Search

363 Background: Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Recently, the combination of PD-(L)1 pathway blockade with chemotherapy has shown synergistic efficacy in a few clinical trials. SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. The purpose of this ongoing phase II trial (ChiCTR2000039909) was to evaluate the efficacy and safety of SHR-1701 combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled systemic treatment-naive patients(pts) with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who had ECOG PS of 0-1. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) combined with up to 6 cycles of albumin-bound paclitaxel (125mg/m2, iv, d1, d8, q3w) and cisplatin (75mg/m2, iv, d1, q3w). For those without progressive disease, maintenance treatment was administrated with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and biomarkers. Results: As of September 21, 2022, 18 pts were enrolled. The median age was 67.5 years (range: 46–75 years) and 16 (88.9%) were male. 10 of the pts (55.6%) presented with distant metastasis. 14 pts were included in the efficacy analysis and 17 were in the safety analysis. The ORR and DCR were 85.7% and 100.0%, respectively. One patient achieved a complete response (CR) which will reach confirmation at next visit. 11 pts had partial response (PR), including 9 confirmed PR, one pending confirmation PR, and one unconfirmed PR. In addition, one PR patient got a CR target lesion. Grade 3-4 treatment-related adverse events (AEs) were observed in 23.5% of pts, including neutropenia (11.8%), leukopenia (5.9%), anemia (5.9%), emesis (5.9%) and rash (5.9%). Immune-related AEs (irAEs) were observed in 52.9%, and only one grade 3 irAE of rash occurred. Conclusions: SHR-1701 plus chemotherapy showed potential clinical benefits with acceptable toxicity as first-line treatment, and it might be a favorable option for pts with advanced ESCC. Clinical trial information: ChiCTR2000039909 .

To investigate the dynamic change of amide proton transfer (APT) imaging before and after irradiation in nasopharyngeal carcinoma (NPC) and the underlying histopathological mechanism. Tumor-bearing BALB/C nude mouse models were established and randomly divided into three groups: high-dose group (20 Gy/2 fractions), low-dose group (10 Gy/2 fractions), and control group (0 Gy). MRI scanning was performed before irradiation and 3rd, 6th, and 9th day post-irradiation. Scanning sequence included T1 weighted, T2 weighted, and APT. HE staining and TUNEL immunofluorescence detection were performed to detect necrosis and apoptosis. After high-dose irradiation, the mean tumor APT values decreased significantly on the 3rd day and 6th day (from 3.83 before radiotherapy to 2.41%, P < 0.001, 3rd day; from 2.41 to 1.80%, P = 0.001, 6th day). For low-dose irradiation, the mean tumor APT values decreased slightly on the 3rd day and 6th day (from 3.52 to 3.13%, P = 0.109, 3rd day; from 3.13 to 3.05%, P = 0.64, 6th day). The mean APT values of nonirradiated tumor changed slightly. In contrast, the average volume of high-dose irradiated tumors did not decrease obviously until the 9th day post-irradiation (from 290 before radiotherapy to 208 mm3 on the 9th day). The low-dose irradiated tumors showed slow growth, and the nonirradiated tumors showed rapid growth. Subsequent HE staining and TUNEL staining showed obvious necrosis characteristics and higher proportion of positive apoptotic cell nucleus in high-dose irradiated tumors, but not nonirradiated tumors. The APT signal intensity decreased after irradiation, which is earlier than the change of tumor volume. What is more, the decrease of APT signal intensity is more significant in high-dose group. Histological analysis showed obvious apoptosis and necrosis histological characteristic in irradiated tumor, which may explain the decrease of APT signal intensity. These results indicate that APT imaging has the potential to serve as a reliable biomarker for response assessment in NPC.

Non-small cell lung cancer (NSCLC), which consists mainly of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), are the leading cause of cancer deaths worldwide. In this study, we performed a comprehensive analysis of the tumor microenvironmental and genetic factors to identify prognostic biomarkers for NSCLC. We evaluated the immune and stromal scores of patients with LUAD and LUSC using data from The Cancer Genome Atlas database with the ESTIMATE algorithm. Based on these scores, the differentially expressed genes were obtained and immune-related prognostic genes were identified. Functional analysis and protein-protein interaction network further revealed the immune-related biological processes in which these genes participated. Additionally, 22 subsets of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment were analyzed with the CIBERSORT algorithm. Finally, we validated these valuable genes using an independent cohort from the Gene Expression Omnibus database. The associations of the immune and stromal scores with patients' clinical characteristics and prognosis were positive in LUAD but negative in LUSC and the correlations of TIICs with clinical characteristics were clarified. Several differentially expressed genes were identified to be potential immune-related prognostic genes. This study comprehensively analyzed the tumor microenvironment and presented immune-related prognostic biomarkers for NSCLC.

Objective To obtain a better understanding of the prevalence and management of pain in patients undergoing radiotherapy for cancer in Shandong Province, China. Methods This cross-sectional study used a questionnaire during face-to-face interviews to collect data from physicians and patients regarding the recognition, prevalence and treatment of pain during the waiting period before commencement of radiotherapy and during the radiotherapy period. Physicians and patients were recruited from 10 tertiary Class A hospitals across Shandong Province, China. Results A total of 184 patients and 87 physicians were recruited to the study. During the waiting period, pain was reported by the physicians according to their experience to affect 26.0% of patients, which almost agreed with the patients’ data (36.5%; 160 of 438). During the radiotherapy period, there was a significant difference in the reported prevalence of pain during the radiotherapy period between the physicians’ data (23.0%) based on their experience and the patients’ data (84.1%; 169 of 201 patients). The majority of physicians (98.9%; 86 of 87) agreed to the use opioids for pain management and 90.8% (79 of 87) were satisfied with the analgesic effect, but more than half of the patients who received pain treatment reported inadequate analgesia. Conclusion There was a high incidence of cancer pain, but insufficient assessment, inadequate treatment and inadequate education about pain in both the waiting and radiotherapy periods.

