Nimotuzumab plus concurrent chemo-radiotherapy in unresectable locally advanced oesophageal squamous cell carcinoma (ESCC): interim analysis from a Phase 3 clinical trial.

BACKGROUND: This prospectively randomised, double-blinded, placebo-controlled, multicenter Phase 3 clinical trial was conducted to assess the efficacy and safety profile of nimotuzumab (nimo) plus concurrent chemo-radiotherapy (CCRT) in patients with unresectable locally advanced ESCC. METHODS: Patients were randomly assigned (1:1) to receive CCRT plus nimotuzumab or placebo. The primary endpoint was overall survival (OS). In addition, interim analysis for short-term response rate was pre-defined. RESULTS: A total of 201 patients were randomised into two groups. Eighty patients in the nimo group and eighty-two in the placebo group were evaluable. Three to six months after treatment, 26 (32.5%) patients achieved complete response (CR) in the nimo group, and 10 (12.2%) in the placebo group (P = 0.002). The ORR of the nimo group was significantly higher than the placebo group (93.8% vs. 72.0%, P < 0.001). The two groups' grade 3-5 adverse drug reactions were 11.1% vs. 10.9% (P > 0.05). CONCLUSIONS: Nimotuzumab, in combination with chemo-radiotherapy, increased the CRR and ORR with a good safety profile. The OS is needed to be followed and finally analysed. CLINICAL TRIAL REGISTRATION: NCT02409186.

Comparison of concurrent chemoradiotherapy with radiotherapy alone for locally advanced esophageal squamous cell cancer in elderly patients: A randomized, multicenter, phase II clinical trial.

This randomized, multicenter, phase II clinical trial was performed to compare the safety and efficacy of concurrent chemoradiotherapy using S-1 (CCRT) with radiotherapy alone (RT) for elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). All eligible patients were randomly assigned to the CCRT group or the RT group at a 1:1 ratio. The CCRT group received 50.4 Gy radiotherapy concurrent with S-1 and the RT group received 59.4 Gy radiotherapy alone. The primary endpoints were toxicity and the overall response rate (ORR), and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). In total, 157 elderly patients with ESCC were recruited from December 2016 to March 2020. By June 2021, the median follow-up duration had reached 38 months. No grade 5 toxicities occurred in either group and the overall rate of severe toxicities (≥grade 3) was higher in the CCRT group (19.2% vs 7.6%; P = .037), particularly neutropenia (7.7% vs 1.3%; P = .06). The CCRT group presented a significantly higher ORR (83.3% vs 68.4%; P = .009) and prolonged PFS (25.7 vs 13.9 months; P = .026) than the RT group. The median OS was 27.3 months in the CCRT group and 19.1 months in the RT group (P = .59). For patients older than 70 years with locally advanced ESCC, concurrent chemoradiotherapy with S-1 had tolerable adverse effects and improved ORR and PFS compared to radiotherapy alone.

Identification of crucial long non-coding RNAs and mRNAs along with related regulatory networks through microarray analysis in esophageal carcinoma.

Esophageal carcinoma (EC) is a tremendous threat to human health and life worldwide. Long non-coding RNAs (lncRNAs) have been identified as crucial players in carcinomas including EC. An in-depth understanding on regulatory networks of lncRNAs contributes to the better management of EC. In this text, 2052 lncRNAs and 3240 mRNAs were found to be differentially expressed in 5 EC tumor tissues versus adjacent normal tissues by microarray analysis. Moreover, 297 carcinoma-related genes were screened out according to pathway and disease annotation analyses. In addition, 410 potential lncRNA-mRNA cis-regulation pairs and 395 lncRNA-mRNA trans-regulation pairs were screened out. Among these genes, 14 trans-regulated and 19 cis-regulated genes were found to be related with carcinomas. Additionally, 42 possible lncRNA-mRNA trans-regulation pairs and 26 cis-regulation pairs were found to be related with carcinomas. Also, 4 differentially expressed transcription factors in EC and lncRNAs possibly regulated by these transcription factors were screened out. Moreover, plenty of common upregulated or downregulated lncRNAs and mRNAs in EC were identified by comparative analysis for our microarray outcomes and previous high-throughput data. Furthermore, we demonstrated that ENST00000437781.1 knockdown inhibited cell proliferation and facilitated cell apoptosis by downregulating SIX homeobox 4 (SIX4) and ENST00000524987.1 knockdown had no influence on anoctamin 1 calcium activated chloride channel (ANO1) expression in EC cells. In conclusion, we identified some crucial lncRNAs and genes along with potential regulatory networks of lncRNAs/genes, deepening our understanding on pathogenesis of EC.

Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial.

BACKGROUND: To report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC). METHODS: Patients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib. CONCLUSIONS: Concurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC. CLINICAL TRIAL REGISTRATION: Trial registration: NCT00686114.

NR2F1-induced NR2F1-AS1 promotes esophageal squamous cell carcinoma progression via activating Hedgehog signaling pathway.

Emerging evidence has uncovered the extremely important roles of long noncoding RNAs (lncRNAs) in the progression of malignant tumors which includes numerous processes of gene regulation. LncRNA NR2F1-AS1 has been confirmed to have close correlation with the tumorigenesis of diverse cancers. However, the underlying regulatory function of it on esophageal squamous cell carcinoma (ESCC) progression is poorly known and thus needs more elucidations. In this study, a markedly elevated expression of NR2F1-AS1 was discovered in ESCC cells. Functional assays demonstrated that NR2F1-AS1 deficiency repressed ESCC progression. Molecular mechanism tests verified that knockdown of NR2F1-AS1 could lower the expression of GLI2 (a key protein molecule of Hedgehog signaling pathway) in ESCC. Additionally, NR2F1-AS1 was confirmed to facilitate ESCC progression via activation of Hedgehog signaling pathway. NR2F1-AS1 activated Hedgehog signaling pathway by regulating GLI2 to upregulate NR2F1 expression in ESCC. Besides, NR2F1 was testified to activate NR2F1-AS1 transcription in ESCC. Final rescue assays further demonstrated that NR2F1 upregulation could reverse the NR2F1-AS1 knockdown-mediated function on ESCC progression. Briefly, NR2F1-induced NR2F1-AS1 promotes ESCC progression through activation of Hedgehog signaling pathway.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Development and Validation of a Nomogram for Predicting Overall Survival to Concurrent Chemoradiotherapy in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma.

This study aims to develop and validate a effective prognostic nomogram for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients undergoing concurrent chemoradiotherapy (CCRT). Retrospective analysis of 503 patients with LA-ESCC given CCRT in our hospital from 2009 to 2016 was conducted. Two-thirds of the patients were randomly assigned to the training set (n = 335), and one-third were assigned to the validation set (n = 168). In order to generate the nomogram, multivariate cox regression analysis was undertaken in the training set for uncovering significant prognostic variables for overall survival. The C-index and calibration plot were used to verify nomogram discrimination and calibration, respectively. Five independent prognostic variables were found and incorporated into a nomogram: age, N stage, location, tumor response, and MLR (monocyte/lymphocyte ratio). The C-indexes of the training set and the validation set were 0.730 and 0.745, respectively. The discrimination and calibration of this nomogram showed good predictive power in both sets. Conclusively, the proposed nomogram may be served as an effective tool for prognostic evaluation of LA-ESCC patients receiving CCRT.

Real-World Efficacy and Safety of Sintilimab-Based Regimens against Advanced Esophageal Cancer: A Single-Center Retrospective Observational Study.

This study is aimed at assessing the sintilimab-based regimens' safety and efficacy for advanced esophageal cancer (EC) treatment in the real world. Cases of advanced EC treated with sintilimab-based regimens in the Anyang Tumor Hospital between 1 January 2020 and 1 August 2021 were retrospectively examined. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were evaluated. Among the 50 included patients, the median PFS was 11.3 months (95% CI: 5.0-17.6 months), and the 1-year PFS rate was 49.2%. The median OS was not reached, and the 1-year OS rate was 67.1%. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were seen in 14% (n = 7), 46% (n = 23), 32% (n = 16), and 8% (n = 4) of the 50 patients, respectively. Therefore, the ORR and DCR were 60% (30/50) and 92% (46/50), respectively. The CR rate of patients with radiotherapy was higher than that without radiotherapy (25% vs. 3.8%, P = 0.031). The 1-year OS rate was higher in patients with radiotherapy than in patients without radiotherapy (85.9% vs. 53.2%, P = 0.020). The most observed AEs included anemia, decrease in white blood cell count, nausea/vomiting, and hypoproteinemia. Sintilimab-based regimens achieved good disease control and tolerance for treating advanced EC in the real world. Combined radiotherapy can improve the efficacy and deserves further study.

