A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma.

PURPOSE: In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated. PATIENTS AND METHODS: Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered. RESULTS: A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group. CONCLUSIONS: The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.

Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial.

IMPORTANCE: Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. OBJECTIVE: To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. INTERVENTIONS: Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. MAIN OUTCOMES AND MEASURES: The primary end point was the 2-year overall survival rate using intention-to-treat analysis. RESULTS: Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02813967.

Circular RNA circ-LRP6 facilitates Myc-driven tumorigenesis in esophageal squamous cell cancer.

Circular RNA (circRNA) circ-LRP6 was recently proven to be a pivotal player in various human diseases. Nevertheless, its role in esophageal squamous cell cancer (ESCC) remains unknown. In the current study, we investigated the expression level, biological function and mechanism of circ-LRP6 in ESCC. Circ-LRP6 was significantly upregulated in ESCC tissues and correlated with malignant clinicopathological characteristics and poor prognosis. Knockdown of circ-LRP6 evidently reduced ESCC cell viability, colony formation and invasion. Circ-LRP6 was mainly located in the cytoplasm and could sponge miR-182 to increase the expression of Myc, a well-documented proto-oncogene. Importantly, circ-LRP6 depletion significantly retarded tumor growth in vivo. And silencing of miR-182 or overexpression of Myc effectively rescued the attenuated aggressive phenotype of ESCC cells caused by circ-LRP6 knockdown. Therefore, our data indicate that circ-LRP6 is a novel oncogenic circRNA in ESCC, targeting the circ-LRP6/miR-182/Myc signaling may be a promising therapeutic approach for ESCC patients.

miR-206 regulates non-small-cell lung cancer cell aerobic glycolysis by targeting hexokinase 2.

Aerobic glycolysis was closely associated with the malignant transformation and prognosis of tumours. miR-206 was found to be downregulated in several cancers. However, whether miR-206 functions in non-small-cell lung cancers (NSCLCs) via the process of aerobic glycolysis remains poorly characterized. Quantitative real-time PCR was performed to detect miR-206 level in NSCLC cells and tissues. The effect of miR-206 on hexokinase 2 (HK2) expression was examined through miR-206 overexpression or miR-206 knockdown. CCK-8 assay and colony formation assay were carried out to explore the role of miR-206 on cell proliferation and colony formation, respectively. The relationship between miR-206 and HK2 was measured by dual-luciferase reporter assay. Glucose consumption, lactate production assay and ATP generation were performed in NSCLC cells following miR-206 and HK2 overexpression. We found that miR-206 was downregulated in NSCLC tissues and cells. miR-206 overexpression downregulated the expression of HK2 via targeting HK2 3'UTR in NSCLC cells. In addition, miR-206 decreased the cell viability and colony formation in NSCLC cells. Furthermore, miR-206 reduced glucose uptake, lactate production and ATP generation in NSCLC cells via HK2 repression. In conclusion, these findings suggested that miR-206 regulated NSCLC cell aerobic glycolysis by targeting HK2.

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for patients with locally advanced esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

The present study evaluated the clinical and prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (dCRT). A total of 517 patients with ESCC were enrolled and analysed retrospectively. The NLR was calculated at three time points: baseline, post-treatment, and at the time of tumor progression. Elevated NLR was defined as a ratio ≥5. High NLR at baseline was present in 204 (39%) patients and was significantly correlated with larger tumour size, advanced TNM stage, worse ECOG performance status, and dCRT response (p < 0.05). At a median follow-up of 17 months, patients with higher NLR at baseline had poorer progression-free survival (PFS) and overall survival (OS). On multivariate analysis, elevated NLR at baseline was independently associated with PFS and OS (HR = 1.529, p < 0.001 for PFS; HR = 1.856, p < 0.001 for OS). In addition, patients with high pre- and post-treatment NLR demonstrated worse clinical outcomes than other groups. Our results suggest that NLR is an independent prognostic indicator for patients with ESCC undergoing dCRT and changes in NLR level with treatment may indicate therapeutic benefit.

Survival benefit of radiotherapy to patients with small cell esophagus carcinoma: an analysis of Surveillance Epidemiology and End Results (SEER) data.

