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Yanjun Wang,1 Jiachen Zhang,1 Yihang Yang,1 Qian Liu,2 Guangming Xu,1 Rui Zhang,1 Qi Pang1 1Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China; 2Department of Histology and Embryology, Shandong University Cheeloo College Medicine, Jinan, 250012, Shandong, China Purpose: Chemotherapy after surgery can prolong the survival of patients with gliomas. Dimethylaminomicheliolide (DMAMCL), a novel chemotherapeutic agent, exhibited antitumor properties in acute myeloid leukemia stem cells and showed an increased drug concentration in the brain. This study aims to investigate the specific anticancer activities and mechanisms of DMAMCL in glioma cells.Materials and methods: In this study, the effects of DMAMCL were evaluated and characterized in U87-MG and U251 glioma cells. Cell viability was assessed by Cell Counting Kit-8. Apoptosis, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) generation were assessed by fluorescence microscopy. Autophagosome formation was observed with transmission electron microscopy, and the autophagy flux was measured by transfecting cells with mRFP-GFP-LC3 adenoviral vectors. Immunofluorescence and Western blot analyses were used to determine the expression of proteins.Results: In the present study, treatment with DMAMCL decreased cell viability and induced apoptosis in U87-MG and U251 glioma cells. Additionally, DMAMCL activated autophagy-mediated cell death as evidenced by the formation of autophagosomes, accumulation of LC3B-II, inhibition of autophagy flux, and increase in cell viability after cotreatment with an autophagy inhibitor. Subsequent experiments showed that the DMAMCL-induced apoptosis and autophagy were possibly mediated by ROS generation and Akt/mTOR signaling pathway inhibition. On the other hand, the ROS scavenger N-acetyl-l-cysteine and the Akt activator insulin-like growth factor-1 attenuated the DMAMCL-induced autophagy and cell death.Conclusion: Our findings revealed that DMAMCL induced apoptosis and autophagic cell death by regulating the ROS/mitogen-activated protein kinase signaling pathway and suppressing the Akt/mTOR signaling pathway in human glioma cells. DMAMCL may be a novel effective anticancer agent, which can target gliomas. Keywords: DMAMCL, apoptosis, autophagy, ROS, glioma

Zhiguo Liu,1 Haixia An,2 Peng Song,3 Dejing Wang,4 Shichun Li,5 Kai Chen,6 Qi Pang7 1Department of Neurosurgery, People’s Hospital of Zhangqiu, Shandong Provincial Hospital Affiliated to Shandong University, Zhangqiu, Jinan, Shandong 250200, People’s Republic of China; 2Department of Oncology, Jinan Zhangqiu Hospital of Traditional Chinese Medicine, Zhangqiu, Jinan, Shandong 250200, People’s Republic of China; 3Department of Orthopedics, People’s Hospital of Zhangqiu, Zhangqiu, Jinan, Shandong 250200, People’s Republic of China; 4Department of Stomatology, People’s Hospital of Zhangqiu, Zhangqiu, Jinan, Shandong 250200, People’s Republic of China; 5Department of Doppler Ultrasonic, People’s Hospital of Zhangqiu, Zhangqiu, Jinan, Shandong 250200, People’s Republic of China; 6Department of Neurology, The Fourth People’s Hospital of Jinan, Tianqiao, Jinan, Shandong 250200, People’s Republic of China; 7Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Huaiyin, Jinan, Shandong 250200, People’s Republic of China Background: Human transmembrane protein 176A (TMEM176A) is upregulated in several tumors. Growing evidence has suggested the high clinical value of TMEM176A as a biomarker for early tumor diagnosis. However, less is known about the function of TMEM176A in glioblastomas (GBMs).Methods: In this study, we systematically analyzed the effect of TMEM176A knockdown and overexpression in GBM cells (U87, T98G and A172) on cell proliferation, cell cycle and cell apoptosis.Results: Our results indicated that TMEM176A acted as a tumor-promoting factor in GBM cells. Moreover, a specific ERK1/2 inhibitor, U0126, suppressed the function of TMEM176A in GBM cells. Therefore, we proposed that TMEM176A may be involved in a pathway including ERK1/2 in the regulation of the cell cycle. Moreover, we also found that TMEM176A affected the expression of Bcl2 and played a central role in apoptosis of GBM cells.Conclusion: Taken together, our results not only elucidated the multiple functions of TMEM176A in GBM cells but also provided a deep insight into the potential targets of TMEM176A in the growth of GBM cells. Keywords: TMEM176A, cell cycle, cell apoptosis, ERK1/2, glioblastomas