Deep Learning for Automated Contouring of Gross Tumor Volumes in Esophageal Cancer.

Purpose: The aim of this study was to propose and evaluate a novel three-dimensional (3D) V-Net and two-dimensional (2D) U-Net mixed (VUMix-Net) architecture for a fully automatic and accurate gross tumor volume (GTV) in esophageal cancer (EC)-delineated contours. Methods: We collected the computed tomography (CT) scans of 215 EC patients. 3D V-Net, 2D U-Net, and VUMix-Net were developed and further applied simultaneously to delineate GTVs. The Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95HD) were used as quantitative metrics to evaluate the performance of the three models in ECs from different segments. The CT data of 20 patients were randomly selected as the ground truth (GT) masks, and the corresponding delineation results were generated by artificial intelligence (AI). Score differences between the two groups (GT versus AI) and the evaluation consistency were compared. Results: In all patients, there was a significant difference in the 2D DSCs from U-Net, V-Net, and VUMix-Net (p=0.01). In addition, VUMix-Net showed achieved better 3D-DSC and 95HD values. There was a significant difference among the 3D-DSC (mean ± STD) and 95HD values for upper-, middle-, and lower-segment EC (p<0.001), and the middle EC values were the best. In middle-segment EC, VUMix-Net achieved the highest 2D-DSC values (p<0.001) and lowest 95HD values (p=0.044). Conclusion: The new model (VUMix-Net) showed certain advantages in delineating the GTVs of EC. Additionally, it can generate the GTVs of EC that meet clinical requirements and have the same quality as human-generated contours. The system demonstrated the best performance for the ECs of the middle segment.

Comparative clinical studies of primary chemoradiotherapy versus S-1 and nedaplatin chemotherapy against stage IVb oesophageal squamous cell carcinoma: a multicentre open-label randomised controlled trial.

INTRODUCTION: Oesophageal squamous cell carcinoma (OSCC) is one of the most commonly occurring devastating tumours worldwide, including in China. To date, the standard care of patients with stage IV OSCC is systemic chemotherapy and palliative care, which results in poor prognosis. However, no consensus has been established regarding the role of radiotherapy in targeting the primary tumour in patients with stage IVa OSCC. Thus, the aim of this study is to assess the effectiveness of primary radiotherapy combined with S-1 and nedaplatin (NPD) chemotherapy in the patients with stage IV OSCC. METHODS AND ANALYSIS: The study is a multicentre, open-label, randomised controlled trial. A total of 180 eligible patients with stage IV OSCC will be randomised into a study group (90 patients) and a control group (90 patients). Patients in the study group will receive radiotherapy to the primary tumour at a dose of 50.4 Gy combined with 4-6 cycles of S-1 and NPD chemotherapy. In the control group, patients will only receive 4-6 cycles of S-1 and NPD chemotherapy. The primary and secondary outcomes will be measured. The differences between the two groups will be statistically analysed with regard to overall survival, the progression-free survival and safety. All outcomes will be ascertained before treatment, after treatment and after the follow-up period.The results of this study will provide evidence on the role of radiotherapy in patients with stage IV OSCC in China, which will show new options for patients with advanced oesophageal cancer. ETHICS AND DISSEMINATION: This study was approved by the Institutional Ethics Committee of The First Hospital Affiliated of Zhengzhou University (approval number: SS-2018-04). TRIAL REGISTRATION: The trial has been registered at the Chinese Clinical Trial Registry (ChiCTR1800015765) on 1 November 2018; retrospectively registered, http://www.chictr.org.cn/index.aspx.

