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Objective The purpose of this study was to initially investigate whether previous antiangiogenic therapy (bevacizumab and endostar) affect the efficacy of anlotinib in patients with lung cancer (LC). Methods We retrospectively collected the clinical data of LC patients treated with anlotinib. They were divided into two groups, namely group A (anlotinib after failure of previous antiangiogenic drugs and group B (no prior use of antiangiogenic drugs). Use propensity score matching (PSM) to control the confounding factors between the groups.Results A total of 160 patients were included in the analysis. The median OS in group A and group B was 11.8 months vs. 16.1 months (P=0.120), and the median PFS was 3.1 months, 4.7 months, respectively (P=0.009). The ORR of the two groups was 9.6% vs. 10.4% (P=0.874), and the DCR was 71.1 % vs. 80.5% (P=0.165).After PSM (n=46), baseline characteristics were equitably comparable between the two groups. It was found that the median OS of the two groups was 14.6 months vs. 16.2 months (P=0.320), and the median PFS was 3.5 months vs. 4.5 months (P=0.040). The ORR of the two groups were 13.0%, 10.9% (P=0.748), and the DCR were 78.3%, 82.6% (P=0.599), respectively. These results provided further evidence that although PFS of group A was relatively shorter than that of group B, it may not affect patients’ OS.Conclusions Previous antiangiogenesis treatments may affect the PFS of patients who receive anlotinib later, but it might not affect the patient’s ORR and OS.

Background: Primary mediastinal yolk sac tumors is a kind of primary mediastinal non-seminomatous germ cell tumor . The current treatment strategies in primary mediastinal non-seminomatous germ cell tumor is neoadjuvant chemotherapy followed by residual mass surgical resection . We reviewed our institutional 5 years' experience with Primary mediastinal yolk sac tumors who treated with platinum-based neoadjuvant chemotherapy and extended resection.Methods： We experienced 10 cases of Primary mediastinal yolk sac tumors from October of 2014 to October of 2019. 7 patients received preoperative platinum-based chemotherapy followed by surgical resection of residual mediastinal mass. The other 3 patients were received initial surgical resection without preoperative chemotherapy.Results：R0 resection was achieved in 8 patients (80%), and R2 resection was in the other 2 patients (20%). All the 7 patients with neoadjuvant chemotherapy were R0 resections, however all of them had viable tumor in their surgical specimen. Morbidities after surgery occurred in 2 patients, including 2 pneumonias ,1 type I respiratory failure and 1 acute left heart failure, and They were died within 2 months after surgery. At the time of writing ,3 patients are alive without evidence of disease,7 patients died , of which 5 patients have died of tumor-related causes and 2 died of postoperative complications. 8 patients were included in the follow-up. Among them 7patients experienced progressed within one year. 8 patients were included in the follow-up,mPFS and mOS in 8 patients were 3.7 months (2.6-41.3m) and 23.15 months (8.6-41.3m) , respectively. The 7 patients with neoadjuvant chemotherapy followed by surgical resection of residual diseases, 2-year survival rate was 57.1%,The 3-year survival rate was 28.6%Conclusion: An aggressive, multidisciplinary treatment including neoadjuvant chemotherapy followed by residual mass surgical resection is the optimal treatment and can be associated with prolonged survival.

Purpose Hypofractionated radiation therapy (HFRT) can induce antitumor T cell responses, particularly in combination with immune checkpoint inhibitors (ICI), but abscopal effects are often precluded by insufficient T cell infiltration of distant, nonirradiated tumors. Additional noncytotoxic, low-dose radiation therapy (LDRT) of distant tumors may enhance the abscopal response, but clinical evidence and preclinical studies for this scenario are lacking. Methods and Materials We investigated whether triple treatment consisting of HFRT, ICI, and LDRT could achieve better systemic antitumor response in bilateral mouse tumor models and in patients with stage IV non-small cell lung cancer. Results Our analyses of bilateral mouse tumor models show that HFRT treatment of the primary tumor combined with LDRT treatment of the abscopal tumor and anti-PD1 therapy enhances the abscopal response compared with HFRT/anti-PD1, HFRT/LDRT, or LDRT/anti-PD1 double treatments; complete cure was observed in more than half of the mice treated with triple therapy. The enhanced abscopal effect was associated with increased infiltration of CD8+ effector T cells and upregulated expression of T cell–attracting chemokines. Of 9 patients with metastatic non-small cell lung cancer who were treated with this triple therapy, 3 and 2 patients showed partial responses and stable disease, respectively. Among 9 relatively large (175.7 ± 42.3 cm3) LDRT lesions, 6 lesions decreased by 28% in size, on average. Conclusions Our study demonstrates preclinically that LDRT of established metastases significantly enhances the abscopal response to HFRT plus ICI. It also shows that additional LDRT was well tolerated by patients and that this treatment profile is effective and worth further study.