Wenjing Yang, Yan Qu, Bingxu Tan, Yibin Jia, Nana Wang, Peng Hu*, Jianbo Wang* Department of Radiation, Qilu Hospital of Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: IκB kinase epsilon (IKBKE; IKKε), a member of the nuclear factor-κB kinase inhibitor family, is upregulated in several human cancers, including breast cancer, prostate cancer, and ovarian cancer. Esophageal squamous cell carcinoma (ESCC) is one of the most common and most aggressively malignant cancers with dismal prognosis. However, the state of IKBKE expression in ESCC is still unknown and its potential value remains unexplored.Patients and methods: IKBKE protein expression was evaluated by immunohistochemistry in 118 paraffin specimens of ESCC treated by curative surgery. All patients were regularly followed up by telephone over 3 years after surgery. The chi-square test, Kaplan–Meier method, and Cox proportional hazard regression model were used to analyze the relationship of IKBKE expression, clinicopathological characteristics, and prognostic value for ESCC.Results: IKBKE expression was 61.9% (73/118) in paraffin-embedded archived ESCC. Its expression was significantly associated with tumor differentiation grade (p=0.045) and advanced TNM (pathologic tumor node metastasis) stages (p=0.023). In univariate analysis, IKBKE expression was closely associated with decreased 3-year disease-free survival (HR 1.804, 95% CI 1.076–3.027; p=0.023) and overall survival (HR 2.118, 95% CI 1.189–3.773; p=0.009). Meanwhile, in multivariate analysis it was identified as an independent prognostic factor for 3-year disease-free survival (HR 1.777, 95% CI 1.034–3.054; p=0.037) and overall survival (HR 2.078, 95% CI 1.138–3.796; p=0.017).Conclusion: Our data indicated for the first time that IKKε expression is a highly recurrent event in ESCC and could play a pivotal role in the evaluation of prognosis. IKBKE upregulation is negatively associated with disease-free survival and overall survival. Therefore, IKBKE could serve as a prognostic variable and potential therapeutic target for this malignancy. Keywords: IKBKE, esophageal squamous cell carcinoma, biomarker, prognosis, immunohistochemistry&nbsp

// Pengxiang Chen 1 , Lihui Han 1 , Cong Wang 1 , Yibin Jia 1 , Qingxu Song 1 , Jianbo Wang 1 , Shanghui Guan 1 , Bingxu Tan 1 , Bowen Liu 1 , Wenqiao Jia 1 , Jianfeng Cui 2 , Wei Zhou 1 and Yufeng Cheng 1 1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China 2 Department of Urology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China Correspondence to: Yufeng Cheng, email: // Keywords : esophageal cancer, squamous cell carcinoma, serum lipids, prognosis Received : August 06, 2016 Accepted : January 06, 2017 Published : February 23, 2017 Abstract This study was to evaluate the prognostic significance of serum lipids in esophageal squamous cell carcinoma patients who underwent esophagectomy. Preoperative serum lipids were collected from 214 patients who were diagnosed with esophageal squamous cell carcinoma. All of the patients received esophagectomy in Qilu Hospital of Shandong University from January 2007 to December 2008. The records and data were analyzed retrospectively. We found that low total cholesterol (for T stage, p = 0.006; for TNM stage, p = 0.039) and low-density lipoprotein cholesterol (for T stage, p = 0.031; for TNM stage, p = 0.035) were associated with advanced T stage and TNM stage. Kaplan-Meier survival analysis indicated that low total cholesterol and low-density lipoprotein cholesterol were associated with shorter disease-free survival(for total cholesterol, p = 0.045; for low-density lipoprotein cholesterol, p < 0.001) and overall survival (for total cholesterol, p = 0.043; for low-density lipoprotein cholesterol, p < 0.001). Lower low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LHR) indicated poorer disease-free survival and overall survival (both p < 0.001). In the multivariate analysis, low-density lipoprotein cholesterol and LHR were independent prognostic factors for disease-free survival and overall survival. In conclusion, our study indicated that preoperative serum total cholesterol and low-density lipoprotein cholesterol are prognostic factors for esophageal squamous cell carcinoma patients who underwent esophagectomy. LHR can serve as a promising serum lipids-based prognostic indicator.