BACKGROUND AND AIMS: Small cell esophageal carcinoma (SCEC) is a rare malignant tumor. So far, few studies are found to research the effect of radiotherapy (RT) to it. This study is designed to explore the prognostic factors, and analyze survival benefit of RT to patients with SCEC. RESULTS: Patients with SCEC were more likely to be in female, older, higher disease stage than those with non-small cell esophageal carcinoma. RT was used in more than 50% SCEC patients. RT tended be reduced as the disease stage raise in SCEC. Univariate and multivariate analysis showed that age, year, disease stage, and RT were the prognostic factors of survival (P < 0.05). RT reduced nearly 75% risks of death in localized stage (P < 0.05), nearly 50% risks of death in regional stage (P > 0.05) and nearly 30% risks of death in distant stage (P > 0.05). METHODS: SCEC patients between 1973 and 2012 were searched from the Surveillance Epidemiology and End Results (SEER) data. Clinical factors including age, year, sex, race, stage, surgery, and RT were summarized. Univariate and multivariate analysis were performed to explore the independent prognostic factors of SCEC. Cox regression survival analysis was performed to evaluate the effect of RT to SCEC based on different stages. CONCLUSIONS: Stage, age, year, and RT are independent prognostic factors of SCEC. Survival benefit of RT exists in any disease stage, but is only statistically significant in localized stage of SCEC.

Survival benefit of surgery with radiotherapy vs surgery alone to patients with T2-3N0M0 stage esophageal adenocarcinoma.

BACKGROUND & AIMS: This study is designed to analyze survival benefit of (neo-) adjuvant radiotherapy to patients with T2-3N0M0 stage esophageal adenocarcinoma (EAC). METHODS: T2-3N0M0 stage EAC patients from 2004 to 2012 were searched from the Surveillance Epidemiology and End Results (SEER) data. Clinical factors including age, sex, race were summarized. Univariate, multivariate analysis, and stratified cox analysis based on different T stages were performed to explore the survival effect of (neo-)adjuvant radiotherapy to T2-3N0M0 stage EAC. RESULTS: T2-3N0M0 stage EAC patients with surgery were more likely to be white race, T3 stage. Univariate analysis showed sex, age, and T stage were the prognostic factors of survival (P<0.05). Multivariate analysis proved (neo-)adjuvant radiotherapy can prolong survival time of T2-3N0M0 stage EAC (P<0.05). Further analysis based on different T stages showed that both neoadjuvant radiotherapy (HR 0.615; 95% CI 0.475-0.797) and adjuvant radiotherapy (HR 0.597; 95% 0.387-0.921) significantly reduced the risk of death of T3N0M0 stage EAC, but neither of which significantly reduced death risk of T2N0M0 stage EAC (P>0.05). CONCLUSIONS: sex, age are the independent prognostic factors of T2-3N0M0 EAC. Significant survival benefit of (neo-)adjuvant radiotherapy is only observed in patients with T3N0M0 stage EAC, but not in those with T2N0M0 stage.

High expression of long non-coding RNA AFAP1-AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

To evaluate the clinical significance of lncRNAs in the resistance to cisplatin-based chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). We focused on lncRNAs which were frequently reported in ESCC or were involved in chemoradiotherapy resistance. LncRNA expressions were examined in paired cisplatin-resistant and parental ESCC cell lines. Dysregulated lncRNAs were further measured in 162 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (dCRT). Then the correlations between lncRNA expression and response to dCRT and prognosis were analyzed. Three lncRNAs (AFAP1-AS1, UCA1, HOTAIR) were found to be deregulated in cisplatin-resistant cells compared with their parent cells. AFAP1-AS1 was significantly up-regulated in tumor tissues compared with adjacent normal tissues (P = 0.006). Furthermore, overexpression of AFAP1-AS1 was closely associated with lymph node metastasis (P < 0.001), distant metastasis (P = 0.016), advanced clinical stage (P = 0.002), and response to dCRT (P < 0.001). Kaplan-Meier survival analysis revealed that high expression of AFAP1-AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001). In the multivariate analysis, high expression of AFAP1-AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004). Thus, high expression of AFAP1-AS1 could serve as a potential biomarker to predict tumor response and survival. Determination of this lncRNA expression might be useful for selection ESCC patients for dCRT. © 2016 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

Survival benefit of induction chemotherapy in treatment for locally advanced nasopharyngeal carcinoma--A time-to-event meta-analysis.