Definition and risk factors of early recurrence based on affecting prognosis of esophageal squamous cell carcinoma patients after radical resection.

Early recurrence after surgery could affect cancerous patients' prognosis, but the definition of early recurrence and its risk factors for esophageal squamous cell carcinoma (ESCC) patients are still unclear. This study analyzed the clinical data of 468 post-surgery recurrent ESCC patients retrospectively. A minimum p-value approach was used to evaluate the optimal cut-off value of recurrence free survival (RFS) to define early recurrence. Risk factors of early recurrence were developed based on a Cox model. The optimal cut-off value of RFS to distinguish early recurrence was 21 months (p <0.001). Independent risk factors for early recurrence included tumor locations (HR=0.562, p <0.001), pathological T stage (HR=1.829, p <0.001), tumor diameter (HR=1.344, p = 0.039), positive lymph nodes (HR=1.361, p <0.001), and total resected lymph nodes (HR=1.271, p = 044). For the late recurrent patients, there was a much more significant survival advantage for recurrence after concurrent chemoradiotherapy than that after sequential chemoradiotherapy and radiotherapy alone (p = 0.0066). In conclusion, this study defined 21 months of RFS as early recurrence and also identified its risk factors. Concurrent chemoradiotherapy was suggested as preferred post-relapse treatment for late recurrent ESCC patients.

Dosimetric comparison of TomoDirect, helical tomotherapy, VMAT, and ff-IMRT for upper thoracic esophageal carcinoma.

BACKGROUND: The new TomoDirect (TD) modality offers a nonrotational option with discrete beam angles. We aim to compare dosimetric parameters of TD, helical tomotherapy (HT), volumetric-modulated arc therapy (VMAT), and fixed-field intensity-modulated radiotherapy (ff-IMRT) for upper thoracic esophageal carcinoma (EC). METHODS: Twenty patients with cT2-4N0-1M0 upper thoracic esophageal squamous cell carcinoma (ESCC) were enrolled. Four plans were generated using the same dose objectives for each patient: TD, HT, VMAT with a single arc, and ff-IMRT with 5 fields (5F). The prescribed doses were used to deliver 50.4 Gy/28F to the planning target volume (PTV50.4) and then provided a 9 Gy/5F boost to PTV59.4. Dose-volume histogram (DVH) statistics, dose uniformity, and dose homogeneity were analyzed to compare treatment plans. RESULTS: For PTV59.4, the D2, D98, Dmean, and V100% values in HT were significantly lower than other plans (all p < 0.05), and those in TD were significantly lower than VMAT and ff-IMRT (all p < 0.05). However, there was no significant difference in the D2 and Dmean values between VMAT and ff-IMRT techniques (p > 0.05). The homogeneity index (HI) differed significantly for the 4 techniques of TD, HT, VMAT, and ff-IMRT (0.03 ± 0.01, 0.02 ± 0.01, 0.06 ± 0.02, and 0.05 ± 0.01, respectively; p  < 0.001). The HI for TD was similar to HT (p = 0.166), and had statistically significant improvement compared to VMAT (p < 0.001) and ff-IMRT (p = 0.003). In comparison with the 4 conformity indices (CIs), there was no significant difference (p > 0.05). For PTV50.4, the D2 and Dmean values in HT were significantly lower than other plans (all p < 0.05), and those in TD were significantly lower than VMAT and ff-IMRT (all p < 0.05). However, there was no significant difference in the D2 and Dmean values between VMAT and ff-IMRT techniques (p > 0.05). No D98 and V100% parameters differed significantly among the 4 treatment types (p > 0.05). HT plans were provided for statistically significant improvement in HI (0.03 ± 0.01) compared to TD plans (0.05 ± 0.01, p = 0.003), VMAT (0.08 ± 0.03, p < 0.001), ff-IMRT (0.08 ± 0.01, p < 0.001). The HI revealed that TD was superior to VMAT and ff-IMRT (p < 0.05). The CI differed significantly for the 4 techniques of TD, HT, VMAT, and ff-IMRT (0.59 ± 0.10, 0.69 ± 0.11, 0.64 ± 0.09, and 0.64 ± 0.11, respectively; p = 0.035). The best CI was yielded by HT. We found no significant difference for the V5, V10, V15, V30, and the mean lung dose (MLD) among the 4 techniques (all p > 0.05). However, the V20 differed significantly among TD, HT, VMAT, and ff-IMRT (21.50 ± 7.20%, 19.50 ± 5.55%, 17.65 ± 5.45%, and 16.35 ± 5.70%, respectively; p = 0.047). Average V20 for the lungs was significantly improved by the TD plans compared to VMAT (p = 0.047), and ff-IMRT (p = 0.008). The V5 value of the lung in TD was 49.30 ± 13.01%, lower than other plans, but there was no significant difference (p > 0.05). The D1 of the spinal cord showed no significant difference among the 4 techniques (p = 0.056). CONCLUSIONS: All techniques are able to provide a homogeneous and highly conformal dose distribution. The TD technique is a good option for treating upper thoracic EC involvement. It could achieve optimal low dose to the lungs and spinal cord with acceptable PTV coverage. HT is a good option as it could achieve quality dose conformality and uniformity, while TD generated superior conformality.