Daquan Wang,* Wencheng Zhang,* Dong Qian, Yong Guan, Xi Chen, Hualei Zhang, Jun Wang, Qingsong Pang Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China *These authors contributed equally to this work Background: Nab-paclitaxel is produced by the combination of paclitaxel particles with human serum albumin. Encouraging efficacy has been observed with nab-paclitaxel-based chemotherapy in a variety of solid tumors. The aim of the study reported here was to evaluate the efficacy and safety of weekly nab-paclitaxel plus cisplatin with concurrent intensity-modulated radiotherapy in patients with locally advanced esophageal cancer. Methods: Seventeen patients with esophageal cancer were enrolled between July 2014 and December 2015.The treatment included radical radiotherapy (95% planning target volume 60Gy/30f) and concurrent chemotherapy comprising nab-paclitaxel 60mg/m2/week plus cisplatin 25mg/m2/week, administered on days 1, 8, 15, and 22 of each 28-day cycle. The end point of this study included objective response rate (ORR), local-recurrence free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). Results: All the patients enrolled in the trial had squamous cell carcinoma. The median follow-up duration was 20.47 months. The ORR was 88.2%. LRFS, DMFS, PFS and OS at 3 years were 61%, 40%, 17% and 35%, respectively. The trial regimen was well tolerated, with grade 3–4 myelosupression, grade 3 radioactive esophagitis, and grade 3 radiation pneumonitis rates of 17.6%, 17.6%, and 11.8%, respectively. Conclusion: Weekly nab-paclitaxel plus cisplatin with concurrent intensity-modulated radiotherapy is an effective and well-tolerated treatment option for inoperable, locally advanced squamous cancer of esophageal. Keywords: nab-paclitaxel, esophageal cancer, squamous cell carcinoma

Hao Xu, Shangchen Xu, Rui Zhang, Tao Xin, Qi Pang Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China Purpose: SIL1 is a ubiquitous protein localized to the endoplasmic reticulum and functions as a cochaperone of BiP. Previous studies have shown that function loss of SIL1 is often associated with neurological diseases, such as Marinesco-Sjögren Syndrome. However, no studies have investigated the function of SIL1 in tumors. In this study we aim to reveal functions of SIL1 and the underlying mechanisms in glioma. Materials and methods: First, by searching on Gene Expression Profiling Interactive Analysis, we examined SIL1 expression and prognostic value in glioblastoma multiforme (GBM) and brain lower grade glioma (LGG). Immunohistochemical analysis (IHC) was also performed to determine the endogenic SIL1 level. Cell counting kit-8 (CCK8) and clone formation assays were used to detect cell proliferation of U251 cells. Cell migration was detected by transwell assay and cell cycle and apoptosis were detected by flow cytometry. Western blot was performed to determine protein expression. Results: We found that the expression of SIL1 was increased by approximately 1.5-fold in GBM and 1.3-fold in LGG compared with normal controls (P

Heming Lu,1,2 Yuying Wu,3 Xu Liu,2 Hailan Jiang,2 Qiang Pang,2 Luxing Peng,2 Jinjian Cheng,2 Shan Deng,2 Junzhao Gu,2 Renfeng Zhao,3 Xiaoxia Hu,3 Changyi Chen,3 Jinming Yu1 1Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China; 2Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China; 3Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China Background: To investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC). Patients and methods: Patients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5–6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5–39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed. Conclusion: Concurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings. Keywords: locally advanced cervical cancer, neoadjuvant chemotherapy, intensity-modulated radiotherapy, anti-EGFR monoclonal antibody, radical surgery, hysterectomy

