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Purpose Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. Patients and methods This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. Results Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65-6.95), and the median OS was 12.2 months (95% CI, 8.99-15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). Conclusion Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.

Acquired radioresistance is one of the main obstacles for the anti‐tumour efficacy of radiotherapy in oesophageal cancer (EC). Recent studies have proposed microRNAs (miRNAs) as important participators in the development of radioresistance in various cancers. Here, we investigated the role of miR‐1275 in acquired radioresistance and epithelial‐mesenchymal transition (EMT) in EC. Firstly, a radioresistant cell line KYSE‐150R was established, with an interesting discovery was observed that miR‐1275 was down‐regulated in KYSE‐150R cells compared to the parental cells. Functionally, miR‐1275 inhibition elevated radioresistance in KYSE‐150 cells via promoting EMT, whereas enforced expression of miR‐1275 increased radiosensitivity in KYSE‐150R cells by inhibiting EMT. Mechanically, we demonstrated that miR‐1275 directly targeted WNT1 and therefore inactivated Wnt/β‐catenin signalling pathway in EC cells. Furthermore, WNT1 depletion countervailed the promoting effect of miR‐1275 suppression on KYSE‐150 cell radioresistance through hampering EMT, whereas WNT1 overexpression rescued miR‐1275 up‐regulation‐impaired EMT to reduce the sensitivity of KYSE‐150R cells to radiation. Collectively, our findings suggested that miR‐1275 suppressed EMT to encourage radiosensitivity in EC cells via targeting WNT1‐activated Wnt/β‐catenin signalling, providing a new therapeutic outlet for overcoming radioresistance of patients with EC.

Background Development of doxorubicin-resistance is the main difficulty for osteosarcoma treatment. LncRNA Taurine upregulated gene 1 (TUG1) has been identified as oncogenic lncRNA in different types of carcinomas and was involved in chemoresistance. We aim to evaluate the anti-proliferative effects and the underlying molecular mechanism of Polydatin in doxorubicin-resistant osteosarcoma. Methods Doxorubicin-resistant osteosarcoma cell lines were established. MTT, colony formation, apoptosis assay, qRT-PCR and Western blotting analysis, immunohistochemistry and animal study were carried out. Results It has been showed Polydatin (50–250 μM) inhibited the cell proliferation in a dose- and time-dependent manner at 24 h, 48 h, and 72 h. Polydatin promoted the cell apoptosis significantly with the highest apoptosis rate >50%. Polydatin down-regulated TUG1 expression and TUG1/Akt signaling suppression was involved in Polydatin treated doxorubicin-resistant osteosarcoma cells. The in vivo study further confirmed the anti-cancer effect of Polydatin and related mechanisms. Conclusions Polydatin may be a novel therapeutic agent for doxorubicin-resistant osteosarcoma treatment and TUG1 would be a potential molecular target.

EMT-related gene expression reportedly exhibits correlation with the anti-tumor immunity of T cells. In the present study, we explored the factors that might affect the efficacy of immunotherapy in colon cancer with treatment. In this regard, RNA-seq and clinical data of 469 colon cancer samples derived from the Cancer Genome Atlas (TCGA) database were used to calculate infiltrating T-cell abundance (ITA), to illustrate a pathway enrichment analysis, and to construct Cox proportional hazards (CPH) regression models. Subsequently, the RNA-seq and clinical data of 177 colon cancer samples derived from the GSE17536 cohort were used to validate the CPH regression models. We found that ITA showed correlation with EMT-related gene expression, and that it was not an independent prognostic factor for colon cancer. However, upon comparison of two groups with the same ITA, higher EMT expression helped predicted a worse prognosis, whereas a higher ITA could help predict a better prognosis upon comparison of two groups with the same EMT. Additionally, seven genes were found to be statistically related to the prognosis of patients with colon cancer. These results suggest that the balance between ITA and EMT-related gene expression is conducive to the prognosis of patients with colon cancer, and TPM1 is necessary to further explore the common target genes of immune checkpoint blockade., Graphical Abstract