Clinical significance of detecting circulating tumor cells in patients with esophageal squamous cell carcinoma by EpCAM­independent enrichment and immunostaining­fluorescence in situ hybridization.

Circulating tumor cells (CTCs) are tumor cells present in the bloodstream, which originate from tumor sites, and are ultimately responsible for metastasis or relapse in several types of cancer. However, to the best of our knowledge, only a few studies have investigated these extremely rare cells in esophageal squamous cell carcinoma (ESCC). In the present study, 63 patients with ESCC and 50 healthy donors were recruited, and the potential clinical significance of CTCs was assessed using subtraction enrichment and immunostaining­fluorescence in situ hybridization. Blood samples were collected at the following times: At first diagnosis, following neoadjuvant chemoradiotherapy, 24 h and 13 days post­surgery, and every 3 months during follow­up. Cytokeratin (CK)­positive and clustered CTCs only accounted for 1% of total CTCs detected, whereas most CTCs were CK­negative aneuploid cells. Patients with ESCC (n=63) had higher CTC counts compared with healthy donors (control group; n=50) (area under curve=0.807, median CTC count, 2 vs. 0). However, there was no statistical association between CTC counts and sex, age, pathological stage, tumor location, tumor depth or lymph node involvement (P>0.05). The association of tumor development with CTC status and other circulating biomarkers was monitored in patients for a further 2 years. The results revealed that a change in CTC counts between first diagnosis and 13 days post­surgery (ΔCTC) of ≥2/7.5 ml peripheral blood could be applied for predicting progression­free survival (hazard ratio, 3.922; 95% confidence interval, 0.907­16.951; P<0.05) in patients with ESCC. In conclusion, ΔCTC evaluation may be a promising indicator for predicting tumor prognosis and the clinical efficacy of treatment in patients with ESCC.

Systemic Inflammation Biomarkers Predict Survival in Patients of Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiotherapy - A Single Center Experience.

Background: Increasing evidence indicates a relationship between systemic inflammation and survival following treatment in various tumors. However, the correlation of systematic inflammation with survival after stereotactic ablative radiotherapy (SABR) in early stage non-small cell lung cancer (NSCLC) has not been well established. Patients and methods: We retrospectively analyzed patients with newly diagnosed early stage NSCLC treated with SABR in a single institution from 2011 to 2015. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte- monocyte ratio (LMR) were calculated as systemic inflammation biomarkers. Overall survival (OS) was the first end-point. Receiver operating characteristic (ROC) was used to determine cut-off points for OS. Univariate and multivariate Cox proportional hazards regression were used to investigate the potential factors associated with OS. Results: In the 63 patients who were eligible for analysis. The median follow up after SBRT was 29.5 months (range 8-67 months) while the 3-year OS was 74.2%. Based on ROC analysis, optimal cut-off values of NLR, PLR, and LMR were 2.06, 199.55 and 4.0, respectively. Significant survival benefit was found in the NLR ≤2.06 group (p=0.028), PLR≤199.55 group (p=0.001), and LMR˃4.0 group (p=0.046). Univariate analysis indicated that low NLR (p=0.011), low PLR (p=0.003), and high LMR (p=0.014) were correlated with improved survival. Multivariate analysis indicated that high PLR (p=0.033) and low LMR (p=0.046) were independent prognostic factors for poor survival. Conclusions: In patients of early stage NSCLC who received SABR, pretreatment NLR, PLR, and LMR could be considered useful prognostic indicators of OS. These metrics may provide reliable and convenient predictors to identify patients who would benefit from SABR.

Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer.

BACKGROUND: This randomised phase III study was conducted to investigate the efficacy of extended nodal irradiation (ENI) and/or erlotinib in inoperable oesophageal squamous cell cancer (ESCC). PATIENTS AND METHODS: Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to one of four treatment groups: group A, radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel 135 mg/m2 day 1 and cisplatin 20 mg/m2 days 1-3, every 4 weeks) plus erlotinib (150 mg per day during chemoradiotherapy); group B, radiotherapy adoption of ENI with two cycles of concurrent TP; group C, radiotherapy adoption of conventional field irradiation (CFI) with two cycles of concurrent TP plus erlotinib; group D, radiotherapy adoption of CFI with two cycles of concurrent TP. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 2-year overall survival rates of group A, B, C and D were 57.8%, 49.9%, 44.9% and 38.7%, respectively (P = 0.015). Group A significantly improved 2-year overall survival compared with group D. The ENI significantly improved overall survival in patients with inoperable ESCC (P = 0.014). The addition of erlotinib significantly decreased loco-regional recurrence (P = 0.042). Aside from rash and radiation oesophagitis, the incidence of grade 3 or greater toxicities did not differ among 4 groups. CONCLUSION: Chemoradiotherapy with ENI and erlotinib might represent a substantial improvement on the standard of care for inoperable ESCC. ENI alone should be adopted in concurrent chemoradiotherapy for ESCC patients.

Prognostic and predictive role of COX-2, XRCC1 and RASSF1 expression in patients with esophageal squamous cell carcinoma receiving radiotherapy.

Identification of biomarkers for predicting radiosensitivity would be useful for administering individualized radiotherapy (RT) to patients with esophageal cancer. The aim of the present study was to evaluate the association between cyclooxygenase-2 (COX-2), X-ray repair cross complementing group 1 (XRCC1), ras association domain family 1 (RASSF1) protein expression, clinicopathological characteristics, radiosensitivity and survival rate in 76 patients with esophageal squamous cell carcinoma (ESCC) who were treated with RT. Positive expression of COX-2, XRCC1 and RASSF1 was identified by immunohistochemistry in 81.6, 52.6 and 59.2% of ESCC cases, respectively. Negative COX-2 expression was associated with tumor (T) stage, node (N) stage, clinical stage and complete response (P<0.05), but not with gender, age, tumor location, differentiation degree, lesion length, progression-free survival (PFS) or overall survival (OS; P>0.05). XRCC1 expression was not associated with the clinicopathological features of ESCC, response to RT, PFS or OS. Positive RASSF1 expression was associated with the clinical stage, response to RT, PFS and OS (P<0.05), but not with gender, age, tumor location, T stage, N stage, differentiation degree or the lesion length (P>0.05). In the subgroup analysis, RASSF1 positive/XRCC1 negative expression was correlated with a longer median OS and PFS (P<0.05). Multivariate analyses revealed that the tumor response and RASSF1 expression were significant prognostic factors. Therefore, positive RASSF1 expression is associated with ESCC RT sensitivity, and may be a useful independent prognostic factor for ESCC.

Effects of nitrosation on the formation of cyanide in publicly owned treatment works secondary effluent.