OBJECTIVES: This paper aims to compare the longtime efficacy of induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT) and concurrent chemoradiotherapy (CCRT) alone in locally advanced nasopharyngeal carcinoma (LANPC) by using time-to-event data based on randomized controlled trials (RCTs). MATERIALS AND METHODS: We searched all RCTs comparing the efficacy between IC+CCRT and CCRT of LANPC in major medical databases including Pubmed, web of science, cochrane, China National Knowledge Internet Web (CNKI), Wanfang, and VIP. The Hazard ratios (HR) of time-to-event data on overall survival (OS), progressive free survival (PFS), distant metastasis failure-free survival (D-FFS), and loco-regional failure-free survival (L-FFS) from the enrolled studies were calculated for this meta analysis. Our primary endpoints were OS, PFS, D-FFS, and L-FFS. RESULTS: Four studies with 798 patients were enrolled for this paper. Compared with in CCRT alone, HRs (95% confidence interval) of OS, PFS, D-FFS and L-FFS were 0.52 (0.21-1.29), 0.66 (0.49-0.90), 0.60 (0.39-0.98) and 0.66 (0.16-2.65) respectively in IC+CCRT. CONCLUSIONS: Induction chemotherapy could significantly reduce the hazard of progression and distant metastasis in LANPC on the basis of concurrent chemoradiotherapy, but do less with the hazard of overall death and loco-regional failure.

Subjective global assessment and prealbumin levels of esophageal cancer patients undergoing concurrent chemoradiotherapy.

AIMS: To evaluate the nutritional status of patients undergoing chemoradiotherapy for esophageal cancer using subjective global assessment (SGA) and association of prealbumin levels to nutritional status. METHODS: A prospective study was performed on 154 patients with esophageal cancer who were treated with concurrent chemoradiotherapy at center of radiation oncology in Huai'an First People's Hospital from January 2012 to May 2013. The patients' nutritional status after receiving concurrent chemoradiotherapy were evaluated using SGA tool. Serum total protein, prealbumin, albumin and other biochemical nutrition parameters including triglyceride, total cholesterol, cholesterol and glucose were determined before beginning and after the end of radiotherapy. RESULTS: Malnutrition developed in 129 (83.8%) patients. According to SGA results, 16.2%, 66.2%, and 17.6% of patients were classified as A, B, or C, respectively. Loss of subcutaneous fat or muscle wasting (odds ratio [OR] 11.522); increased metabolic demand/ stress (OR 8.637); ankle, sacral edema, or ascites (OR 3.229) and weight loss ≥5% (OR 2.294) were significantly associated with malnutrition (SGA B or C; p < 0.001). Prealbumin level after the end of radiotherapy was significantly lower in patients with malnutrition (17 ± 5 g/ dl vs. 21 ± 5 g/dl, p = 0.005), but it showed no difference before beginning radiotherapy (24 ± 4 g/dl vs. 22 ± 5 g/ dl, p > 0.05). On the other hand, there was no significant difference in term of other nutrition parameters whether before beginning or after the end of radiotherapy (p > 0.05). CONCLUSIONS: The prevalence of malnutrition was high in esophageal cancer patients undergoing concurrent chemoradiotherapy. The results serve as a basis for implementation of nutrition intervention to patients being treated at radiotherapy departments. Prealbumin showed relation with SGA rating and should be considered as a sensitive nutritional biomarker for evaluating nutritional status of esophageal cancer patients undergoing concurrent chemoradiotherapy.

