff value of the SII for predicting prognosis was assessed by receiver operating characteristic (ROC) curves with the maximum log-rank values. The discriminative ability of predicting prognosis was calculated and compared using the Kaplan–Meier method and log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were combined to evaluate the prognostic impact of the blood index on overall survival (OS) and progression-free survival (PFS). Only those parameters that proved to be associated with statistically significant differences in clinical outcomes were compared in multivariate analysis using a multiple Cox proportional hazard regression model to identify independent prognostic factors. Results. Of the total enrolled patients, 53.2% and 46.8% have high SII and low SII, respectively. In this study, Kaplan–Meier curve analysis revealed that the median PFS was 9 months (range: 2–22 months) and the median OS was 18 months (range: 4–37 months). Applying an optimal cutoff of 480 (SII), the median PFS was better in the low SII group patients (11.5 vs. 9 months), and the median OS was significantly longer in the low SII group patients (20 vs. 18 months). A SII > 480 was significantly associated with worse OS (HR: 2.196; 95% CI 1.259–3.832; P = 0.006 ) and PFS (HR: 2.471; 95% CI 1.488–4.104; P < 0.001 ) according to univariate analysis. In multivariate analysis, only age (HR: 2.159; 95% CI 1.205–3.869; P = 0.010 ), KPS (HR: 1.887; 95% CI 1.114–3.198; P = 0.018 ), and SII (HR: 1.938; 95% CI 1.046–3.589; P = 0.035 ) were independently correlated with OS, and SII (HR: 2.224; 95% CI 1.298–3.810; P = 0.004 ) was an independent prognostic predictor of PFS, whereas we found that other inflammation-based indices lost their independent value. Conclusions. The SII, which is an integrated blood parameter based on platelet, neutrophil, and lymphocyte counts, may be an independent prognostic indicator and may be useful for the identification of NSCLC patients with brain metastases after stereotactic radiotherapy at high risk for recurrence.

Cisplatin-based chemoradiation is the standard of care for patients with locally advanced cervical cancer. Nevertheless, an increasing number of radio-resistant tumors still recur. Three hundred cervical cancer patients with FIGO stages IB2–IVA and no para-aortic lymphadenopathy (> 10 mm) will be enrolled. All patients will be randomly divided into four arms to receive either (1) intensity modulated radiation therapy (IMRT), (2) RapidArc, (3) positron emission tomography/computed tomography (PET/CT) with F-18 fluorodeoxyglucose (FDG), or (4) Comet assay-guided IMRT, PET/CT, and Comet assay-guided RapidArc. All patients will receive definitive radiotherapy consisting of external beam whole pelvic radiation therapy and high-dose rate intracavitary brachytherapy. Cisplatin 30 mg/m2 weekly will be administered concurrently for five courses. Two to four cycles of TP (Taxol 135 mg/m2, D1, and DDP 75 mg/m2, D1–3) sequential chemotherapy will be performed according to MRI or PET/CT after cisplatin-based chemoradiation. The primary outcome measure is progression-free survival, and the second outcome measures are overall survival and time to progression. RapidArc has an obvious advantage in improving the degree of target coverage, improving organs at risk, sparing healthy tissue, and significantly reducing the treatment time. FDG-PET/CT can increase the agreement between biopsies and delineated tumor volume and has the potential to positively impact the course of treatment. The Comet assay is attractive as a potential clinical test of tumor radiosensitivity. During radiotherapy, accurately defining disease areas is critical to avoid the unnecessary irradiation of normal tissue. Based on FDG-PET/CT and Comet assay, higher doses can be safely delivered to accurate tumor volumes, while the doses to the bladder and rectum are relatively low. ClinicalTrials.gov Protocol Registration and Results System Receipt Release Date: May 21, 2017 – Retrospectively registered. NCT03163979 .

