Elective nodal irradiation versus involved-field irradiation for stage II-IV cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy: a retrospective propensity study with 8-year survival outcomes.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is suggested as the standard treatment for cervical esophageal squamous cell carcinoma (CESCC). This retrospective propensity study compared the 8-year survival outcomes and acute treatment toxicities of these patients treated with elective nodal irradiation (ENI) versus involved-field irradiation (IFI). MATERIALS AND METHODS: Patients with stage II-IV CESCC treated with dCCRT at the Fourth Hospital of Hebei Medical University between January 1, 2007 and December 31, 2020 were enrolled in the study. All the patients were restaged according to the American Joint Commission 8th edition criteria. The propensity score matching (PSM) was used to minimize the effects of treatment selection bias and potential confounding factors including sex, age, ECOG score, clinical T stage, clinical N stage, clinical TNM stage and radiation dose between the ENI group and IFI group. Survival and the prognostic factors were evaluated. RESULTS: The 131 eligible patients underwent ENI (60 patients, 45.8%) or IFI (71 patients, 54.2%). The median follow-up time was 91.1 months (range, 23.8-182.0 months) for all the patients. The median OS, 1-, 3-, 5-, and 8-year OS rates were 44.4 months, 87.8%, 55.1%, 38.3%, and 27.2%, respectively. After PSM, there were 49 patients in each group. The median OS, 1-, 3-, 5-, and 8-year OS rates for ENI and IFI group were 32.0 months, 83.7%, 48.5%, 38.5% and 31.1% versus 45.2 months, 89.8%, 52.5%, 37.5%, 26.1%, respectively (P = 0.966; HR 0.99, 95% CI 0.61-1.61). Similar locoregional control was obtained in both groups. The tendency of leukocytopenia and neutropenia was higher in ENI than in IFI (59.2% vs. 38.8%; P = 0.068 and 30.6% vs. 14.3%; P = 0.089) at the end of dCCRT. CONCLUSION: Cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy has a satisfactory prognosis with organ conservation. The involved-field irradiation might be a better alternative owing to similar overall survival outcomes and local control with less toxicity of myelosuppression.

Comparison of neoadjuvant immunotherapy plus chemotherapy versus chemotherapy alone for patients with locally advanced esophageal squamous cell carcinoma: A propensity score matching.

Objectives: Clinical studies on immune checkpoint inhibitors (ICIs) combined with neoadjuvant chemotherapy (nCT) have been carried out for the resectable esophageal squamous cell carcinoma (ESCC). So far, few studies have compared the survival outcomes of nCT plus ICIs and nCT alone. This study aimed to compare the efficacy and safety of neoadjuvant ICIs combined with nCT versus nCT followed by esophagectomy for patients with resectable locally advanced ESCC. Methods: A retrospective analysis of ESCC patients underwent nCT or nCT combined with ICIs followed by esophagectomy (from March 2013 to April 2021) was performed. A 1:1 propensity score matching (PSM) with a caliper 0.01 was conducted to balance potential bias. Results: A total of 47 comparable pairs of ESCC patients receiving nCT and nCT combined with ICIs were selected for the final analysis. The tumor regression grade (TRG) 0 and pathologic complete response (pCR) rates in the nCT+ICIs group were significantly higher than those of the nCT group (21.7% vs. 4.5%, P=0.016; and 17.0% vs. 2.1%, P=0.035, respectively). The rate of nerve invasion was 4.3% in the nCT+ICIs group, significantly lower than 23.4% of the nCT group (P=0.007). The incidences of adverse events in the nCT+ICIs group were similar compared with the nCT group and there was no grade 5 toxicity in either group. The 1-, 2-year disease-free survival rates (DFS) were 95.7%, 80.7% and 76.1%, 63.8% in the two groups (P=0.001, and P=0.046, respectively). The 1-year OS was improved in the nCT+ICIs group, which was close to a statistical difference (95.7% vs. 84.8%, P=0.074). Local recurrence rate in the nCT+ICIs group was 6.4%, significantly lower than 21.3% of the nCT group (P=0.036), while there was no significant difference in the distant metastasis. Conclusions: Compared with nCT alone, neoadjuvant immunotherapy plus nCT for patients with locally advanced ESCC has an advantage in pathological response, and could improve DFS with a good safety and feasibility, while long term survival validation is still needed further.