Objetivos: Evaluar el estado nutricional de los pacientes sometidos a quimioterapia para cáncer esofagico usando subjetiva evaluación mundial(SGA) y Asociación de prealbumina a niveles de estado nutricional. Métodos: Se realiza un estudio prospectivo en 154 pacientes con cáncer esofágico que fueron tratados con quimiorradioterapia concurrente en centro de Oncología de radiación en Huai 'an First People' s Hospital desde enero de 2012 a mayo de 2013. El estado nutricional de los pacientes después de recibir quimiorradioterapia concurrente fueron evaluados utilizando la herramienta de SGA. Albúmina, prealbúmina, proteína sérica total, nutrición y otros parámetros bioquímicos, incluyendo triglicéridos, colesterol total, colesterol y glucosa fueron determinados antes de empezar y después del final de la radioterapia. Resultados: La desnutrición desarrollada en 129 (83,8%) pacientes. Según SGA resultados, 16,2%, 66,2%, y 17,6% de los pacientes fueron clasificados como a, B, o C, respectivamente. La pérdida de grasa subcutánea o atrofia muscular (odds ratio [OR] 11.522); demanda metabolica creciente / estrés (o 8.637); tobillo edema sacro, o ascitis (o -) y la perdida de peso ≥ 5% (o 3) estuvieron significativamente asociados con la malnutrición (SGA B o C; p < 0,001). El nivel de prealbúmina después del final de la radioterapia fue significativamente menor en los pacientes con desnutrición (17 ± 5 g / dl vs. 21 ± 5 g / dl, p = 0,005), pero no mostró diferencia antes de comenzar la radioterapia (24 ± 4 g / dl vs. 22 ± 5 g / dl, p > 0,05). Por otro lado, no hubo diferencia significativa en el plazo de otros parámetros si la nutrición fue antes de comenzar o después del final de la radioterapia (p > 0,05). Conclusiones: La prevalencia de la malnutrición era alta en cáncer de esófago en pacientes sometidos a quimiorradioterapia concurrente. Losresultados sirven de base para la aplicación de la intervención en materia de nutrición para pacientes en tratamiento en los servicios de radioterapia. La prealbumina mostró relación con SGA a valorar y debe ser considerado como un biomarcador sensible nutricional para evaluar el estado nutricional de cáncer esofágico en pacientes sometidos a quimiorradioterapia concurrente.

Combined downregulation of microRNA-133a and microRNA-133b predicts chemosensitivity of patients with esophageal squamous cell carcinoma undergoing paclitaxel-based chemotherapy.

microRNA-133a (miR-133a) and miR-133b, located on chromosome 18 in the same bicistronic unit, have been commonly identified as being downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the correlation of miR-133a/b expression with efficacy of paclitaxel-based chemotherapy and clinical outcome of ESCC patients. miR-133a expression and miR-133b expression were examined in 100 newly diagnosed ESCC patients prior to treatment by quantitative real-time PCR. Then, the patients received four cycles of paclitaxel-based chemotherapy, the short-term treatment efficacy was evaluated, and a 3-year follow-up was performed. Expression levels of miR-133a and miR-133b were both significantly lower in ESCC tissues compared to adjacent noncancerous tissues (both P < 0.001). In addition, combined miR-133a/b downregulation was found to be closely correlated with advanced tumor stage (P = 0.02) and poor differentiation (P = 0.01). Moreover, the response rate of ESCC patients to paclitaxel-based chemotherapy was significantly higher in combined miR-133a/b downregulation group compared with other groups (P = 0.02). Furthermore, univariate and multivariate Cox analyses revealed that tumor stage and combined expression of miR-133a/b were independent prognosis factors in ESCC patients. Our data offer the convincing evidence that combined expression of miR-133a and miR-133b may predict chemosensitivity of patients with ESCC undergoing paclitaxel-based chemotherapy, implying its importance in applying 'personalized cancer medicine' in the clinical treatment of ESCC. We also identified combined expression of miR-133a and miR-133b as an effective prognostic marker of this malignancy.

Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer.

BACKGROUND: The radiation resistance of prostate cancer remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of berberine, a commonly used natural product, on the radiosensitivity of prostate cancer. METHODS: Prostate cancer cell line LNCaP and DU-145 were subjected to hypoxia and/or ionizing radiation (IR), in the presence or absence of berberine treatment. Cell growth and colony formation, and apoptosis were evaluated. Moreover, LNCaP cells were xenografted into nude mice and subjected to IR and/or berberine treatment. The expression of HIF-1α and VEGF in prostate cancer cells and xenografts was detected by Western blot analysis. RESULTS: Berberine increased radiosensitivity of prostate cancer cells and xenografts in a dose dependent manner, and this was correlated with the inhibition of HIF-1α and VEGF expression. CONCLUSIONS: Berberine may inhibit the expression of HIF-1α and VEGF and thus confer radiosensitivity on prostatic cancer cells. Berberine has potential application as an adjuvant in radiotherapy of prostatic cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1519827543125021.