Abnormal paired box 9 (PAX9) expression is associated with tumorigenesis, cancer development, invasion and metastasis. The present study investigated the prognostic significance of PAX9 in esophageal squamous cell carcinoma (ESCC) and its role in predicting radiation sensitivity. A total of 52.8% (121/229) ESCC tissues were positive for PAX9. The 1-, 3- and 5-year disease-free survival (DFS) rates were 72.2, 35.2 and 5.6%, respectively, and the overall survival (OS) rates were and 86.1, 44.4, and 23.1%, respectively, in PAX9-positive tumors. In PAX9-negative tumors, the one-, three- and five-year DFS rates were 76.9, 47.9 and 24.0%, and the OS rates were 90.9, 57.9 and 38.8%, respectively. Univariate analysis revealed that PAX9, differentiation, T stage, lymph node metastasis, and tumor-node-metastasis stage were associated with OS. Multivariate analysis of DFS and OS revealed that the hazard ratios for PAX9 were 0.624 (95% CI: 0.472–0.869, P=0.004) and 0.673 (95% CI: 0.491–0.922, P=0.014), respectively. Patients that received adjuvant therapy exhibited significant differences in the 5-year DFS (P

// Xuan Chen 1 , Qingbao Li 2 , Cong Wang 1 , Wenzhe Xu 3 , Lihui Han 1 , Yuan Liu 1 , Bowen Liu 1 , Shanghui Guan 1 , Bingxu Tan 1 , Jianbo Wang 1 , Nana Wang 1 , Qingxu Song 1 , Yibin Jia 1 , Jianzhen Wang 1 , Linli Zhao 1 , Yufeng Cheng 1 1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China 2 Department of Cardiac Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, China 3 Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China Correspondence to: Yufeng Cheng, email: qiluchengyufeng@163.com Keywords: ESCC, IDH1, protein expression, diagnosis, prognosis Received: July 28, 2016 Accepted: November 09, 2016 Published: November 15, 2016 ABSTRACT We aimed to investigate the pattern of expression and clinical significance of isocitrate dehydrogenase 1(IDH1) in esophageal squamous cell carcinoma (ESCC). The IDH1 expression was determined by quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis using 38 pairs of frozen tissues. Enzyme-linked immunosorbent assay was employed to measure 67 pairs of serum samples from patients and their controls to evaluate its diagnostic value. Immunohistochemistry analysis of 111 formalin-fixed paraffin embedded tissue samples was conducted for explaining its prognostic value. After shRNA transfection, CCK8 and clonal efficiency assays were carried on for verifying the function of IDH1 in vitro . Increased expression at mRNA ( P < 0.001) and protein levels (immunohistochemistry: P < 0.001, Western blot analysis: P < 0.001) were observed. Similarly, the IDH1 expression in serum from patients with ESCC was significantly upregulated relative to that from healthy controls ( P < 0.001). Kaplan–Meier curve indicated that IDH1 upregulation predicted worse overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses identified IDH1 expression as an independent prognostic factor for OS and PFS. Furthermore, OD450 values and colony numbers were decreased in sh-IDH1 groups (all P < 0.05). In conclusion, IDH1 is upregulated in patients with ESCC and can be used as a good potential biomarker for diagnosis and prognosis.

The impact of yes-associated protein (YAP) on the prognosis of patients with esophageal squamous cell cancer (ESCC) and its mechanism of action has seldom been reported. In the present study, the role of YAP on the prognosis of patients with ESCC and the mechanism of action of YAP in promoting the progression of ESCC was investigated. Tumor tissue samples from patients with ESCC were collected and the level of YAP expression was detected using immunohistochemical staining. In addition, YAP was knocked-down in ESCC cell lines and the effects on cell migration and invasion were examined. The expression levels of vimentin, N-cadherin, and E-cadherin were further investigated to examine the association between YAP and epithelial-mesenchymal transition (EMT). Results showed that overexpression of YAP was associated with larger lymph node metastasis and poor disease-free survival and overall survival. Compared with patients in early stage ESCC, the association was more significant in patients with late stage ESCC. Univariate and multivariate analyses further indicated that YAP expression could be an independent prognostic factor for ESCC. Downregulation of YAP inhibited cell migration and invasion. Western blot analysis showed that when YAP was knocked down, expression levels of vimentin and N-cadherin were reduced, whereas that of E-cadherin was increased. In conclusion, the results indicates that YAP expression level could be a novel marker for predicting the prognosis of patients with ESCC, and YAP-promoted tumor migration and invasion might be through EMT in ESCC.

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]

The transforming growth factor-β (TGF-β) signaling pathway plays an important role in tumorigenesis by exerting either a tumor-suppressing or tumor-promoting effect. Long non-coding RNAs (lncRNAs), a newly discovered class of non-coding RNAs, have been widely studied in recent years and identified as crucial regulators of various biological processes, including cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Recent evidence, addressing the crosstalk between the TGF-β signaling pathway and lncRNAs in cancer, found that several members of the TGF-β pathway are targeted by lncRNAs, and the production of hundreds of lncRNAs is induced by TGF-β treatment. This review will summarize the latest progress on the investigation of TGF-β pathway and lncRNA network in regulating cancer development. Further study on the network would provide a better understanding of carcinogenesis and have potentials for the prevention and treatment of malignant diseases.