Background: The prognostic significance of the lymph node (LN) classification for small bowel neuroendocrine tumors (SBNETs) remains unknown. The aim of the present study was to evaluate and compare the prognostic assessment of different LN staging systems.Methods: Patients with SBNETs were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to determine the cutoff value of the resected lymph nodes (RLNs), negative lymph nodes (NLNs), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS). Survival analyses were performed using Kaplan–Meier curves with log-rank test. Logistic regression analysis was used to evaluate the differences between different periods. Univariate and multivariate Cox proportional hazards models were used to assess the prognostic value of different LN staging systems on cause-specific survival (CSS). The relative discriminative abilities of the different LN staging systems were assessed using the Akaike information criterion (AIC) and the Harrell consistency index (HCI).Result: A total of 3,680 patients were diagnosed with SBNETs between 1988 and 2014 from the SEER database. A significant difference over time (1988–1999 vs. 2000–2014) was seen in age (P

Radiotherapy plays an important therapeutic role in esophageal cancer (EC). However, acquired radioresistance impairs the efficacy of radiotherapy, often leading to treatment failure. Therefore, it is important to develop novel radiosensitizers to enhance the clinical treatment of EC. The purpose of this study was to investigate the role of artesunate (ART) on radiosensitivity of human EC cell line TE-1. We found that ART inhibited the proliferation of EC cells and enhanced the radiosensitivity of TE-1 cells (SER = 1.24). In vivo tumor growth of xenografts was inhibited markedly by irradiation (IR) combined with ART, with a tumor inhibition rate of 53.76% in IR + ART group vs. 41.13% in IR-alone group. Pretreatment with ART significantly prompted cell apoptosis and reversed the IR-induced G2/M arrest. ART treatment could aggravate DNA damage of EC cells and prolong the formation of γ-H2AX foci induced by IR. ART up-regulated P21 and down-regulated the expression of cyclin D1, RAD51, RAD54, Ku70 and Ku86 protein of irradiated TE-1 cells. These findings support that ART induce radiosensitivity of TE-1 cells in vitro and in vivo, and may prove to be a promising radiosensitizer for EC treatment. Keywords: Artesunate (ART), Radiosensitivity, Esophageal cancer, γ-H2AX

Background: The rates of locoregional and distant recurrence for esophageal squamous cell carcinoma (ESCC) patients underwent radical esophagectomy remain high. The purpose of this study is to explore an optimal postoperative therapeutic modality by investigating the efficacy of various adjuvant therapies in the treatment of ESCC. Methods: We retrospectively reviewed 408 ESCC patients underwent thoracic esophagectomy and 3-field lymph node dissection from 2010 to 2015. Patients were classified into surgery alone (Group S), adjuvant chemotherapy (Group CT) and postoperative chemotherapy plus radiotherapy (Group CRT), respectively. Univariate and multivariate Cox regression analyses were used to analyze prognostic factors and survival. Results: The overall survival (OS) and disease-free survival (DFS) were similar among groups. Postoperative CT and CRT both were beneficial for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment compared with surgery alone. The 3-year OS and DFS for patients with 3 or more lymph nodes involvement were 30.8%, 53.7%, 50.5% and 19.9%, 41.6%, 34.0% for Group S, CT, and CRT, respectively (p=0.04; p=0.004, respectively). There was no notable difference in OS and DFS between the adjuvant Group CT and CRT (p=0.42; p=0.49, respectively). Postoperative CRT significantly reduced the rates of distant metastasis and overall recurrence for patients with positive lymph nodes (p=0.042; p=0.01, respectively). Number of metastatic lymph nodes, extent of resection, and AJCC stage were independent predictors of survival. Grade 1-2 myelosuppression was experienced significantly more frequently by patients in Group CRT than those in Group CT (P=0.03). Late toxicities were rare and manageable overall. Conclusions: Postoperative CT and CRT both were associated with better survival for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment. Postoperative CRT was significantly more effective at reducing the rates of distant metastasis and overall recurrence for patients with positive lymph nodes.