Xin-Wei Guo,1,* Yang-Chen Liu,2,* Fei Gao,2,* Sheng-Jun Ji,3 Ju-Ying Zhou,1 Lei Ji,1 Shao-Bing Zhou2 1Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Taixing People’s Hospital of Yangzhou University, Taixing, People’s Republic of China; 3Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, People’s Republic of China *These authors contributed equally to this work Background: The purpose of this study was to investigate the prognostic values of Nutritional Risk Screening 2002 (NRS-2002) and hematologic inflammation markers in patients with esophageal squamous cell carcinoma (ESCC) receiving curative esophagectomy. Materials and methods: A total of 277 patients with ESCC treated with standard curative esophagectomy were retrospectively analyzed. These patients were grouped for further analysis according to the systemic inflammation score (SIS), the combination of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (CNP) score and NRS-2002 score. The Kaplan–Meier method and log-rank test were adopted to calculate and compare the progression-free survival (PFS) and overall survival (OS) rates with these parameters. The Cox proportional hazards model was used to carry out univariate and multivariate analyses. Receiver operating characteristic (ROC) curves were applied to verify the accuracy of SIS, CNP and NRS-2002 for survival prediction. Results: In univariate analysis, the following factors were significantly associated with poor PFS and OS: sex, T stage, N stage, TNM stage, SIS, CNP and NRS-2002 (all P

// Xin Ding 1, 2, 3, * , Hao-Hao Wu 1, 2, 3, * , Sheng-Jun Ji 1, 4 , Shang Cai 1, 2, 3 , Pei-Wen Dai 1, 2, 3 , Mei-Ling Xu 1, 2, 3 , Jun-Jun Zhang 1, 2, 3 , Qi-Xian Zhang 1, 2, 3 , Ye Tian 1, 2, 3 and Quan-Hong Ma 5 1 Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China 2 Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China 3 Suzhou Key Laboratory for Radiation Oncology, Suzhou, China 4 Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China 5 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China * Co-first author Correspondence to: Ye Tian, email: dryetian@126.com Keywords: hippocampus, cognitive dysfunction, neurogenesis, dendritic spine, p75 NTR Received: October 24, 2016 Accepted: February 22, 2017 Published: March 23, 2017 ABSTRACT Cognitive deficits, characterized by progressive problems with hippocampus-dependent learning, memory and spatial processing, are the most serious complication of cranial irradiation. However, the underlying mechanisms remain obscure. The p75 neurotrophin receptor (p75 NTR ) is involved in a diverse arrays of cellular responses, including neurite outgrowth, neurogenesis, and negative regulation of spine density, which are associated with various neurological disorders. In this study, male Sprague-Dawley (SD) rats received 10 Gy cranial irradiation. Then, we evaluated the expression of p75 NTR in the hippocampus after cranial irradiation and explored its potential role in radiation-induced synaptic dysfunction and memory deficits. We found that the expression of p75 NTR was significantly increased in the irradiated rat hippocampus. Knockdown of p75 NTR by intrahippocampal infusion of AAV8-shp75 ameliorated dendritic spine abnormalities, and restored synapse-related protein levels, thus preventing memory deficits, likely through normalization the phosphor-AKT activity. Moreover, viral-mediated overexpression of p75 NTR in the normal hippocampus reproduced learning and memory deficits. Overall, this study demonstrates that p75 NTR is an important mediator of irradiation-induced cognitive deficits by regulating dendritic development and synapse structure.