Efficacy and safety of neoadjuvant chemoradiotherapy plus apatinib for patients with locally advanced, HER2-negative, Siewert's type II-III adenocarcinoma of esophagogastric junction: a single-arm, open-label, phase II trial.

This study aimed to investigate the efficacy and safety of concurrent neoadjuvant chemoradiotherapy (CRT) plus apatinib in treating locally advanced, HER2-negative, Siewert's type II-III adenocarcinoma of esophagogastric junction (AEG) patients. Thirty eligible patients were analyzed in this single-arm, open-label, phase II trial. Patients received neoadjuvant regimen as follows: two cycles of apatinib (orally, 250 mg/day on day 1-28), two cycles of capecitabine (orally, 1,000 mg/m2 twice daily on day 1-14), oxaliplatin (intravenously, 130 mg/m2 on day 1), and concurrent radiotherapy (a total dose of 45 Gy in 25 fractions) started on day 1 of chemotherapy. Then, surgery was performed within 8-12 weeks after the completion of neoadjuvant therapy. This trial was registered on the ClinicalTrials.gov website (access number: NCT03349866). After neoadjuvant CRT plus apatinib treatment, 18 (60.0%) patients achieved objective response, 29 (96.7%) patients achieved disease control, and 20 (66.7%) patients achieved down-staging. Encouragingly, tumor regression grade (TRG) 0, TRG 1, TRG 2 and TRG 3 were observed in 33.3%, 20.0%, 30.0% and 10.0% patients, respectively; the pathological complete response rate was 33.3%, and the R0 resection rate was 93.3%. Regarding survivals, the 1-year and 2-year progression-free survival rates were 96.7% and 88.1%, respectively. Meanwhile, the 1-year and 2-year overall survival rates were 100.0% and 96.6%, respectively. As to safety, the majority of the adverse events were of mild grade, and the post-operative complications were manageable. In conclusion, neoadjuvant CRT plus apatinib exhibits high efficacy and acceptable tolerance in patients with locally advanced, HER2-negative, Siewert's type II-III AEG.

Clinicopathological characteristics and prognosis of brain metastases in elderly patients with esophageal carcinoma.

BACKGROUND: Brain metastases (BM) from esophageal carcinoma (EC) is clinically rare and has not yet been reported in elderly patients. This study aimed to investigate the clinicopathological characteristics, outcomes and prognostic factors of BM in elderly patients with EC, in order to provide guidance for clinical practice. METHODS: A total of 20 EC patients older than 65 years who were diagnosed with BM were identified from the fourth Hospital of Hebei Medical University between January 1, 2009 and December 31, 2018. Survival was evaluated by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The median time from diagnosis of EC to BM was 11.8 months (0-249.2 months). The median overall survival (OS) was 4.8 months (1.13-23.3 months), with 20% of patients achieving the 1-year survival rate. Patients with KPS score of ≥70 had a significantly better OS than those with KPS score<70 (8.4 vs. 3.9 months, p = 0.033). Compared to patients without brain radiotherapy, patients with brain radiotherapy showed better outcomes in both median OS (8.4 vs. 2.9 months) and 1-year survival rate (23.1% vs. 14.3%, p = 0.043). The median OS of patients with radiotherapy combined with chemotherapy and/or targeted therapy and radiotherapy alone was 9.7 months (3.4-23.3 months) and 7.2 months (1.7-18.4 months), respectively, with no significant difference between the two groups (p = 0.215). CONCLUSIONS: Brain radiotherapy provided clinically meaningful survival benefit for elderly patients with BM from EC. Thus, active treatments for those patients might be required.