Qing Pang,1,* Hao Jin,1,* Kai Qu,2,* Zhongran Man,1 Yong Wang,1 Song Yang,1 Lei Zhou,1 Huichun Liu1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 2Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China *These authors contributed equally to this work Background: Recent studies have showed that nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce the risk of several types of cancer. However, epidemiological evidence of the association between NSAIDs intake and the risk of hepatocellular carcinoma (HCC) remains controversial. Methods: To assess the preventive benefit of NSAIDs in HCC, we simultaneously searched the databases of PubMed, EmBase, Web of Science, and Scopus and screened eligible publications. Results: A total of twelve articles (published from 2000 to 2017) from five countries were identified by retrieval. We observed a significantly lower risk of HCC incidence among users of NSAIDs than among those who did not use NSAIDs (pooled hazard ratio [HR] value =0.81, 95% confidence interval [CI]: 0.69–0.94). No evidence of publication bias was observed (Begg’s test, P=0.755; Egger’s test, P=0.564). However, when stratified according to the categories of NSAIDs, users of non-aspirin NSAIDs (HR =0.81, 95% CI: 0.70–0.94), but not aspirin (HR =0.77, 95% CI: 0.58–1.02), showed a statistically significant reduced HCC incidence. We also found that NSAIDs use significantly reduced the recurrent risk of HCC, with a HR value of 0.79 (95% CI: 0.75–0.84), whereas there was no statistically significant association between NSAIDs use and HCC mortality, with a HR value 0.65 (95% CI: 0.40–1.06). Conclusion: Taken together, our meta-analysis demonstrates that NSAIDs significantly reduce the incident and recurrent risk of HCC. Keywords: NSAIDs, aspirin, hepatocellular carcinoma, incidence, recurrence

Hao Jin,1–3 Geliang Xu,2 Qiang Zhang,3 Qing Pang,3 Meifang Fang3 1School of Medicine, Shandong University, Jinan, 2Department of Hepatic Surgery, Anhui Provincial Hospital, Hefei, 3Department of Hepatobiliary Surgery, The First Affiliated Hospital, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China Background: Synaptotagmin-7 (Syt-7) is a member of the synaptotagmin (Syt) family, which plays an important role in many physiological and pathological processes. However, to the best of our knowledge, there is no study describing its function in tumors, particularly in hepatocellular carcinoma (HCC). Therefore, in this study, we examined the role of Syt-7 in HCC and attempted to elucidate its underlying mechanism. Materials and methods: We examined the expression levels of Syt-7 in HCC cell lines and normal hepatocytes by real-time quantitative polymerase chain reaction analysis. The effects of Syt-7 knockdown on in vitro cell growth were assessed by Celigo image cytometry, MTT assay, colony formation assay, and cell cy cle analysis. In vivo tumorigenesis was evaluated using a nude mouse model. The underlying molecular mechanism was evaluated using a PathScan Stress Signaling Antibody Array. Results: Syt-7 mRNA levels were highly expressed in Huh-7 and Hep3B cells; moderately expressed in SMMC-7721, HepG2, and BEL-7402 cells; and lowly expressed in normal hepatocytes L-O2. Functional experiments demonstrated that Syt-7 knockdown significantly suppressed cell proliferation and induced cell cycle arrest by increasing phosphorylation of Chk1 and p53. Furthermore, Syt-7 knockdown remarkably reduced the growth of xenograft tumors in mice. Conclusion: The results of this study suggest that Syt-7 plays a vital role in tumorigenesis and in the development of HCC. Syt-7 can be used as a new diagnostic and therapeutic target in HCC. Keywords: hepatocellular carcinoma, Syt-7, Chk1, p53, cell cycle

Wencheng Zhang,1 Qingsong Pang,1 Cihui Yan,2 Qifeng Wang,3 Jingsong Yang,3 Shufei Yu,3 Xiao Liu,3 Zhiyong Yuan,1 Ping Wang,1 Zefen Xiao3 1Department of Radiation Oncology, 2Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Purpose: The purpose of this study was to investigate the potential effect of activation of epidermal growth factor receptor (EGFR) signaling pathway on the expression of programmed death-ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) cells with EGFR overexpression. Methods: Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor (EGF) with or without EGFR-specific inhibitor AG-1478, and then EGFR signaling array was applied to analyze the potential signaling pathways involved. Results: This study found that PD-L1 expression increased significantly in an EGFR-dependent manner by the activation of EGFR signaling and decreased sharply when EGFR signaling was blocked. The upregulated expression of PD-L1 was not associated with EGFR-STAT3 signaling pathway, but may be affected by EGFR–PI3K–AKT, EGFR–Ras–Raf–Erk, and EGR–PLC-γ signaling pathways. Conclusion: The expression of PD-L1 can be regulated by EGFR signaling activation in ESCC, which indicates an important role for EGFR-mediated immune escape and potential molecular pathways for EGFR-targeted therapy and immunotherapy. Keywords: epidermal growth factor receptor, programmed death-ligand 1, esophageal squamous cell carcinoma, immune checkpoint