Hepatoma-derived growth factor (HDGF) is a novel jack-of-all-trades in cancer. Here we quantify the prognostic impact of this biomarker and assess how consistent is its expression in solid tumors. A comprehensive search strategy was used to search relevant literature updated on October 3, 2014 in PubMed, EMBASE and WEB of Science. Correlations between HDGF expression and clinicopathological features or cancer prognosis was analyzed. All pooled HRs or ORs were derived from random-effects models. Twenty-six studies, primarily in Eastern Asia, covering 2,803 patients were included in the analysis, all of them published during the past decade. We found that HDGF overexpression was significantly associated with overall survival (OS) (HROS=2.35, 95%CI=2.04-2.71, p

Background. RACK1 is known to be involved in tumor progression, and its prognostic value on many kinds of tumors has been identified. However, there are limited studies about the functional role of RACK1 in esophageal squamous cell carcinoma (ESCC). Patients and methods. RACK1 expression was examined in 100 ESCC tissue samples using immunohistochemistry staining. RACK1 was knocked-down in ESCC cell lines by shRNA. The effects on cell proliferation, invasion and migration were examined in ESCC cell lines and nude mouse model. Vimentin and E-cadherin were introduced to further study the association between RACK1 and EMT. Results. RACK1 expression was significantly associated with the tumor length (P = 0.012), diameter

N staging predicting esophageal cancer patient prognosis has been studied. Lymph node ratio, which is considered to show metastatic lymph node status more accurately, is found to have prognostic significance in several tumors. We investigated whether lymph node ratio (LNR) was associated with the prognosis of esophageal cancer in this study. Esophageal cancer patients who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were studied. A total of 209 cases were evaluated in this study. The median disease-free survival (DFS) of this cohort was 35.2 months, and 5-year DFS rate was 32.1%. The median overall survival (OS) was 46.4 months, and 5-year OS rate was 40.0%. Kaplan-Meier survival analysis revealed that patients with LNR higher than 0.2 had significantly poorer DFS (p 0.001) and OS (p 0.001) than those with LNR less than 0.2. In a multivariate analysis, LNR was found to be an independent prognostic factor for DFS (p = 0.008, HR 1.863, 95% CI 1.180-2.942) and OS (p = 0.025, HR 1.708, 95% CI 1.068-2.731). N stage (p = 0.028, HR 1.626, 95% CI 1.055-2.506) was also found to be an independent prognostic factors for OS. Subgroups analysis revealed significant difference in OS and DFS rates between different LNR categories within the same N stages (p 0.05) but not between different N stages within the same LNR category (p 0.05). LNR was recognized as an independent factor in both OS and DFS in esophageal cancer. Besides, LNR showed a better prognostic value than N stage for esophageal cancer.

Gastric cancer remains the second cause of cancer-related death worldwide. The aim of this study was to investigate the effects of shorter dinner-to-bed time, post-dinner walk, and obesity on gastric cardia adenocarcinoma (GCA) risk. The study subjects consisted of 146 GCA patients and 166 healthy controls roughly matched by gender and age. Conditional logistic regression was used to calculated odds ratio (OR) and 95 % confidence intervals (CIs). The adjusted ORs of GCA for subjects with shorter dinner-to-bed time were 4.18 (95 % CI 2.10–8.33) compared with those with longer dinner-to-bed time. What is more, when reflux symptom was added into the multivariate models, risk estimate for shorter dinner-to-bed time decreased greatly, but still remained statistically significant (p = 0.007). Post-dinner walk was associated with a significantly decreased GCA risk (adjusted OR 0.54; 95 % CI 0.31–0.94). When subjects were analyzed according to post-dinner walk, the adjusted OR of GCA for shorter dinner-to-bed time relative to longer dinner-to-bed time was much higher for non-walking subjects (adjusted OR 20.21) than walking subjects (adjusted OR 1.39). We further found a significant interaction between shorter dinner-to-bed time and post-dinner walk regarding the risk of GCA (adjusted OR 0.07; p = 0.001). We found that shorter dinner-to-bed time was associated with significantly increased GCA risk, partly depending on reflux symptoms, while post-dinner walk was related to a significantly decreased GCA risk and could greatly attenuate the GCA risk attributable to shorter dinner-to-bed time.

Esophageal squamous cell carcinoma (ESCC) remains a significant cause of morbidity and mortality worldwide. The aim of the study was to investigate the effects of shorter dinner-to-bed time and post-dinner walk on ESCC risk. A matched case–control study with 232 ESCC patients and 286 age- and gender-matched healthy controls enrolled was conducted. Conditional logistic regression was used to calculated odds ratio (OR) and 95 % confidence intervals (95 % CI). The adjusted ORs of ESCC for subjects with shorter dinner-to-bed time (

Recent studies have identified loss of stromal caveolin-1 (Cav-1) expression as a new prognostic histological characteristic in various types of human cancers. However, the clinical and pathological significance of stromal Cav-1 expression in esophageal squamous cell carcinoma (ESCC) remains largely unknown. We examined Cav-1 expression in both tumor and stromal cells in ESCC tissue by immunohistochemical analysis to evaluate its clinicopathological significance and prognostic value. A total of 110 patients with ESCC who underwent surgical resection were included in this study. The expression of Cav-1 in both tumor and stromal cells in esophageal tumor tissues was examined immunohistochemically. Cav-1 expression was found in the cytoplasm of both tumor and stromal cells. Tumor Cav-1 overexpression was observed in 37.3 % tumors, which correlated to deeper tumor invasion (p = 0.038). Down-regulation of stromal Cav-1 expression was observed in 40.9 % tumors. The stromal Cav-1 down-regulation group had more lymph node metastases and more locoregional recurrences than those with higher expression (p = 0.020 and p = 0.002, respectively). In addition, down-regulation of stromal Cav-1 expression was associated with shorter disease-free survival (p