Are People With Blood Group O More Susceptible to Nasopharyngeal Carcinoma and Have Worse Survival Rates? A Systematic Review and Meta-Analysis.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a common malignant tumour in Southeast Asia, especially in southern China. ABO blood groups have been proven to play an important role in many cancers. However, it is still controversial whether the ABO blood group has a definite relationship to susceptibility to NPC and the prognosis of NPC patients. This meta-analysis was performed to elucidate the correlation between ABO blood group and NPC to provide more data for clinical practice. METHODS: A systematic search was performed of the Chinese National Knowledge Infrastructure (CNKI), Wanfang, Web of Science, EMBASE, and PubMed databases up to December 31, 2020. Stata 11.0 statistical software was used for this meta-analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 studies including 6938 patients with NPC were selected. Blood group O was relevant to Chinese NPC patients, and patients with blood group O had a significantly lower incidence of NPC, while blood group A had no correlation with susceptibility to NPC. There was no difference in the 3-year overall survival (OS), locoregional relapse-free survival (LRRFS) or distant metastasis-free survival (DMFS) rates between patients with blood group O and those with non-O blood groups; worse 5-year OS, LRRFS and DMFS rates were found in patients with blood group O, whereas blood group A was not related to prognosis. CONCLUSION: Blood group O in Chinese patients with NPC seems to be a protective factor for morbidity. However, once patients with blood group O are diagnosed with NPC, this blood group often indicates unfavourable OS, LRRFS and DMFS rates. It is recommended that more attention should be paid to the influence of blood group factor on patients in the treatment of NPC.

Do Higher Radiation Doses with Concurrent Chemotherapy in the Definitive Treatment of Esophageal Cancer Improve Outcomes? A Meta-Analysis and Systematic Review.

Background: To investigate the effects and safety profile of radiation dose escalation utilizing computerized tomography (CT) based radiotherapy techniques (including 3-Dimensional conformal radiotherapy, intensity-modulated radiotherapy and proton therapy) in the definitive treatment of patients with esophageal carcinoma (EC) with definitive concurrent chemoradiotherapy (dCCRT). Methods: All relevant studies utilizing CT-based radiation planning, comparing high-dose (≥ 60 Gy) versus standard-dose (50.4 Gy) radiation for patients with EC were analyzed for this meta-analysis. Results: Eleven studies including 4946 patients met the inclusion criteria, with 96.5% of patients diagnosed with esophageal squamous cell carcinoma (ESCC). The high-dose group demonstrated a significant improvement in local-regional failure (LRF) (OR 2.199, 95% CI 1.487-3.253; P<0.001), two-year local-regional control (LRC) (OR 0.478, 95% CI 0.309-0.740; P=0.001), two-year overall survival (OS) (HR 0.744, 95% CI 0.657-0.843; P<0.001) and five-year OS (HR 0.683, 95% CI 0.561-0.831; P<0.001) rates relative to the standard-dose group. In addition, there was no difference in grade ≥ 3 radiation-related toxicities and treatment-related deaths between the groups. Conclusion: Under the premise of controlling the rate of toxicities, doses of ≥ 60 Gy in CT-based dCCRT of ESCC patients might improve locoregional control and ultimate survival compared to the standard-dose dCCRT. While our review supports a dose-escalation approach in these patients, multiple ongoing randomized trial initial and final reports are awaited to evaluate the effectiveness of this strategy.

Comparison of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy for esophageal cancer: a meta-analysis.

Aim: To compare the clinical efficacy of neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) for esophageal cancer. Methods: Randomized controlled trials reporting on the comparison of nCRT and nCT for esophageal cancer were identified. Results: Three eligible randomized controlled trials were identified and included with a total of 375 patients (189 nCRT, 186 nCT). Outcomes showed that compared with nCT group, R0 resection and pathologic complete response (pCR) rates were significantly increased in nCRT group. However, no significant difference was seen in 3- and 5-year progression-free survival or 3- and 5-year overall survival. Conclusion: The addition of radiotherapy to neoadjuvant chemotherapy results in higher R0 resection rate and pCR rate, without significantly impacting survival.

Clinical complete response after chemoradiotherapy for carcinoma of thoracic esophagus: Is esophagectomy always necessary? A systematic review and meta-analysis.