Baozhong Zhang, Lujun Zhao, Zhiyong Yuan, Qingsong Pang, Ping Wang Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, People’s Republic of China Objective: The use of postoperative radiotherapy (PORT) remains controversial for Stage IIIA-N2 non-small-cell lung cancer (NSCLC) patients, a possible reason is that IIIA-pN2 NSCLC diseases are a heterogeneous group with different clinicopathologic features. The aim of this research was to prove whether the mediastinal lymph nodes’ (LNs) skipping status could indicate the necessity of the PORT for the pN2 NSCLC patients.Methods: The skip metastasis was defined as pN0N2 (no N1 LN involved), and nonskip metastasis was pN1N2 (one or more N1 LNs involved). Patients were divided into two groups: LNs nonskip and LNs skip, and postoperative chemoradiotherapy (POCRT) and postoperative chemotherapy. Then, the LN nonskip and LN skip groups were further divided into subgroups: POCRT and point of care testing (POCT) for subgroup analysis.Results: There were 220 cases included in the analysis, and 43 of them received PORT. On univariate analysis, the median 3-year progression-free survival (PFS) was, respectively, 16 months (27.7%) for the LN skip group and 11 months (15.3%) for the LN nonskip group (P=0.001). The median 3-year overall survival (OS) was, respectively, 35 months (47.0%) for the LN skip group and 27 months (38.7%) for the LN nonskip group (P=0.025). The median 3-year local recurrence-free survival (LRFS) was, respectively, 25 months (41.0%) for the LN skip group and19 months (29.9%) for the LN nonskip group (P=0.014). The median 3-year distant metastasis-free survival (DMFS) was, respectively, 22 months (32.5%) for the LN skip group and 15 months (20.4%) for the LN nonskip group (P=0.013). The median 3-year PFS was, respectively, 17 months (25.6%) for the POCRT group and 12 months (18.6%) for the POCT group (P=0.037). Although the POCRT group showed better OS, LRFS, and DMFS than the POCT group, the results showed no statistical significance. In subgroup analysis, there was no statistical significance in the Kaplan–Meier analysis between subgroups, but it showed that POCRT resulted in better PFS, OS, and DMFS in both LN skip and LN nonskip subgroups; this advantage was more obvious in the LN skip subgroup.Conclusion: The LN skip status is closely related to the survival of the IIIA-N2 NSCLC disease, and the LN skip patients may get more benefit in PFS and LRFS than the LN nonskip patients from PORT. Keywords: non-small-cell lung cancer (NSCLC), N2, postoperative chemoradiotherapy (POCRT), LN skip/nonskip, PFS, OS, DMFS

Dong Qian,1 Jingjing Cheng,1 Xiaofeng Ding,1 Xiuli Chen,1 Xi Chen,1 Yong Guan,1 Bin Zhang,2 Jiefu Wang,3 Puchun Er,1 Minghan Qiu,1 Xianliang Zeng,1 Yihang Guo,1 Huanhuan Wang,1 Lujun Zhao,1 Dan Xie,4 Zhiyong Yuan,1 Ping Wang,1 Qingsong Pang1 1Department of Radiotherapy, 2Department of Lung Cancer, 3Department of Colorectal Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 4State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China Abstract: PinX1 plays positive and negative roles in the maintenance of telomerase and telomeres, as well as in tumorigenesis. The aim of the present study was to investigate the expression and clinical significance of PinX1 in colorectal carcinoma (CRC) and to determine the effect of PinX1 on CRC cell proliferation and apoptosis. A total of 86 CRC patients treated with radical resection and 5-fluorouracil-based adjuvant chemotherapy were enrolled in this study. The expression dynamics of PinX1 was detected by immunohistochemistry in the CRC patients and 25 normal colonic mucosa controls. PinX1 expression was significantly reduced in tumor tissues as compared to normal tissues, and the rate of PinX1 protein low/negative expression in CRC and normal tissues was 60% (52/86) and 24% (6/25), respectively (P=0.037). In addition, PinX1 downregulation was significantly associated with short overall survival (P=0.016) and disease-free survival (P=0.042) in CRC patients. Cox proportional hazards model further revealed that PinX1 expression was an independent factor in predicting overall survival and disease-free survival for CRC patients. Furthermore, we demonstrated that ectopic overexpression of PinX1 in CRC cells inhibited their proliferation, promoted apoptosis, repressed telomerase activity, and induced telomere shortening. These findings suggest that PinX1 may be a prognostic biomarker for CRC patients’ survival and that it inhibits cell proliferation and promotes apoptosis by repressing telomerase activity and inducing telomere shortening. Targeting PinX1 may therefore provide a novel therapeutic strategy for CRC patients. Keywords: colorectal carcinoma, PinX1, cell proliferation, apoptosis, telomerase, telomere, prognostic biomarker