To extrapolate the infiltration levels of immune cells in patients with lower-grade gliomas (LGGs) using magnetic resonance imaging (MRI)-based radiomic features. A retrospective dataset of 516 patients with LGGs from The Cancer Genome Atlas (TCGA) database was analysed for the infiltration levels of six types of immune cells using Tumor IMmune Estimation Resource (TIMER) based on RNA sequencing data. Radiomic features were extracted from 107 patients whose pre-operative MRI data are available in The Cancer Imaging Archive; 85 and 22 of these patients were assigned to the training and testing cohort, respectively. The least absolute shrinkage and selection operator (LASSO) was applied to select optimal radiomic features to build the radiomic signatures for extrapolating the infiltration levels of immune cells in the training cohort. The developed radiomic signatures were examined in the testing cohort using Pearson’s correlation. The infiltration levels of B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils and dendritic cells negatively correlated with overall survival in the 516 patient cohort when using univariate Cox’s regression. Age, Karnofsky Performance Scale, WHO grade, isocitrate dehydrogenase mutant status and the infiltration of neutrophils correlated with survival using multivariate Cox’s regression analysis. The infiltration levels of the 6 cell types could be estimated by radiomic features in the training cohort, and their corresponding radiomic signatures were built. The infiltration levels of B cells, CD8+ T cells, neutrophils and macrophages estimated by radiomics correlated with those estimated by TIMER in the testing cohort. Combining clinical/genomic features with the radiomic signatures only slightly improved the prediction of immune cell infiltrations. We developed MRI-based radiomic models for extrapolating the infiltration levels of immune cells in LGGs. Our results may have implications for treatment planning.

Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR–Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856 ). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3–74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0–0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR–Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy. In a first-in-human phase I trial of patients with advanced lung cancer, infusions of autologous T cells edited to delete the PD-1 gene via CRISPR–Cas9 were well tolerated and did not lead to severe treatment-related adverse events.

// Ruxing Xi 1 , Shupei Pan 1 , Xin Chen 2 , Beina Hui 1 , Li Zhang 1 , Shenbo Fu 1 , Xiaolong Li 3 , Xuanwei Zhang 1 , Tuotuo Gong 1 , Jia Guo 1 , Xiaozhi Zhang 1 , Shaomin Che 1 1 Department of Radiotherapy, The First Hospital Affiliated of Xi’an Jiao Tong University, Xi’an, Shaan Xi, 710061, P.R.China 2 Department of Radiotherapy, People’s Hospital of Shaanxi Province, Xi’an, Shaan Xi, 710068, P.R.China 3 Department of Radiotherapy, The People’s Liberation Army 323 Hospital, Xi’an, Shaan Xi, 710054, P.R.China Correspondence to: Xiaozhi Zhang, email: zhang9149@sina.com Shaomin Che, email: chersm@126.com Keywords: esophageal squamous cell carcinoma, HPV16 E6-E7, CSCs, PI3K, p75NTR Received: October 22, 2015 Accepted: July 16, 2016 Published: July 30, 2016 ABSTRACT High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China. We aim to investigate the potential role and mechanism of HPV16 in ESCC development and progress. Our following researches demonstrated that ESCC cells which were stably transfected by HPV16 E6-E7 lentiviral vector showed a remarkable cancer stem-like cells (CSCs) phenotype, such as: migration, invasion, spherogenesis, high expression of CSCs marker in ESCC---p75NTR, chemoresistance, radioresistance, anti-apoptosis ability in vitro and cancerogenesis in vivo . HPV16 E6-E7 induced PI3K/Akt signaling pathway activation and this affect could be effectively inhibited by LY294002, a specific PI3K inhibitor. It was also indicated that the inhibition of PI3K/Akt signaling pathway by PI3K and Akt siRNA reverse the effect which induced by HPV16 E6-E7 in ESCC cells. Taken together, the present study demonstrates that HPV16 E6-E7 promotes CSCs phenotype in ESCC cells through the activation of PI3K/Akt signaling pathway. Targeting the PI3K/Akt signaling pathway in HPV16 positive tissues is an available therapeutic for ESCC patients.