BACKGROUND: Although a clinical complete response (cCR) after chemoradiotherapy (CRT) could lead to a better prognosis, the choice of a following strategy, such as surgical or non-surgical approach, remains controversial. METHODS: All articles relevant to a comparison of surgical and non-surgical treatment (including further definitive chemoradiotherapy or active surveillance) for esophageal carcinoma patients with a cCR after CRT were retrieved for meta-analysis. The final date for data retrieval was 30 June 2018. RESULTS: Four retrospective studies including 648 patients met the inclusion criteria: 620 with squamous cell carcinoma and 28 with adenocarcinoma. The CRT + surgery group had an advantage over the non-surgery group in regard to two-year disease-free survival (DFS); however, the two groups showed similar results in five-year DFS. The CRT + surgery group had an advantage over the non-surgery group in two-year overall survival (OS); nevertheless, the two groups showed similar results in five-year OS. CONCLUSIONS: Based on the available evidence, the addition of surgery to thoracic locally advanced esophageal carcinoma patients with a cCR after neoadjuvant CRT provided no advantage to long-term survival. As an exception, the two-year DFS and OS could be improved. This research conclusion might be more suitable to patients with squamous cell carcinoma.

Comparison of elective nodal irradiation and involved-field irradiation in esophageal squamous cell carcinoma: a meta-analysis.

It remains controversial whether radical radiotherapy in patients with esophageal squamous cell carcinoma (ESCC) still requires elective nodal irradiation (ENI), or only involved-field irradiation (IFI). In this study, a meta-analysis was conducted to compare ENI and IFI in the treatment of ESCC, in order to provide guidance for clinical practice. Literature on the use of ENI and IFI in the treatment of ESCC was retrieved, and the last access date was 31 December 2017. A meta-analysis was performed to evaluate the relative advantages and disadvantages of using ENI and IFI. Ten studies, involving a total of 1348 patients, were included in this analysis; of these, 605 patients underwent radiotherapy only, and 743 underwent radiochemotherapy. There was no significant difference in the 1-, 2- or 3-year local control rates between ENI and IFI, or in the 1-, 2- or 3-year overall survival rates. However, the incidences of ≥Grade 3 acute esophagitis and pneumonia were significantly lower in the IFI group. There were no differences in the rates of ≥Grade 3 myelosuppression or of out-field recurrence or metastasis between these two groups. Thus, neither local control rates nor overall survival rates differed significantly between the ENI and IFI groups, but in the latter group, incidences of severe radiation esophagitis and pneumonia were significantly lower. IFI was not associated with an increase in out-field recurrence or metastasis.

[Lymph node metastasis patterns and influencing factors in patients with limited esophageal small cell carcinoma].

OBJECTIVE: To explore the patterns and influencing factors of lymph node metastasis in limited esophageal small cell carcinoma (PESCC). METHODS: A total of 98 limited stage PESCC patients who underwent surgery were selected for this study. The lymph node metastasis ratio at different sites, depth of invasion, tumor length and other factors were analyzed to assess their influence on lymph node metastasis. RESULTS: Among the 98 PESCC cases, 46 cases had lymph node metastasis (46.9%). 100 out of 833 lymph nodes had metastasis, with a metastasis ratio of 12.0%. For upper thoracic esophageal small cell carcinomas, lymph node metastasis ratios were 42.9%, 12.5%, 0 and 0 in the superior mediastinum, middle mediastinum, inferior mediastinum and abdominal cavity, respectively. In the middle thoracic PESCCs, the lymph node metastasis ratios were 18.8%, 7.7%, 15.7%, and 15.3%, respectively. In the lower thoracic PESCCs, the lymph node metastasis ratios were 0, 0, 27.3% and 23.5%, respectively. Lymph node metastasis rates in PESCCs at stages T1, T2, T3, T4 were 15.4%, 42.3%, 63.9%, and 80.0%, respectively. The lymph node metastasis ratios in PESCCs at stages T1, T2, T3, T4 were 2.0%, 8.3%, 17.8% and 25.0%, respectively. Lymph node metastasis rate and lymph node metastasis ratio at different T stages were of significant difference (P<0.05 for all). Lymph node metastasis rates in patients with tumor <3 cm, 3-5 cm, and >5 cm were 30.6%, 46.9% and 66.7%, respectively, and lymph node metastasis ratios were 5.4%, 11.0% and 21.1%, respectively. Lymph node metastasis rate and lymph node metastasis ratio in patients with different tumor length had significant differences (P<0.05 for all). Lymph node metastasis ratio was 11.6% in the Chr-A negative and weak positive group, much higher than 4.3% in the Chr-A positive group (P=0.013). There was a tendency that lymph node metastasis ratio of NSE-positive group was higher than that of NSE-negative and weak positive group (P=0.069). The logistic univariate analysis did not find high risk factors of distant lymph node metastasis (all P>0.05). Logistic multivariate analysis found that only depth of invasion was a risk factor of lymph node metastasis in limited PESCC (P=0.002). CONCLUSIONS: Esophagus small cell carcinomas sometimes have early lymph node metastases in many sites and distant range. The middle thoracic PESCCs tend to have extensive metastasis quite common in the upper mediastinal lymph nodes. Lower mediastinal and abdominal lymph node metastases are often seen in lower thoracic PESCCs. The depth of invasion and tumor length are main factors influencing mediastinal lymph node metastasis. The depth of invasion is an independent risk factor for lymph node metastasis.