Objective: The correlation between high body mass index and outcomes after esophagectomy has not been systematically addressed. Some studies have shown that patients with a high body mass index had better overall survival and disease-free survival compared with those with a normal/low body mass index, whereas others have shown that the body mass index was not of prognostic value. Methods: Ninety-nine patients with esophageal squamous cell carcinoma were retrospectively reviewed in this study. Patients’ postoperative overall and disease-free survivals were compared between the two groups (body mass index ,24.00 kg/m 2 and body mass index 24.00 kg/m 2 ). Results: There were 66 patients in the low/normal body mass index group (body mass index ,24.00 kg/m 2 ) and 28 patients in the high body mass index group (body mass index 24.00 kg/m 2 ). Although disease recurrence were more frequent in the high body mass index group vs. the low/normal body mass index group, there was no significant difference noted (60.7%, 40.9%, P ¼ 0.078). The 3-year overall survival rates were 60.6% in the low/ normal body mass index group and 57.1% in the high body mass index group (P ¼ 0.392). The 3-year disease-free survival rates were higher in the low/normal body mass index group vs. the high body mass index group (56.1%, 39.3%, P ¼ 0.048). On multivariate analysis, the number of lymph node metastases (hazard ratio: 1.192, 95% confidence interval: 1.076‐1.320, P ¼ 0.001) was recognized as an independent prognostic factor for overall survival. Both body weight loss (hazard ratio: 2.153, 95% confidence interval: 1.027‐4.511, P ¼ 0.042) and the number of lymph node metastases (hazard ratio: 1.669, 95% confidence interval: 1.297‐ 2.146, P , 0.001) were significantly and independently associated with disease-free survival. Conclusions: Our results suggest that high body mass index appears to shorten disease-free survival in esophageal squamous cell carcinoma patients and further studies are needed to detect the mechanism.

We aimed to examine Notch2 expression in oesophageal squamous cell carcinoma (ESCC) patients and to evaluate its prognostic potential. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were utilized to investigate the Notch2 expression status and prognostic value. Furtherly, CCK8 and clonogenic assays were conducted to determine if Notch2 inhibition by shRNA could lead to a decrease in the proliferation and survival of ESCC cells. A notably higher Notch2 expression level was found in ESCC tissues at the mRNA (P P = 0.004; western blot: P = 0.021). Log-rank analysis demonstrated that Notch2 overexpression was significantly associated with worse overall survival (OS) (29.1% vs. 49.1%; P = 0.013) and progression-free survival (PFS) (15.3% vs. 34.4%; P = 0.006) rates in ESCC patients. The multivariate analysis revealed Notch2 as an independent prognostic factor for OS and PFS (P = 0.002 and 0.006, resp.). Besides, in vitro assays showed that OD450 values and colony formations were significantly reduced in Notch2-shRNA group (all P

We aimed to value the diagnostic potential of serum miR-1297 in esophageal squamous cell cancer (ESCC). Its expression level was detected in 156 pairs of patients with ESCC and healthy volunteers using quantitative real-time polymerase chain reaction (qRT-PCR) method. It was statistically decreased in ESCC patients compared with healthy controls. AUC based on serum miR-1297 was 0.840 ± 0.035 in discovery group and 0.837 ± 0.034 in validation group. Further analysis on early-stage patients revealed that the AUC was 0.819 ± 0.053 in discovery group and 0.814 ± 0.044 in validation group. Its sensitivity and specificity were promising. In conclusion, serum miR-1297 can serve as an ideal indicator for the diagnosis of ESCC.

This retrospective study was designed to estimate the efficacy and toxicity of definitive radiotherapy with concurrent or sequential docetaxel/S-1 for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Of the 62 eligible patients enrolled in this study during January 1, 2010 to December 31, 2014 from Qilu Hospital, Shandong University, Shandong Province, 39 patients received 3 cycles of docetaxel/S-1 during and after radiotherapy (concurrent chemoradiotherapy, CCRT), and 23 patients had radiotherapy followed by 3 cycles of docetaxel and S-1 (sequential chemoradiotherapy, SCRT). The CR of CCRT and SCRT groups were 48.72 and 21.74 %, respectively (p = 0.035). The median progress-free survival (PFS) of CCRT group (23.5 months) was significantly higher than SCRT group (11.7 months; p = 0.004). The median overall survival (OS) of CCRT group (33.5 months) also was significantly higher than SCRT group (24.0 months; p = 0.004). At 2 years, in this patient population, the rate of PFS of CCRT group was (44.2 ± 8.2 %), significantly higher than SCRT group (11.9 ± 9.6 %; p = 0.002). The 2-year OS rate of CCRT (68.6 ± 7.5 %) was significantly higher than SCRT group as well (42.0 ± 14.0 %; p = 0.002). The incidence of adverse events was higher in CCRT than SCRT group. No grade 4 or grade 5 adverse events occurred in our study. Definitive radiotherapy with concurrent or sequential docetaxel and S-1 for inoperable locally advanced ESCC was very well tolerated and remarkably active. In both CCRT and SCRT groups, acute toxicities were manageable. This regimen holds promises for treatment of esophageal carcinoma and warrants further investigation.