Cyanide has been detected in the effluents of some publicly owned treatment works (POTWs) at levels exceeding the influent concentration. The presence of nitrite ion (NO2-) as a common constituent in domestic wastewater effluents may play an important role in the formation of cyanide through reaction with certain kinds of organic compounds, especially aromatic compounds. Laboratory studies with seven organic compounds (aniline. p-toluidine, phenol, 1,2,4-trihydroxybenzene, L-serine, glycine, and benzoic acid) revealed that cyanide can be formed by reaction of nitrite with some of these compounds. The most substantial free cyanide (HCN. CN-) production observed at 25 degrees C was 0.15 mg/L from reaction of 0.01 mM 1.2.4-trihydroxybenze with 5 mg/L nitrite for 72 hours. Substantial free cyanide formation was also observed at pH 2-4 in experiments with POTW effluents when reactive organics and nitrite were both added to wastewater. Formation of cyanide through nitrosation was strongly pH dependent, being most significant at low pH (2 to 4) and negligible at neutral-to-high pH. This result points to nitrous acid (HNO2) as being more reactive than the dissociated NO2- ion. The reaction of these nitrite species with organics also occurs in conventional analyses for total cyanide which involve distillation under strongly acidic conditions. Sufficient sample pretreatment with sulfamic acid at the time of sampling, not at the time of analysis. is highly recommended to prevent biasing analytical measurement of total cyanide in POTW effluents.

Effects of thiocyanate on the formation of free cyanide during chlorination and ultraviolet disinfection of publicly owned treatment works secondary effluent.

Cyanide has been detected in effluent of some publicly owned treatment works (POTWs) at levels exceeding influent concentration. Thiocyanate (SCN-) is a cyanide-related compound encountered in most POTW influents and may be decomposed to free cyanide (CN-) under some circumstances. Effects of SCN- on the formation of cyanide during chlorination and UV disinfection were studied through a laboratory study with synthetic solutions and POTW secondary effluent. Results indicated that CN- was detected in SCN- solutions after chlorination in which the chlorine dose or reaction time was not sufficient to destroy SCN-completely, thus ensuring no residual chlorine to destroy any CN-produced. It was also found that SCN can be broken down to yield cyanide by UV irradiation. In addition, SCN- was observed to cause significant positive error in the conventional total cyanide analysis technique involving acidic distillation and colorimetric measurement when nitrate was present in the sample.

Formation of free cyanide and cyanogen chloride from chloramination of publicly owned treatment works secondary effluent: laboratory study with model compounds.

The potential generation of cyanide species in wastewater upon chlorination in the presence of residual ammonia (resulting in chloramine formation) was investigated in experiments with synthetic solutions and publicly owned treatment works (POTW) secondary effluent. This study demonstrated that low concentrations (approximately 5 to 25 microg/L as cyanide) of cyanogen chloride (CNCI), a highly toxic cyanide species not measured in total or free cyanide analyses, could be detected as a result of chloramination reactions in POTW secondary effluent. The potential for chloramination of nitrogen-bearing organic compounds to yield CNCl and/or free cyanide was demonstrated in experiments with synthetic solutions spiked with selected precursor organics: L-serine, benzene, catechin, and humic acid. The amino acid L-serine yielded the largest concentrations of CNCI upon chloramination. Additionally, detectable cyanide (approximately 10 microg/L) was observed in solutions of L-serine and in POTW secondary effluent that was chloraminated followed by dechlorination to prevent destruction of any free cyanide produced. Thus, chlorination of POTW secondary effluent containing residual ammonia can lead to chloramination of organic compounds and the resulting production of CNCl and free cyanide.

The occurrence of cyanide formation in six full-scale publicly owned treatment works.

This paper presents results from an intensive monitoring program implemented at six full-scale publicly owned treatment works (POTWs) to investigate the fate and formation of cyanide in wastewater treatment processes, with a focus on chlorination and dechlorination processes. A review of historical monitoring data for cyanide species in these POTWs was also conducted. This POTW monitoring program provided a database for the investigation of cyanide formation in wastewater secondary treatment. Data from participating POTWs showed evidence of cyanide formation in this 1-year monitoring effort, although the cyanide formation pattern varied significantly from one plant to another and among seasons. Generally, the chlorination of thiocyanate (SCN-) seems to be the most important mechanism for the formation of cyanide in wastewater treatment processes, especially in chlorination and dechlorination. This hypothesis is supported by the findings of a related laboratory study of mechanisms of cyanide formation in POTWs. It is recommended that POTWs monitor SCN in influent and secondary effluent to identify its presence and adjust chlorine dose appropriately.