Han Zhang,1,* Xin-Wei Guo,2,* Xiao-Xiang Yin,2,* Yang-Chen Liu,2 Sheng-Jun Ji3 1School of Mathematics, Nanjing Normal University, Taizhou College, Taizhou 225300, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Taixing People’s Hospital of Yangzhou University, Taixing 225400, People’s Republic of China; 3Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sheng-Jun JiDepartment of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215002, People’s Republic of ChinaTel +86 18914087033Email happy168123@aliyun.comObjective: To investigate the therapeutic effect and survival outcome using nomogram by incorporating significant inflammatory markers in patients with thoracic esophageal squamous cell carcinoma (ESCC) who received chemoradiotherapy (CRT) or single radiotherapy (RT).Method: A total of 266 patients diagnosed with thoracic ESCC receiving standard curative RT only or concurrent CRT were retrospectively analysed. The patients were grouped for statistical analysis depending on the median values of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein/albumin (CRP/Alb) ratio. The therapeutic effect was analysed by univariate and multivariate logistic analyses. The survival prognosis was estimated by univariate and multivariate Cox analyses. At last, the nomogram was developed by incorporating the significant inflammatory markers and clinicopathological parameters, and the predictive value was verified by calibration curve, concordance index (C-index) and decision curve.Results: The treatment responses were highly associated with clinical stage, tumor location, NLR, PLR and CRP/Alb ratio (all P

Purpose: Positive results have appeared among nonmetastatic breast cancer patients with the use of cognitive behavioral therapy (CBT). However, earlier stage patient results have been mixed. This novelty of this study was the focus on stage I and II breast cancer patients. The objective of the current study was to conduct a meta-analysis of psychosocial functions in early-stage breast cancer survivors to determine its efficacy. Methods: A search of Cochrane Library, EMBASE, MEDLINE, PsycInfo, and PubMed yielded 3237 abstracts, which were independently evaluated by research pairs. Meta-analysis was conducted on 8 studies that included a total of 1053 patients. Psychosocial functions were categorized according to 3 domains: (1) anxiety, (2) depression, and (3) quality of life. Results: Improvement in anxiety was observed in patients treated with CBT relative to controls without CBT ( P = .04). Depression and quality of life improvement was not observed in the CBT group within or after 4 months of treatment ( P > .05). Conclusions: The results indicated that observed improvements in anxiety in patients with early-stage breast cancer were moderate. The effectiveness of CBT for the improvement of patient outcomes could not be determined, given the methodological and clinical shortcomings of the included trials.

Supplemental Digital Content is available in the text, Background: Radiotherapy concurrent with cisplatin is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, survival, recurrence, compliance, and acute adverse effects were compared between weekly and triweekly cisplatin-based concurrent chemoradiotherapy regimens for treatment of cervical cancer. Methods: A systematic search for relevant studies was conducted using PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects models were used for pooled analysis. The endpoints were overall survival, recurrence, compliance, and acute adverse effects reported as odds ratios (ORs) and 95% confidence intervals (CIs). Results: Eight randomized controlled trials met the inclusion criteria. No significant differences were observed between the 2 arms with respect to recurrence, survival, and acute adverse effects (all P > .05). However, the triweekly cisplatin regimen was associated with significantly lower incidence of local recurrence (OR, 1.72; 95% CI, 1.07–2.78; P = .03), radiotherapy completion (OR, 2.08; 95% CI, 0.99–4.38; P = .05), and anemia (OR, 2.10; 95% CI, 1.01–4.37; P = .05), while a weekly cisplatin regimen was associated with a lower risk of leukopenia (OR, 0.57; 95% CI, 0.42–0.92; P = .00) and thrombocytopenia (OR, 0.55; 95% CI, 0.31–0.97; P = .04). Conclusions: Triweekly cisplatin-based chemotherapy significantly reduced local recurrence with tolerable toxicity and might be the optimal regimen in concurrent chemoradiotherapy for locally advanced cervical carcinoma.