MicroRNA-613 (miR-613) plays important roles in tumorigenesis and cancer progression. We aimed to evaluate its expression level and potential for diagnosis and prognosis in esophageal squamous cell cancer (ESCC). We examined miR-613 expression in 60 pairs of ESCC cancerous and matched paracancerous tissues, serum samples from 75 ESCC patients and 75 healthy volunteers, and 105 formalin-fixed paraffin-embedded (FFPE) tissue samples using quantitative reverse transcription polymerase chain reaction. Receiver-operating characteristic (ROC) curve analysis, Kaplan-Meier method, and Cox regression were applied to analyze its diagnostic and prognostic value. MiR-613 was significantly decreased in ESCC tissue compared with paracancerous tissue (P < 0.001). Moreover, the expression level of miR-613 was significantly reduced with increased T stage of ESCC. Statistically significant difference between ESCC patients and healthy controls in expression level of miR-613 (0.89 ± 0.73 vs. 1.71 ± 1.03, P < 0.001) was found. The area under the ROC curve (AUC) based on serum miR-613 was 0.767 ± 0.040. We also performed analysis on early-stage patients and revealed that the AUC value was 0.728 ± 0.052 (P < 0.001). The Kaplan-Meier curve revealed that the downregulation of miR-613 was related to worse overall survival (OS) and progression-free survival (PFS) of ESCC patients (P = 0.018 and P = 0.035, respectively). Furthermore, the multivariate analysis identified miR-613 to be an independent prognostic factor for OS and PFS (P = 0.031 and P = 0.006, respectively) In conclusion, miR-613 is significantly reduced in cancerous tissue and serum samples of ESCC patients. It can serve as an ideal indicator for the diagnosis and prognosis of ESCC.

Background: Smoking is well-known as a risk factor for esophageal squamous cell carcinoma. However, little is known about the effect of this factor on survival. Methods: Esophageal cancer patients who underwent esophagectomy without any preoperative therapy were retrospectively reviewed. Patients’ postoperative overall and disease-free survivals were compared between 2 groups (non-heavy smokers and heavy smokers). Results: A total of 109 cases were evaluated in this study. The 5-year OS rate of the non-heavy smokers was 53.2% and 32.3% for the heavy group. The 5-year DFS rate of the non-heavy smokers was 51.1% and 27.4% for the heavy group. Kaplan-Meier survival analysis revealed that heavy smokers had significantly poorer OS (P=0.018) and DFS (P=0.009) than non-heavy smokers. In multivariate analysis, smoking was found to be an independent prognostic factor for OS (P=0.003; HR: 2.186; 95% CI: 1.309-3.650) and DFS (P=0.001; HR: 2.471; 95% CI: 1.467-4.163). Conclusion: Smoking was associated with survival among patients with ESCC, and it was recognized as an independent factor in both OS and DFS.

Background Socioeconomic status (SES) has been focused on as a key determinant of the incidence of cancer, cancer stage at diagnosis as well as treatment choices in western countries. However, to the authors’ knowledge, little work has been done concerning the relationship of SES and esophageal cancer in China. Methods Patients diagnosed with primary esophageal cancer from January to December 2007 in Qilu hospital were included. Socioeconomic status was determined by a questionnaire including religion, years of schooling and high education, place of residence, occupation, annual household income, and insurance. Results A total of 238 cases were collected in this study. Linear-by-linear association testing revealed that health-care delay was significantly associated with SES (P = 0.009). Multivariable logistic regression analysis revealed that increased health-care delay (>2 months) was more frequently observed in patients with lower SES (OR 2.271; 95% CI 1.069–4.853). Patients diagnosed at TNM I and II were more frequently in higher SES groups (P = 0.017). The association test was statistically significant for undergoing surgical resection only (P = 0.015) and chemotherapy (P = 0.015). Multivariable logistic regression analysis revealed that surgical resection only was less performed in higher SES group compared with lower SES group (OR 0.372; 95% CI 0.188–0.734). For chemotherapy, higher SES patients had a three-fold higher likelihood compared with lower SES group (OR 3.042; 95% CI 1.335–6.928). Conclusion Socioeconomic status was found to be associated with health-care delay, tumor stage and treatment modalities in esophageal cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0579-9) contains supplementary material, which is available to authorized users.

Background Patients with malignant disease frequently present with activated coagulation pathways, which are potentially associated with tumor progression and prognosis. The aims of the study were to investigate the clinical significance of preoperative plasma fibrinogen level and platelet count in esophageal squamous cell carcinoma (ESCC) treated by curative surgery. Methods A total of 119 patients with ESCC treated by curative surgery in Qilu Hospital of Shandong University were included in the study. Results The preoperative plasma fibrinogen levels in the patients with ESCC ranged from 2.2 to 6.91 g/L (mean ± SD, 3.85 ± 0.95 g/L). The incidence of hyperfibrinogenemia was 43.7% (52/119, cut-off value 4.0 g/L). Hyperfibrinogenemia was found to be positively correlated with increased tumor length (P = 0.027), increased depth of invasion (P = 0.013), advanced pathological stages (P = 0.011), and disease recurrence (P = 0.026). The platelet counts ranged from 78 × 109/L to 936 × 109/L (mean ± SD, 254.51 ± 89.26 × 109/L). The incidence of thrombocytosis was 20.2% (24/119, cut-off value 300 × 109/L). Thrombocytosis was more frequently seen in male gender (P = 0.029) and non-smokers (P = 0.008). Plasma fibrinogen levels were significantly correlated with platelet counts (r = 0.018, P = 0.048). Hyperfibrinogenemia was significantly associated with poor disease-free (P = 0.009, hazard ratio (HR) = 1.784, 95% confidence interval (CI) = 1.153 to 2.761) and overall (P = 0.003, HR = 1.992, 95% CI = 1.259 to 3.152) survivals in univariate analysis, but not an independent prognostic indicator in multivariate analysis. Thrombocytosis was not significantly associated with disease-free (P = 0.765, HR = 0.918, 95% CI = 0.524 to 1.608) or overall (P = 0.809, HR = 1.072, 95% CI = 0.618 to 1.891) survivals in univariate analysis. Conclusions The study suggested that hyperfibrinogenemia is a valuable predictor for disease progression in ESCC. Anticoagulation therapy might be considered to control cancer progression in future studies.