Meat consumption is associated with esophageal cancer risk in a meat- and cancer-histological-type dependent manner.

BACKGROUND: We conducted a systematic review and meta-analysis of meat intake and esophageal cancer risk, with subgroup analyses based on meat type and histological type of cancer. AIMS: The purpose of this study was to investigate the association between meat intake and risk of esophageal cancer. METHODS: We searched MEDLINE, EMBASE and Cochrane Library (April 2013) for cohort and case-control studies that assessed meat intake and esophageal cancer risk. Random-effect or fixed-effect models were used to pool relative risks (RRs) from individual studies with heterogeneity and publication bias analyses carried out. Seven cohort and 28 case-control studies were included. RESULTS: The summary RRs for esophageal cancer for the highest versus lowest consumption categories were 1.19 (95 % confidence interval [CI] 0.98-1.46) for total meat, 1.55 (95 % CI 1.22-1.96) for red meat, 1.33 (95 % CI 1.04-1.69) for processed meat, 0.72 (95 % CI 0.60-0.86) for white meat, 0.83 (95 % CI 0.72-0.96) for poultry, and 0.95 (95 % CI 0.76-1.19) for fish. When striated by histological subtype, positive associations were seen among esophageal squamous cell carcinoma and red meat, white meat and poultry, and esophageal adenocarcinoma with total meat and processed meat. CONCLUSIONS: Meat consumption is associated with esophageal cancer risk, which depends on meat type and histological type of esophageal cancer. High intake of red meat and low intake of poultry are associated with an increased risk of esophageal squamous cell carcinoma. High meat intake, especially processed meat, is likely to increase esophageal adenocarcinoma risk. And fish consumption may not be associated with incidence of esophageal cancer.

Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein.

Currently, unresectable esophageal squamous cell carcinoma (ESCC) is primarily treated by chemoradiotherapy. However, the outcome has not improved significantly due to radioresistance of cancer cells. This study aimed to determine the radiosensitizing effect of LCL161, a novel second mitochondrial-derived activator of caspase (Smac) mimetic, in ESCC cells. ESCC cell lines were treated with LCL161 or radiation, alone or in combination. Cell proliferation was detected by MTT assay. Radiosensitization was evaluated by clonogenic survival assay. Cell apoptosis was detected by flow cytometry. The results showed that LCL161 potently sensitized ESCC cells to radiation with a sensitization enhancement ratio of 1.4-2.0. LCL161 increased radiation-induced DNA double-stranded breaks and promoted the apoptosis of ESCC cells, which could be abrogated by a pan-caspase inhibitor z-VAD-FMK. Furthermore, LCL161 decreased the level of cIAP1 in ESCC cells in a dose-dependent manner and synthesized with irradiation to promote the activation of caspase 8 and the upregulation of TNFα expression in ESCC cells. In conclusion, LCL161 acts as a strong radiosensitizer in human esophageal cancer cells by inhibiting the expression of cIAP1 and promoting the activation of caspase 8, leading to enhanced apoptosis.

Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.