BackgroundRecently, several studies observed that locally advanced cervical carcinoma with negative excision repair crross-complementation group one enzyme expression has better outcomes in cisplatin-based chemotherapy or chemoradiotherapy than carcinoma with positive excission repair cross-complementation group one enzyme expression. In this meta-analysis, we quantitatively evaluated the prognostic value of excission repair cross-complementation group one enzyme expression in locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy.MaterialsA systematic search for relevant studies was conducted in the PubMed, Cochrane Library, EMBASE and Medline databases. Fixed- or random-effects models were used for pooled analysis. The endpoints were overall survival and disease-free survival () reported as ORs and 95% CIs. The effects of excission repair cross-complementation group one enzyme expression on the clinicopathological parameters were measured by the pooled ORs and their 95% CIs.ResultsEight studies (612 patients in total) satisfied the inclusion criteria. Negative/low excission repair cross-complementation group one enzyme expression was significantly associated with better overall survival (OR, 1.92; 95% CI, 1.22 to 3.05; P = 0.005) and disease-free survival (OR, 5.77; 95% CI, 1.90 to 17.54; P = 0.002). Additionally, there were significant associations between excission repair cross-complementation group one enzyme expression and lymph node metastasis (OR, 2.57; 95% CI, 1.28 to 5.16; P = 0.008).ConclusionsThis meta-analysis suggested that pretreatment excission repair cross-complementation group one enzyme expression might be a useful biomarker to predict prognoses for locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy.

Shao-Bing Zhou,1,* Xin-Wei Guo,1,* Liang Gu,1,* Sheng-Jun Ji2 1Department of Radiation Oncology, Affiliated Taixing People’s Hospital of Yangzhou University, Taixing, 2Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, People’s Republic of China *These authors contributed equally to this work Background: The purpose of this study was to clarify whether pretreatment tumor burden-related index, including the gross tumor volume (GTV) of metastatic lymph nodes (VLN) and maximum diameter of metastatic lymph nodes (DLN), and inflammatory markers, consisting of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), are useful for assessing the therapeutic effects and prognosis with secondary lymph node metastasis (LNM) receiving chemoradiotherapy (CRT) or radiotherapy (RT) alone after resection of esophageal squamous cell carcinoma (ESCC). Patients and methods: A total of 119 patients with secondary LNM after resection of ESCC were recruited and received curative RT only or CRT. The enrolled patients were grouped according to the median values of NLR, PLR, VLN, and DLN. The relationship between the responsiveness to treatment and these markers was analyzed by logistic analysis. The Kaplan–Meier method and log-rank test were adopted to calculate and compare the overall survival (OS) rates with these markers. The Cox models were used to carry out multivariate analyses. Results: Univariate logistic regression analysis showed that the responses to treatment were highly associated with treatment method (P=0.011), NLR (P=0.000), PLR (P=0.003), VLN (P=0.000), and DLN (P=0.000). Next, multivariate logistic regression analysis showed that therapeutic method (hazard ratio [HR]=1.225, P=0.032), NLR (HR=2.697, P=0.019), and VLN (HR=4.607, P=0.034) were independent risk factors for tumor response. Additionally, Kaplan–Meier survival analysis of this cohort revealed that NLR (Χ2=27.298, P=0.000), PLR (Χ2=16.719, P=0.000), VLN (Χ2=48.823, P=0.000), DLN (Χ2=40.724, P=0.000), and treatment methods (Χ2=18.454, P=0.018) were significantly associated with OS. Furthermore, multivariate analysis was performed, and the results showed that therapeutic method (HR=1.223, P=0.048), NLR (HR=2.000, P=0.018), VLN (HR=2.379, P=0.020), and DLN (HR=2.901, P=0.002) were considered independent prognostic factors for OS. Conclusion: This study found that NLR and VLN were promising as predictive markers for therapeutic effects, and NLR combined with VLN and with DLN might be useful biomarkers in predicting outcomes in patients with secondary LNM receiving CRT or single RT after esophagectomy. Keywords: esophageal carcinoma, tumor volume, hematological markers, therapeutic response, prognostic factor, chemoradiotherapy

e15500 Background: The aim is to assess the value of systemic immune-infflammation index (SII) in elderly patients with esophageal squamous cell cancer after radiotherapy. Methods: Total 128 patients larger than 65 years were included. The optimal threshold of SII was determined by establishing a receiver operating characteristic (ROC) curve, and the relationship between SII and prognosis was analyzed. Results: The ROC curve showed that the optimal threshold of the pretherapeutic SII for predicting the efficacy of radiotherapy was 700.97. Univariate analysis showed that SII was significantly associated with radiotherapy (P