Yan Deng, Qing Pang, Run-Chen Miao, Wei Chen, Yan-Yan Zhou, Jian-Bin Bi, Su-Shun Liu, Jing-Yao Zhang, Kai Qu, Chang Liu Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi Province, People’s Republic of China Background: Pretreatment nutritional and immunological statuses play an indispensable role in predicting the outcome of patients with various types of malignancies. The purpose of this study is to evaluate the predictive value of albumin/globulin ratio (AGR) in overall survival (OS) and recurrence in patients with hepatocellular carcinoma (HCC) following radical hepatic carcinectomy. Patients and methods: This retrospective study included a total of 172 patients with HCC with complete medical and follow-up information between 2002 and 2012. AGR was calculated according to the following formula: AGR = albumin/globulin. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff value. The associations of AGR with clinicopathological characteristics and prognosis were assessed. Further multivariate analysis using Cox regression model and subgroup analysis was performed to evaluate the predictive value. Results: Receiver operating characteristic curve determined 37.65, 31.99, and 1.48 as the optimal cutoff values of albumin, globulin, and AGR in terms of 5-year OS or death, respectively. On the basis of the cutoff value of AGR, all the patients were divided, respectively, into low-AGR (n=105) and high-AGR (n=67) groups. AGR was found to be significantly correlated with age, cancer embolus, international normalized ratio, and postoperative outcome (P

Qing Pang, Jian-Bin Bi, Zhi-Xin Wang, Xin-Sen Xu, Kai Qu, Run-Chen Miao, Wei Chen, Yan-Yan Zhou, Chang Liu Department of Hepatobiliary Surgery, the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi Province, People’s Republic of China Background: Several hepatic cirrhosis-derived noninvasive models have been developed to predict the incidence and outcomes of hepatocellular carcinoma (HCC). We aimed to investigate the prognostic significance of the two novel established cirrhosis-associated models based on gamma-glutamyl transpeptidase (GGT) and platelets in hepatitis B-associated HCC. Methods: We retrospectively evaluated 182 HCC patients with positive hepatitis B surface antigen who received radical therapy at a single institution between 2002 and 2012. Laboratory data prior to operation were collected to calculate the GGT to platelets ratio (GPR) and the S-index. Predictive factors associated with overall survival and recurrence-free survival were assessed using log-rank test and multivariate Cox analysis. Additional analyses were performed after patients were stratified based on cirrhosis status, tumor size, therapy methods, and so forth, to investigate the prognostic significance in different subgroups. Results: During a median follow-up time of 45.0 months, a total of 88 (48.4%) patients died and 79 (43.4%) patients recurred. The cut-off points for GPR and S-index in predicting death were determined to be 0.76 and 0.56, respectively. Compared with patients with a lower GPR, those with GPR ≥0.76 had a higher probability of cirrhosis and a larger tumor (both P

Kai Qu,1,* Qing Pang,1,* Ting Lin,1 Li Zhang,2 Mingliang Gu,3 Wenquan Niu,4 Chang Liu,1,* Ming Zhang5 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi Province, People’s Republic of China; 2Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China; 3Chinese Academy of Sciences Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People’s Republic of China; 4State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Recent studies have showed interleukin 10 (IL-10) is a critical cytokine that determines antiviral immune response and is related to virus-associated cancers. However, whether genetically elevated circulating IL-10 levels are associated with the risk of human papilloma virus and Epstein–Barr virus-associated cancers (HEACs) is still unclear. Mendelian randomization method was implemented to meta-analyze available observational studies by employing IL-10 three variants (-592C>A, -819C>T, and -1082A>G) as instruments. A total of 24 articles encompassing 11,170 subjects were ultimately eligible for the meta-analysis. Overall, there was a significant association between IL-10 promoter variant -1082A>G and HEACs under allelic and dominant models (both PG was significant for nasopharyngeal cancer under allelic, homozygous genotypic and dominant models (all P