// Hongqin Zhao 1, * , Lili Li 2, * Huafang Su 2 , Baochai Lin 2 , Xuebang Zhang 2 , Shengliu Xue 2 , Zhenghua Fei 2 , Lihao Zhao 2 , Qintuo Pan 3 , Xiance Jin 2 , Congying Xie 2 1 Departments of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, 325000 2 Departments of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, 325000 3 Departments of Eye Fundus Surgery, Eye Hospital of Wenzhou Medical University, Wenzhou, China, 325002 * These authors contributed equally to this work Correspondence to: Xiance Jin, email: jinxc1979@hotmail.com Congying Xie, email: wzxiecongying@163.com Keywords: cervical cancer, chemoradiotherapy, consolidation chemotherapy, cisplatin, paclitaxel Received: March 23, 2016 Accepted: June 30, 2016 Published: July 06, 2016 ABSTRACT A phase III randomized study on the efficacy and safety of consolidation chemotherapy with paclitaxel plus cisplatin following radical hysterectomy and adjuvant chemoradiotherapy (CRT) in the treatment of high risk early-stage cervical cancer were reported. 146 eligible patients were randomized to arm A receiving concurrent CRT or arm B receiving CRT plus consolidation chemotherapy, respectively. An interim analysis showed a trend of improvement on disease-free survival (DFS) and overall survival (OS) in arm B with hazard ratios (HR) of 1.25 (95% CI = 0.60–2.60, p = 0.55) and 1.43 (95% CI = 0.64–3.20, p = 0.38) for DFS and OS, respectively. The 3-year DFS and OS were 82.0% vs.74.3%, and 86.6% vs. 78.3% for patients receiving CRT plus consolidation chemotherapy and CRT alone, respectively. There was significant difference between the two arms in distant alone recurrence ( p = 0.048). Multivariate analysis indicated that pathologic type was a significant prognostic factor for OS ( p = 0.045), positive pelvic nodes were significantly associated with both OS ( p =0.02) and DFS ( P =0.03). Grade 2 to 4 gastrointestinal disorder ( p = 0.95), radiation enteritis ( P =0.48), radiation cystitis ( p = 0.27) and radioepidermitis ( p = 0.46) were similar in the two arms. Overall rates of grade 0–2/3–4 myelosuppression were 87.7%/12.3% for arm A and 74.6%/25.4% for arm B, respectively, but this difference was not statistically significant ( p = 0.05). In conclusion, concurrent CRT plus consolidation chemotherapy may play a potential role in further improving survival outcomes for high-risk early stage cervical cancer patients compared CRT alone.

Background In the era of intensity-modulated radiotherapy (IMRT), the role of additional concurrent chemotherapy (CC) to radiotherapy (RT) after induction chemotherapy (IC) compared to IC followed by RT alone remains unclear for stage II-IVB nasopharyngeal carcinoma (NPC) patients. The aim of this study was to evaluate the efficacy and toxicities of IC/RT and IC/CCRT in the treatment of NPC with volumetric modulated arc therapy (VMAT). Methods From January 2012 to March 2016, a total of 217 NPC patients were retrospectively assessed. Of the 217 patients, 139 patients received IC followed by VMAT alone and 78 patients received IC plus CCRT. Overall survival (OS), progression-free survival (PFS) and toxicities were assessed. Results The 5-year OS, PFS rates were 57.5%, 41.8% and 47.8%, 38.4% for the IC/RT and IC/CCRT arms, respectively, without significant difference in survival between the two groups (both p > 0.05). Multivariate analysis indicated that treatment modality (IC/RT vs. IC/CCRT) was not an independent prognostic factor for OS or PFS. Grade 3–4 leukopenia/neutropenia (3.60% vs. 20.51%, p