e14679 Background: This study aimed to investigate the role of neurotrophin receptor TrkA in cranial radiation-induced memory decline. Methods: Single dose of 10Gy 4MeV electron beam whole brain irradiation (WBI) was given to young male Sprague-Dawley rats (50–60g, day 21). 3 months after WBI, western blot was performed to detect protein level of TrkA and its downstream signaling molecules. The Morris water maze test was performed to evaluate the consequence of WBI on hippocampus-dependent memory formation. Immunohistochemistry was performed to evaluate the consequence of WBI on neurogenesis. For overexpression of TrkA, Adeno-associated virus were injected at the rate of 0.2μl/min (n = 15-20 per group). After that, Morris water maze test was performed again. Results: In Morris water maze test, WBI lead to notable memory deficit, the irradiation rats spent longer latency time than control rats (p < 0.05). In the spatial probe trial, the irradiation rats spent less time in the target quadrant than control rats (p < 0.05). Immunohistochemistry showed that cranial irradiation inhibited proliferation and neurogenesis in hippocampus. The protein level of TrkA expression decreased significantly at 3 months after irradiation compared with control group. Phosphorylation of PI3k, AKT, ERK1/2, CREB were also observed to be significantly inhibited (all p < 0.05). Next, we explored the irradiation-induced apoptotic signal transduction. The increased expression of JNK, caspase-3/9 and reduced expression of BCl2 confirm the irradiation induced apoptosis. After Adeno-associated virus injection, AAV-overexpression TrkA rats showed less escape latency time (p < 0.05) and spent more time (p < 0.05) in the target quadrant than AAV-irradiation rats, but still more escape latency time (p < 0.05) and spent less time (p < 0.05) in the target quadrant than AAV-control rats. Additionally, immunofluorescence staining showed AAV-overexpression-TrkA also rescued radiation-induced neurogenesis impairment Conclusions: TrkA may play a critical role in radiation-induced memory deficit, which indicate the data may have important therapeutic implications.

e13545 Background: Cognitive deficit was the most serious complication of cranial irradiation in brain metastatic carcinoma. However, the underlying mechanisms remain obscure. Dendrites are the anatomic bases of synaptic contact and action potential propagation. Alterations of dendritic architecture may contribute to radiation-induced memory dysfunction. Methods: 21-day-old Sprague-Dawley rats received 10Gy cranial irradiation. 1 and 3 months later, Morris Water Maze, Fear Conditioning test and novel object recognition were used to test the memory function. Golgi staining was used to assess changes in dendritic spine density and morphology. Moreover, cytoskeletal proteins PSD-95 were analyzed with Western blot. Results: Our data showed that 10Gy cranial irradiation induced significant decline in the spatial memory and memory retention of rats and accompanied the morphological changes in dendritic spines. The result revealed significant reductions in spine density at 1 month (40.58%) and 3 months (28.92%) in the DG. In CA1 basal dendrites, irradiation resulted in a significant reduction (33.29%) in spine density only at 1month postirradiation. Compared to control, mushroom spines reduced at 1 month (7.17%, 10.01%) and 3 months (9.29%, 11.94%) post irradiation in DG and CA1 basal dendrites, respectively. Also, we found PSD-95 depletion coincided in time with alteration in dendritic spines. Conclusions: These data suggest that cranial irradiation decreased the dendritic spine density and mushroom spines, which may be associated with radiation-induced memory dysfunction. Acknowledgment: This study was supported by the National Natural Science Foundation of China 81402517 and the Suzhou Science and Technology Project SYS201651.