Radiation therapy is one of the most important treatments for unresectable and locally advanced esophageal squamous cell carcinoma (ESCC), however, the response to radiotherapy is sometimes limited by the development of radioresistance. Sinomenine hydrochloride (SH) has anticancer activity, but its effect on the radiosensitivity of ESCC is unclear. We determined the effect of SH on the radiosensitivity of ESCC cells and elucidated its potential radiosensitization mechanisms in vitro and in vivo. ESCC cells were subjected to SH and radiation, both separately and in combination. Untreated cells served as controls. The CCK-8 assay was used to evaluate cell proliferation, and the clonogenic assay to estimate radiosensitization. Flow cytometry was used to investigate cell cycle phases and cell apoptosis. Bcl-2, Bax, cyclin B1, CDK1, Ku86, Ku70, and Rad51 expression was evaluated using western blotting. In vivo, tumor xenografts were created using BALB/c nude mice. Tumor-growth inhibition was recorded, and Ki-67 and Bax expression in the tumor tissues was assessed using immunohistochemistry. SH inhibited ESCC cell growth and markedly increased their radiosensitivity by inducing G2/M phase arrest. SH combined with radiation therapy significantly increased ESCC cell apoptosis. The molecular mechanism by which SH enhanced radiosensitivity of ESCC cells was related to Bcl-2, cyclin B1, CDK1, Ku86, Ku70, and Rad51 downregulation and Bax protein expression upregulation. SH combined with radiation considerably delayed the growth of tumor xenografts in vivo. Immunohistochemical analysis showed that in the SH combined with radiation group, the expression of Bax was significantly higher while that of Ki-67 was lower than the expressions in the control groups. Taken together, our findings showed that SH could improve the sensitivity of radiation in ESCC cells by inducing G2/M phase arrest, promoting radiation-induced apoptosis and inhibiting DSB-repair pathways. SH appears to be a prospective radiosensitizer for improving the efficacy of radiotherapy for ESCC.

This study was intended to determine whether antidepressant outcome to SSRIs was associated with catecholamine gene polymorphisms and neuroendocrine factors in patients of Chinese Han ethnicity with MDD.A total of 290 MDD patients were recruited and received a 6-week randomized double-blinded treatment. Cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), 3'-triiodothyronine (T3), thyroxine (T4), free triiodothyronine (fT3), and free thyroxine (fT4) levels were measured at the baseline. Allele, genotype, and haplotype frequencies of catecholamine genes were compared between responders and non-responders, remission and non-remission groups respectively.We found that genotype frequency of the rs1800544 polymorphism in the DRD4 gene was significantly different between responders and non-responders (P0.05). Also the frequency of the rs1800544 CG genotype was significantly higher (P0.05) in responders (51.4%) than that in non-responders (35.8%). No significant difference was found between responders and non-responders, remission and non-remission groups in the SNPs polymorphisms in the TPH, SLC6A2, SLC6A3, or DRD2 genes. The combination of all neuroendocrine factors, clinical characteristics and gene polymorphisms predicted 74.8% of the variation in SSRI response and 65.5% in SSRI remission.Polymorphisms of the DRD4 gene were associated with SSRI response in Chinese Han MDD patients. A combination of clinical characteristics, neuroendocrine factors, and gene polymorphisms might be able to predict the outcome to SSRIs.

Purpose Hypofractionated radiation therapy (hRT) combined with immune checkpoint blockade can induce T-cell–mediated local and abscopal antitumor effects. We had previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between days 5 and 8 after hRT. Because TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses combined with anti-programmed cell death 1 (PD1) antibody treatment. Methods and Materials In mice bearing 2 B16-CD133 melanoma tumors, the primary tumor was irradiated with 3 × 9.18 Gy in 3 or 5 days or with 5 × 6.43 Gy in 10 days; an anti-PD1 antibody was given weekly. The mice were monitored for tumor growth and survival. T-cell responses were determined on days 8 and 15 of treatment. The role of regional lymph nodes was studied by administering FTY720, which blocks lymph node egress of activated T cells. Tumor growth measurements after combination treatment using short or extended hRT and control treatment were also performed in the wild-type B16 melanoma and 4T1 breast carcinoma models. Results In the B16-CD133 model, growth inhibition of irradiated primary and nonirradiated secondary tumors and overall survival were similar with all 3 hRT/anti-PD1 combinations, superior to hRT and anti-PD1 monotherapy, and was strongly dependent on CD8+ T cells. TIL infiltration and local and systemic tumor-specific CD8+ T-cell responses were also similar, regardless of whether short or extended hRT was used. Administration of FTY720 accelerated growth of both primary and secondary tumors, strongly reduced their TIL infiltration, and increased tumor-specific CD8+ T cells in the lymph nodes draining the irradiated tumor. In the 4T1 model, local and abscopal tumor control was also similar, regardless of whether short or extended hRT was used, although the synergy between hRT and anti-PD1 was weaker. No synergies were found in the B16 wild-type model lacking an exogenous antigen. Conclusions Our data suggest that combination therapy with hRT schedules extending into the period during which treatment-induced T cells infiltrate the irradiated tumor can provoke local and systemic antitumor effects similar to those with therapy using shorter schedules, if the regional lymph nodes supply sufficient tumor-specific T cells. This has implications for planning clinical RT/immune checkpoint blockade trials.