Recent studies demonstrated a significantly increased frequency of epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). The purpose of this study is to investigate the effect of first-line and second-line EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC with MPEs harboring exon 19 deletion and L858R mutation. From 2010 to 2015, 203 NSCLC patients with MPEs harboring EGFR mutation treated with EGFR-TKIs were reviewed. The efficacy were evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. The objective response rate (ORR) and disease control rate (DCR) for patients treated with first-line and second-line EGFR-TKIs were 21.9%, 91.4% and 14.7%, 85.3%, respectively. The overall median PFS and OS of enrolled NSCLC patients with MPE were 9.3 months (95% CI, 8.4–10.2 months), 20.9 months (95% CI, 18.9–22.9 months) after first-line TKIs, and 7.6 months (95% CI, 6.6–8.6 months), 15.3 months (95% CI, 13.6–15.9 months) after second-line TKIs. The exon 19 deletion arm had a longer median PFS (9.4 vs 7.1 months, p=0.003) and OS (16.8 vs 13.8 months, p=0.003) compared with the L858R mutation arm after second-line TKIs. In a conclusion, EGFR genotype was an independent predictor of PFS and OS. No significant side effects differences between the two mutation groups was observed for first or second-line EGFR-TKIs. This study demonstrated that EGFR mutations are significant predictors for advanced NSCLC patients with MPE receiving second-line EGFR-TKIs treatment.

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non–small cell lung cancer (NSCLC). Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals. Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively. Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311–9. ©2017 AACR.

Background Acquired radioresistance during radiotherapy is considered as the most important reason for local tumor recurrence or treatment failure. Circular RNAs (circRNAs) have recently been identified as microRNA sponges and involve in various biological processes. The purpose of this study is to investigate the role of circRNAs in the radioresistance of esophageal cancer. Methods Total RNA was isolated from human parental cell line KYSE-150 and self-established radioresistant esophageal cancer cell line KYSE-150R, and hybridized to Arraystar Human circRNA Array. Quantitative real-time PCR was used to confirm the circRNA expression profiles obtained from the microarray data. Bioinformatic tools including gene ontology (GO) analysis, KEGG pathway analysis and network analysis were done for further assessment. Results Among the detected candidate 3752 circRNA genes, significant upregulation of 57 circRNAs and downregulation of 17 circRNAs in human radioresistant esophageal cancer cell line KYSE-150R were observed compared with the parental cell line KYSE-150 (fold change ≥2.0 and P

Acquired radioresistance during radiotherapy has significantly affected the treatment efficacy in esophageal cancer. Many of radioresistant cancer cells demonstrated epithelial-mesenchymal transition (EMT).We found in previous study that a radioresistant cell line (KYSE-150R) possessed EMT characteristic with cyclin D1 overexpression. Cyclin D1 has been demonstrated to affect the radiation sensitivity in cancer cells. To elucidate the molecular functions of cyclin D1 on EMT phenotypes and esophageal cancer radiosensitivity, we treated the radioresistant esophageal cancer cells (KYSE-150R) and parental cells (KYSE-150) with cyclin D1 small interfering RNA (siRNA). The cell proliferation rate of KYSE-150R and the radiation survival fraction were significantly decreased in cyclin D1 siRNA treatment group. Knocking down cyclin D1 resulted in G0/G1 arrest in KYSE-150R cells. The average number of irradiation-induced γ-H2AX foci increased in the cells treated with cyclin D1 siRNA, indicating impaired DNA double-strand break (DSB) repair in KYSE-150R cells. Cyclin D1 also reversed EMT phenotypes with significantly increased expression of E-cadherin in KYSE-150R cells. However, cyclin D1 siRNA have no radiosensitizing effects on KYSE-150 cells, with no obvious change in EMT marker expression .Our work showed that EMT phenotypes can be reduced and the radiosensitivity of esophageal cancer cells can be enhanced by inhibiting cyclin D1.

Background Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM. Methods A total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire. Results The average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable. Conclusions Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.