e15725 Background: Pancreatic cancer is an uncommon but fatal malignant tumor, only 20% of which show any significant response to chemo-radiotherapy. Tumor metabolism research revealed that pancreatic cancer cells highly dependent on cholesterol uptake. So, in the present study, we have determined the effectiveness of atorvastatin, one drug originally used to lower cholesterol, against pancreatic carcinogenesis in various pancreatic cancer cell lines. Methods: To investigate atorvastatin effects in pancreatic cancer cells, two cell lines (PANC-1 and SW1990) were treated with different atorvastatin doses. The anti-proliferative, apoptotic and anti-invasive properties of atorvastatin were evaluated using MTS, cytoplasmic histone-DNA fragmentation and matrigel invasive assays, respectively. And western blot was used to evaluate the neurotrophin receptor signaling of NGF/Trk A, BDNF/TrkB and NT3/Trk C. Results: Atorvastatin suppressed pancreatic cancer cells proliferation, clone formation and invasion in a dose-dependent manner. The dose of atorvastatin at 10^-5mmol/L would be able to achieve obvious anti-tumor effect in vitro. Cell-cycle analysis demonstrated that cells were arrested in the S phase. Western blot showed increased protein expression of cleaved caspase-3, caspase-9, p21, p-chk2 and decrease in protein level of NGF/Trk A and NT3/Trk C. Conclusions: The current results demonstrated the anti-tumor effects of atorvastatin on pancreatic cancer cells, providing initial evidence towards its potential therapeutic use. Acknowledgment:This study was supported by Suzhou Cancer Clinical Medical Center Szzx201506.

Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague-Dawley rats received a single dose of 20Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF-pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF-pCREB signaling in non-irradiation group. These results suggest that forced running exercise offers a potentially effective treatment for radiation-induced cognitive deficits.

Purpose/Objective(s): Histone deacetylase (HDAC) inhibitors are potential drug candidates to complement radiation therapy, and have shown a radiosensitizing effect in preclinical models of solid tumor malignancies. The molecular mechanisms underlying HDAC inhibitor effects on radiosensitivity are elusive, however. In order to investigate the mechanism of HDAC inhibitor-induced radiosensitization, we investigated the effects of multiple HDAC inhibitors on DNA double strand break (DSB) formation, DSB repair, and DNA damage-induced signaling events via high-throughput screening techniques. Materials/Methods: We developed a high-throughput automated microscopy assay to assess effects on elements of DNA damage-mediated signaling through quantification of H2AX phosphorylation, cell cycle profiling, and cell survival following IR-induced DSBs in U2OS osteosarcoma cells. We then applied this assay to a library of diverse HDAC inhibitors as well as a collection of shRNAs targeting the individual HDACs. We next assessed DSB induction and repair kinetics on a selection of active HDAC inhibitors with CometChip, a novel high-throughput adaptation of the single-cell DSB comet assay that facilitates automated imaging and analysis of DSB content by achieving a uniform single-cell spacing with a single focal plane. Results: Data from our screening platform suggest that class I HDAC inhibitors potently elevate H2AX phosphorylation and have mild cell cycle effects. Effects on cell proliferation indicate that in these cells there is not a robust enhancement of radiation-induced cell death. Our investigation using CometChip demonstrated that HDAC inhibition did not achieve strong effects on DSB induction or repair kinetics. Using both FACS analysis and live cell imaging, we find that some HDAC inhibitors also enhance G2/M cell cycle arrest and decrease cell proliferation, even in the absence of irradiation. Conclusions: Our data suggest that HDAC inhibitors influence radiation effects primarily through altering IR-induced signaling events, rather than through an increased frequency of DNA DSBs or a repression of DSB repair. This may have important implications for the clinical use of these agents. The two assay techniques we have developed can readily be extended to many tumor cell lines as a screening platform to identify candidate drugs to advance to preclinical and clinical studies. Author Disclosure: B. Greenberger: None. M.E. Pacold: None. J.J. Tay: None. R. Alter: None. Q. Huang: None. J. Ge: None. J.E. Bradner: None. B.P. Engelward: None. M.B. Yaffe: None. S.R. Floyd: None.