OBJECTIVE: The efficacy of postoperative concurrent radiochemotherapy (POCRT) on IIIA-pN2 non-small cell lung cancer (NSCLC) is still unclear. The aim of this randomized controlled trial was to compare POCRT with postoperative chemotherapy (POCT) alone in terms of survival and relapse patterns. METHODS: Patients with completely resected IIIA-pN2 NSCLC were randomized into POCRT or POCT groups. Chemotherapy consisted of paclitaxel (175 mg/m(2)) and cisplatin (60 mg/m(2)) administered intravenously for four cycles on day 1, 22, 43, and 64. Patients in the POCRT group received radiotherapy (50.4 Gy/28 fractions) concurrently with the first 2 cycles of chemotherapy. RESULTS: This study recruited 140 participants and was closed early because of slow accrual. Data were analyzed for 135 of them including 66 cases in the POCRT group and 69 cases in the POCT group. Patients were followed-up for a median period of 45 months. The POCRT group had a median survival (MS) of 40 months and a 5-year overall survival (OS) rate of 37.9%. The POCT group had a MS of 28 months and a 5-year OS rate of 27.5%. The hazard ratio for death in the POCRT group was 0.69 (95% CI: 0.457-1.044, P=0.073). We observed a disease-free survival (DFS) of 28 months and a 5-year DFS rate of 30.3% in the POCRT group. Likewise, we observed a DFS of 18 months and a 5-year DFS rate of 18.8% in the POCT group. The recurrence hazard ratio in the POCT group was 1.49 (95% CI: 1.008-2.204, P=0.041). Subgroup analysis revealed that POCRT significantly increased the OS rate of the patients with ≥2 pN2 lymph nodes (P=0.021). The POCRT group had a significantly lower local relapse (P=0.009) and distant metastasis (P=0.05) rates as compared to that of the POCT group. One case died of pyemia and 9 cases suffered from grade 3 and 4 acute radiation esophagitis. The two groups had similar and tolerable hematologic toxicities. CONCLUSIONS: Compared with POCT, POCRT increased both local/regional and distant DFS rate of the patients with IIIA-pN2 NSCLC, but not the OS rate. Considering the relatively small sample size of the current study, caution should be taken when adopting the conclusions.

Berberine radiosensitizes human nasopharyngeal carcinoma by suppressing hypoxia-inducible factor-1α expression.

CONCLUSION: Berberine confers radiosensitivity on nasopharyngeal carcinoma (NPC) and this is associated with the down-regulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. Berberine could be a promising radiosensitizer for NPC radiotherapy. OBJECTIVES: NPC has a poor prognosis. Radiotherapy as first-line therapy significantly increases patient survival but radioresistance is a problem. This study aimed to investigate the radiosensitizing effects of berberine on NPC and explore the underlying mechanisms. METHODS: CNE-1 and CNE-2 cells were exposed to hypoxia and treated with berberine at different concentrations. The MTT assay, clonogenic assay, and flow cytometry were performed to analyze cell proliferation, colony formation, and apoptosis. The expression of HIF-1α and VEGF was assessed by Western blot and immunofluorescence analysis. Male nude mice inoculated subcutaneously with CNE-2 cells were used to examine the sensitizing effects of berberine in vivo. RESULTS: Berberine efficiently radiosensitized NPC cells and xenografts in mice, and inhibited hypoxia/radiation-induced up-regulation of HIF-1α and VEGF expression.

Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo.

Radiation therapy is an important treatment approach for esophageal squamous cell carcinoma (ESCC). However, how to promote radiation sensitivity in ESCC remains a challenge. This study aimed to evaluate the effects of berberine, a common used Chinese medicine, on the radiosensitivity of ESCC. ECSS cell line ECA109 and TE13 were subjected to hypoxia and/or ionizing radiation (IR), in the presence or absence of berberine treatment. Cell growth and survival, and apoptosis were evaluated. In addition, ECA109 cells were xenografted into nude mice and subjected to IR and/or berberine treatment. The expression of HIF-1α and VEGF was detected by western blot and immunohistochemical analysis. Our results showed that berberine increased radiosensitivity of ESCC cells and xenografts, and this was associated with the inhibition of HIF-1α and VEGF expression. These data suggest that berberine may be a potential radiotherapy sensitization drugs due to its significant anti-hypoxia activity.

[A randomized controlled trial of intensity-modulated radiation therapy plus docetaxel and cisplatin versus simple intensity-modulated radiation therapy in II-III stage esophageal carcinoma].