Hongqing Zhuang,* Hailing Hou,* Zhiyong Yuan, Jun Wang, Qingsong Pang, Lujun Zhao, Ping WangDepartment of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, People's Republic of China*These authors contributed equally to this workPurpose: The aim of this study was to investigate radiation pneumonitis and its associated risk factors in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy.Materials and methods: We conducted an analysis of patients with nonoperable stage IIIA–IV non-small-cell lung cancer who were treated with concurrent thoracic radiotherapy and erlotinib (ClinicalTrials.gov identifier: NCT00973310). The Common Terminology Criteria for Adverse Events version 3.0 grading system was applied to evaluate the incidence of radiation pneumonitis. The lung dosimetric parameters were recorded in accordance with the treatment plan, and the study endpoint was radiation pneumonitis at grade 2 or more.Results: Among the 24 selected clinical cases, nine were identified with radiation pneumonitis of grade 2 or above (37.5%). This included four cases with grade 2 (16.7%), two cases with grade 3 (8.3%), and three cases with grade 5 (12.5%). The results showed that the planning target volume was a significant factor affecting the incidence of radiation pneumonitis. All lung dosimetric parameters exhibited statistically significant differences between patients with pneumonitis and patients without pneumonitis. The receiver operating characteristic (ROC) curve analysis showed that all lung dosimetric parameters were useful in predicting the incidence of radiation pneumonitis. In addition, the threshold values of V5, V10, V15, V20, V30, and mean lung dose were >4%, >29%, >27%, >22%, >17% and >1,027 cGy, respectively.Conclusion: Special attention should be paid to the adverse effects of radiation pneumonitis in concurrent thoracic radiotherapy and erlotinib treatment. Lung dosimetric parameters are important predictive factors in radiation pneumonitis.Keywords: erlotinib, thoracic radiotherapy, radiation pneumonitis, dosimetric parameter, threshold value for lung radiation

Objective: This study aimed to evaluate the safety and efficacy of intensity-modulated radiotherapy (IMRT) plus nimotuzumab with or without concurrent chemotherapy (CCT) for patients with locally advanced nasopharyngeal carcinoma (LA-NPC)., Patients and Methods: A total of 50 newly diagnosed patients with LA-NPC treated at the Affiliated Hospital of Jiangnan University between November 2011 and January 2017 were retrospectively analyzed. All patients received the combined treatment modality of nimotuzumab plus IMRT. Nimotuzumab was administered concurrently with IMRT at a weekly dose of 200 mg. Neoadjuvant, concurrent or adjuvant chemotherapy with the doublet regimen of taxanes (docetaxel or paclitaxel) plus platinum (cisplatin or nedaplatin) were administered. Among the 50 patients, 43 (86.0%) received ≥6 cycles of nimotuzumab (median 7 cycles, range 2-14 cycles) and 29 (58.0%) received two cycles of CCT with docetaxel plus nedaplatin., Results: With a median follow-up of 28.0 months, the 2-year progression-free survival (PFS) and overall survival were 83.29% (95% confidence interval [CI]: 67.93%-91.72%) and 97.67% (95% CI: 84.62%-99.67%), respectively. Both univariate and multivariate analyses revealed that cycles of nimotuzumab were significantly associated with PFS. Patients who received ≥6 cycles of nimotuzumab showed a better PFS than those receiving <6 cycles ( P =0.006), whereas the addition of CCT failed to improve PFS. Oral mucositis was the most common adverse event, which was recorded as grade 3-4 in 18 (36.0%) patients. Besides, two (4.0%) patients experienced nimotuzumab-related anaphylaxis, and no skin rash was found in any patient. Subgroup analysis revealed that the patients who received CCT had more grade 3-4 adverse events as compared to those who did not receive CCT (62.1% vs 33.3%, P =0.045)., Conclusion: The regime of nimotuzumab plus IMRT for the treatment of LA-NPC was well tolerated, with encouraging survival data, and it could be an effective treatment alternative for patients with LA-NPC. Further clinical trials are needed to confirm these findings., Competing Interests: Disclosure The authors report no conflicts of interest in this work.