Zhenyu Shao,1 Jingyu Shao,2 Bingxu Tan,1 Shanghui Guan,1 Zhulong Liu,1 Zengjun Zhao,1 Fangfang He,1 Jian Zhao3 1Department of Radiotherapy, Cancer Centre, Qilu Hospital, Shandong University, Ji’nan, Shandong, People’s Republic of China; 2Affiliated Hospital of Northwest Institute of Mechanical and Electrical Engineering, Xianyang, Shaanxi, People’s Republic of China; 3Department of Thoracic Surgery, Qilu Hospital, Shandong University, Ji’nan, Shandong, People’s Republic of China Purpose: Nanostructured lipid carriers (NLC) represent an improved generation of lipid nanoparticles. They have specific nanostructures to accommodate drugs/genes, and thus achieve higher loading capacity. The aim of this study was to develop transferrin (Tf)-decorated NLC as multifunctional nanomedicine for co-delivery of paclitaxel (PTX) and enhanced green fluorescence protein plasmid.Methods: Firstly, Tf-conjugated ligands were synthesized. Secondly, PTX- and DNA-loaded NLC (PTX-DNA-NLC) was prepared. Finally, Tf-containing ligands were used for the surface decoration of NLC. Their average size, zeta potential, drug, and gene loading were evaluated. Human non-small cell lung carcinoma cell line (NCl-H460 cells) was used for the testing of in vitro transfection efficiency, and in vivo transfection efficiency of NLC was evaluated on mice bearing NCl-H460 cells.Results: Tf-decorated PTX and DNA co-encapsulated NLC (Tf-PTX-DNA-NLC) were nano-sized particles with positive zeta potential. Tf-PTX-DNA-NLC displayed low cytotoxicity, high gene transfection efficiency, and enhanced antitumor activity in vitro and in vivo.Conclusion: The results demonstrated that Tf-PTX-DNA-NLC can achieve impressive antitumor activity and gene transfection efficiency. Tf decoration also enhanced the active targeting ability of the carriers to NCl-H460 cells. The novel drug and gene delivery system offers a promising strategy for the treatment of lung cancer. Keywords: co-delivery, nanostructured lipid carriers, transferrin decoration, active targeting systems, paclitaxel

Table S3. Multivariable logistic regression analysis of between SES and health-care delay.

Table S6. Linear-by linear association between TNM stage and treatment modalities.

Table S5. Multivariable logistic regression analysis of between SES and treatment modalities.

Table S2. Linear-by linear association between SES and health-care delay/tumor stage /treatment.

Table S4. Multivariable logistic regression analysis of between SES and tumor stage.

Table S1. Patient characteristics.

Objective: Cancer-associated fibroblasts (CAFs; α-SMA positivity), as a representative of the tumor microenvironment, play an important role in influencing the proliferation, invasion and metastasis of cancer cells. The objective is to investigate the prognostic value of CAFs density in esophageal squamous cell carcinoma (ESCC) after surgery. Method: A total of 95 patients who underwent esophagectomy for ESCC in 2007 were included in this study. These specimens were immunostained with α-smooth muscle actin (α-SMA) antibodies to quantify CAFs. Antibodies D2-40 and CD34 were used to evaluate the lymphatic vessel density (LVD) and microvessel density (MVD) of the lesions. The Cox proportional hazards model was used to determine the hazard ratio of CAFs density on 3-year overall survival and 3-year disease-free survival. The correlation between CAFs density and lymphatic vessel density (LVD) or microvessel density (MVD) were analyzed. Results: 3-year overall survival rate in the CAF-poor group (63%) was significantly better than those in the CAF-rich group (42%) (P < 0.01). In the Cox univariate and multivariate analysis of 3-year overall survival, the hazard ratio (HR) of CAFs density was 1.870 (95% CI 1.033-3.385; P = 0.039) and 2.196 (95% CI 1.150-4.193; P = 0.017), respectively. CAFs density was proved to be an independent prognostic factor for 3-year overall survival. CAFs density correlated significantly with increased LVD and MVD in ESCC. Conclusion: CAFs density may be a marker for predicting prognosis and guiding therapeutic management of ESCC.