Astrocyte elevated gene-1 (AEG-1) is associated with tumor genesis and progression in a variety of human cancers. This study aimed to explore the significance of AEG-1 in glioma and investigate whether it correlated with radioresistance of glioma cells. Immunohistochemical staining showed that the intensity of AEG-1, CD133 and PPP6c protein expression in glioma tissues increased significantly, mainly in the cytoplasm. The expression rate of AEG-1, CD133 and PPP6c were 85.9% (67/78), 60.3% (47/78) and 65.8% (51/78), respectively. AEG-1 expression was correlated with age (r = 0.227, P = 0.045), clinical stage (r = 0.491, P0.05). The expression of AEG-1 was positively correlated with the expression of CD133 (r = 0.240, P = 0.035) and PPP6c (r = 0.250, P = 0.027). In addition, retrieved data on TCGA implied co-occurrence of genomic alterations of AEG-1 and PPP6c in glioblastoma. Our findings indicate that AEG-1 is positively correlated with CD133 and AEG-1 expression. It may play an important role in the progression of glioma and may serve as potential novel marker of chemoresistance and radioresistance.

The skill level of teleoperator plays a key role in the telerobotic operation. However, plenty of experiments are required to evaluate the skill level in a conventional assessment. In this paper, a novel brain-based method of skill assessment is introduced, and the relationship between the teleoperator's brain states and skill level is first investigated based on a kernel canonical correlation analysis (KCCA) method. The skill of teleoperator (SoT) is defined by a statistic method using the cumulative probability function (CDF). Five indicators are extracted from the electroencephalo-graph (EEG) of the teleoperator to represent the brain states during the telerobotic operation. By using the KCCA algorithm in modeling the relationship between the SoT and the brain states, the correlation has been proved. During the telerobotic operation, the skill level of teleoperator can be well predicted through the brain states.

Ruxing Xi,1 Xiaozhi Zhang,1 Xin Chen,1 Shupei Pan,1 Beina Hui,1 Li Zhang,1 Shenbo Fu,1 Xiaolong Li,2 Xuanwei Zhang,1 Tuotuo Gong,1 Jia Guo,1 Shaomin Che1 1Department of Radiotherapy, The First Affiliated Hospital of Xi’an Jiao Tong University, 2Department of Radiotherapy, The People’s Liberation Army 323 Hospital, Xi’an, People’s Republic of China Background: Previous studies indicate that human papillomavirus 16 (HPV16) infection plays a pivotal role in the etiology of esophageal squamous cell carcinoma (ESCC). We aim to detect the influence of HPV16 infection on ESCC patient prognosis. Patients and methods: Immunohistochemical staining for HPV16 E6 oncoprotein, the low-affinity p75 neurotrophin receptor (p75NTR), and phosphatidylinositol 3-kinase (PI3K) was performed on 103 archived surgical specimens from patients with ESCC and 54 control samples from patients with benign esophageal tumor or inflammatory lesions. All patients were from the Shaan Xi Province, People’s Republic of China. Results: HPV16 E6 expression was significantly higher in the ESCC group (P56 years (P

Until now, no large series studies on the clinicopathological features of primary liver tumors (PLTs) in mainland China have been reported. The authors retrospectively investigated 3,160 cases of PLTs surgically resected at Shanghai Oriental Hospital of Hepatobiliary Surgery between January 1982 and January 1996. Most of them are true neoplasms, others are tumor-like lesions. The 3,160 cases of PLTs could be divided into 3 groups of 25 types arising from three germinal layers, of which tumor-like lesions (Group 1) were of 4 types involving 112 cases (3.5%), benign PLTs (Group 2) were of 10 types involving 499 cases (15.8%) and malignant PLTs (Group 3) were of 11 types involving 2,549 cases (80.7%). The most common type of lesion in each group was solitary necrotic nodule, cavernous hemangioma and hepatocellular carcinoma (HCC), accounting for 73.2%, 74.3% and 96.6% of their respective groups. The patients ranged in age from 5 months to 79 years (mean, 45.7 years), but the age distribution and sex ratio varied reciprocally from group to group and from lesion to lesion. For example, the mean age of the patients in Group 1 was 39.1 years of age, whereas in Group 2 and Group 3, it was 45.9 years and 49.6 years, respectively. The sex ratio of men to women was 2.6:1 in Group 1, 1:1.1 in Group 2 and 7.7:1 in Group 3. The rates of serum HBsAg positivity and concomitant liver cirrhosis in the patients with HCC were 74.4% and 72%, respectively, and the concomitant rate of cirrhosis in small HCC (