OBJECTIVE: To compare the efficacy and toxicity of intensity- modulated radiation therapy plus chemotherapy (IMRT-TP) with simple intensity-modulated radiation therapy (IMRT) in the treatment of locally advanced esophageal carcinoma. METHODS: A total of 170 eligible patients with locally advanced esophageal carcinoma were recruited prospectively from September 2004 to April 2008 and randomly divided into IMRT-TP group and IMRT group. Two groups were treated with IMRT of 6MV-X. The radiation dose was 60 Gy in 30 fractions in IMRT-TP group and 66 Gy in 30 fractions in IMRT group. The regimen of chemotherapy consisted of docetaxel and cisplatin in IMRT-TP group for 2 cycles. RESULTS: Of 170 patients, 160 completed the trial, including 75 patients of IMRT-TP group and 85 of IMRT group. As compared to IMRT group, total recurrence rate [69.3% (52/75) vs. 84.7% (72/85), P=0.020] and local recurrence rate [50.7% (38/75) vs. 67.1% (57/85), P=0.035] decreased in IMRT-TP group, the 5-year overall survival (29.3% vs. 15.3%, P=0.031) and 5-year recurrence free survival (24.0% vs. 10.6%, P=0.015) increased in IMRT-TP group. While severe side effect ratio increased obviously in IMRT-TP group [54.7% (41/75) vs. 4.7% (4/85), P=0.000]. CONCLUSION: As compare to simple IMRT, IMRT plus docetaxel and cisplatin can decrease the local recurrence rate, prolong the overall survival and regression-free survival, but bring more side effects.

Red and processed meat intake is associated with higher gastric cancer risk: a meta-analysis of epidemiological observational studies.

BACKGROUND: Red and processed meat was concluded as a limited-suggestive risk factor of gastric cancer by the World Cancer Research Fund. However, recent epidemiological studies have yielded inconclusive results. METHODS: We searched Medline, EMBASE, and the Cochrane Library from their inception to April 2013 for both cohort and case-control studies which assessed the association between red and/or processed meat intake and gastric cancer risk. Study-specific relative risk estimates were polled by random-effect or fixed-effect models. RESULTS: Twelve cohort and thirty case-control studies were included in the meta-analysis. Significant associations were found between both red (RR: 1.45, 95% CI: 1.22-1.73) and processed (RR: 1.45, 95% CI: 1.26-1.65) meat intake and gastric cancer risk generally. Positive findings were also existed in the items of beef (RR: 1.28, 95% CI: 1.04-1.57), bacon (RR: 1.37, 95% CI: 1.17-1.61), ham (RR: 1.44, 95% CI: 1.00-2.06), and sausage (RR: 1.33, 95% CI: 1.16-1.52). When conducted by study design, the association was significant in case-control studies (RR: 1.63, 95% CI: 1.33-1.99) but not in cohort studies (RR: 1.02, 95% CI: 0.90-1.17) for red meat. Increased relative risks were seen in high-quality, adenocarcinoma, cardia and European-population studies for red meat. And most subgroup analysis confirmed the significant association between processed meat intake and gastric cancer risk. CONCLUSIONS: Our findings indicate that consumption of red and/or processed meat contributes to increased gastric cancer risk. However, further investigation is needed to confirm the association, especially for red meat.

[Application of simplified intensity modulated radiation therapy in gastric cancer after operation].

OBJECTIVE: To elucidate the application and the dosimetry characteristic of the simplified intensity modulated radiation therapy (sIMRT) for gastric cancer after operation, and to compare the dose distribution with intensity modulated radiation therapy (IMRT) and three-dimension conformal radiation therapy (3D-CRT). METHODS: Twelve patients with gastric cancer after operation were enrolled in this study. 3D-CRT plan, 5-field IMRT plans (20 degree, 80 degree, 180 degree, 280 degree, 340 degree) and 5-field sIMRT plans (20 degree, 80 degree, 180 degree, 280 degree, 340 degree) were performed for each patient. The conformal index (CI), heterogeneity index (HI) of the planning target volume (PTV) and the dose of normal organs were analyzed with the dose volume histogram (DVH). The total MU and treatment time were also compared. RESULTS: The sIMRT and IMRT plans had comparable CI (sIMRT>IMRT>3D-CRT), and showed better dose conformity but worse homogeneity than 3D-CRT. The percentage of volume receiving 20 Gy, 25 Gy, 30 Gy and 40 Gy by liver were significantly lower in sIMRT than that in 3D-CRT, and comparable to IMRT. All the dose volumes to kidneys with sIMRT were still significantly lower as compared to 3D-CRT, and comparable to IMRT. The sIMRT plan was better than IMRT plan in total MU and treatment time. CONCLUSIONS: sIMRT has comparable dose distribution in patients with gastric cancer to IMRT, but is significantly better than 3D-CRT. Treatment time of sIMRT is the shortest. So sIMRT technique can be applied more simply.