Backgroud and aim: Podoplanin (D2-40) is a specific marker for lymphatic endothelium. The vast majority of previous studies on podoplanin immunostaining in esophageal squamous cell carcinoma (ESCC) focused on identifying lymphatic vessel invasion (LVI) and counting lymphatic vessel density (LVD) and had contradictory results. Recent studies show podoplanin expression on cancer cells or tumor stroma in several cancers, which have specific significance; but the status in ESCC remains unclear. Therefore, the aim of this study was to further study and summarize the clinicopathological significance of podoplanin immunoreactivity in ESCC. Materials and methods: We examined podoplanin expression in tissue specimens from 107 patients with ESCC by immunohistochemistry. Podoplanin positive lymphatic vessels in intratumoral and peritumoral tissues and podoplanin positive expression in cancer cells and tumor stroma were analyzed, and correlated with clinicopathologic parameters and three-year overall and free-disease survival. Results: 34 (31.8%) and 28 (26.2%) of 107 specimens had podoplanin positive expression in cancer cells and tumor stroma, respectively. Logistic regression analysis showed high intratumoral lymphatic vessel density (I-LVD) and podoplanin positivity in cancer cells were increased risks of lymph node metastasis (LNM) (OR = 2.45, P = 0.03; OR = 0.35, P = 0.01, respectively). Survival analysis showed that I-LVD was a significant factor related to poor three-year overall and free-disease survival (P = 0.04, P = 0.03, respectively). Conclusions: Previous data and our results show that podoplanin seems to be a useful marker to predict LNM, recurrence, and worse prognosis in ESCC; in particular, LVI, high I-LVD, and podoplanin positivity in cancer cells are associated with LNM, recurrence and overall survival.

MicroRNAs (miRNAs) are small non-coding RNA molecules, which act as post-transcriptional regulators of gene expression and have been implicated in initiation, progression and treatment outcome of diverse cancers. Single nucleotide polymorphisms (SNPs), as the most common type of genetic variation, also exist in miRNA genes and can lead to alteration in miRNA expression resulting in diverse functional consequences. Emerging studies have evaluated the association of miRNA SNPs with cancer risk, but the results remain inconclusive. To assess the relationship between miRNA SNPs and cancer risk, we performed a meta-analysis of 18 studies involving 20660 subjects for miR-146a rs2910164 polymorphism and 21 studies involving 26,018 subjects for miR-196a2 rs11614913 polymorphism. As for rs2910164, no significant association of cancer risk was found in the overall analysis. In subgroup analysis by cancer type, ethnicity, source of controls and sample size, significant association of cancer risk was mainly found in papillary thyroid carcinoma, primary liver cancer, cervical cancer, Caucasian population and small sample size studies. For rs11614913, significant results were found in all the tested genetic models and T allele or its carriers were associated with decreased cancer risk in overall analysis (T vs. C: OR = 0.888, 95% CI 0.84-0.938; TT+TC vs. CC: OR = 0.897, 95% CI 0.828-0.971). In stratified analysis by cancer type and ethnicity, significant association of cancer risk was observed in breast cancer, lung cancer, colorectal cancer and Asian population, but not in Caucasian population. During further stratified analysis by source of controls and sample size, results similar to those of overall analysis were found in all of the subgroups. Taken together, our results indicated that miR-196a2 rs11614913 T variant probably contribute to decreased susceptibility to cancer. However, limited evidence was found for association of miR-146a rs2910164 with cancer risk, and further well-designed studies with large sample size will be necessary to validate the effect of miR-146a rs2910164 on cancer susceptibility.

Objective:Tumor-stroma ratio (TSR) has been identified as a new and practicable prognostic histological characteristic of solid tumors. The aim of this study was to evaluate the prognostic value of TSR in resected esophageal squamous cell carcinoma (ESCC).Methods:A total of 95 patients who underwent esophagectomy for ESCC were included in this study. TSR was assessed visually on the hematoxylin-eosin–stained tissue sections of surgical specimens by two independent observers. Patients with more than 50% intratumor stroma were quantified as the stroma-rich group and those with less than 50% as the stroma-poor group.Results:No significant differences were observed in patient, tumor, and treatment characteristics between the stroma-rich and stroma-poor groups. The 3-year overall survival and disease-free survival rates were 64% and 57%, respectively, in the stroma-poor group, and 23% and 23%, respectively, in the stroma-rich group. Both 3-year overall and disease-free survival rates in the stroma-poor group were significantly better than those in the stroma-rich group (p < 0.01). In a multivariate analysis, TSR was identified as a highly significant prognostic factor for 3-year overall survival (hazard ratio 3.450; p = 0.001) and 3-year disease-free survival (hazard ratio 2.995; p = 0.001), independent of pTNM stage and radicality of the primary tumor.Conclusion:Stroma-rich tumors were associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic histological characteristic in ESCC. TSR is simple and quick to determine, is reproducible, and could be easily incorporated in routine histological evaluation.

Background The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The main aims of the study were to investigate the clinical significance of tumor-infiltrating neutrophils and neturophil-to-CD8+ lymphocyte ratio (NLR), and to analyze the distribution of tumor-infiltrating neutrophils and CD8+ lymphocytes in ESCC treated by curative resection. Methods The expressions of CD66b and CD8 were assessed with double staining immunohistochemistry in the surgical specimens from 90 patients with ESCC treated by curative surgery. Results We showed that increased intratumoral neutrophils were significantly associated with lymph node metastasis (P = 0.016), and advanced pathological stages (P = 0.013). Decreased peritumoral CD8+ lymphocyte density was more frequently observed in patients with single positive lymph node (p = 0.045). Peritumoral NLR was significantly associated with advanced T stages (p Conclusions Increased intratumoral neutrophils were an independent poor prognostic factor and peritumoral NLR was significantly associated with disease progression in ESCC treated by curative surgery, suggesting the possible effect of immune misbalance of tumor microenvironment in facilitating ESCC progression. Immunotherapy targeted to the above predictors should be considered in the future.