[Effect of silencing HIF-1α by RNA interference on adhesion and invasion of the human nasopharyngeal carcinoma cell line CNE-1].

OBJECTIVE: To investigate the effects of HIF-1α on adhesion and invasion of human nasopharyngeal carcinoma CNE-1 cells under hypoxia and underlying molecular mechanisms. METHODS: CoCl2was used to mimic tumor hypoxic microenvironment. mRNA and protein expressions of HIF-1α, E-cadherin and CXCR4 in CNE-1 cells at different hypoxic time phases were detected by RT-PCR and ELISA respectively. The influences of silencing HIF-1α using RNA interference on E-cadherin and CXCR4 expressions were evaluated. Adhesion test Transwell invasion test were used to evaluate the effects of HIF-1α gene silencing on cell adhesion and invasion. RESULTS: Under hypoxia, HIF-1α mRNA expression in CNE-1 cells was stable, but its protein expression increased obviously (P<0.05). Both mRNA and protein expressions of E-cadherin were decreased significantly with prolonged hypoxia, while mRNA and protein expressions of CXCR4 increased significantly (P<0.05). After silencing HIF-1α gene, expression of E-cadherin protein was up-regulated, but with down-regulated expression of CXCR4 protein, with a decrease significantly in adhesion rate or invasive cell number of CNE-1 cells (P<0.05). CONCLUSIONS: Hypoxia can increase HIF-1α protein expression in nasopharyngeal carcinoma cell line CNE-1. Silencing HIF-1α by RNA interference can reduce inhesion and invasion abilities of CNE-1 cells, which may be mediated by down-regulating E-cadherin expression and up-regulating CXCR4 expression.

[Relationship between hypoxia inducible factor-1α and esophageal squamous cell carcinoma: a meta analysis].

OBJECTIVE: To explore the expression of hypoxia inducible factor-1α(HIF-1α) in esophageal squamous cell carcinoma and its correlation with clinicopathological features. METHODS: Original literatures in foreign languages regarding correlation between HIF-1α and esophageal squamous cell carcinoma were identified from Cochrane Library, PubMed, EMbase database, and Chinese original literatures were from CBM, CNKI. All analyses were performed by Stata 11.0 software. Histological grade, degree of differentiation, T stage, lymph node metastasis, tumor stage, lymphatic invasion and vascular invasion were analyzed using pooled odds ratio (OR) with 95% confidence interval (CI). RESULTS: A total of 14 studies including 1 121 patients were enrolled in this meta analysis. Comparing with normal tissue, the expression of HIF-1α in esophageal squamous cell carcinoma was significantly enhanced (OR = 0.088, 95% CI: 0.061-0.129, P = 0.000); HIF-1α was significantly associated with T stage and lymph node metastasis (OR = 0.421, 95% CI: 0.222-0.798, P = 0.008; OR = 0.387, 95% CI: 0.207-0.725, P = 0.003). High expression of HIF-1α was correlated with an increased depth of tumor invasion, more lymph node metastasis and advanced tumor stage, whereas there was no relation to the degree of differentiation, histological grade, tumor stage, lymphatic invasion and vascular invasion. CONCLUSIONS: High expression of HIF-1α protein correlates with an increased risk of esophageal squamous cell carcinoma. HIF-1α may be an indicator for T stage, lymph node metastasis and tumor stage, but further studies are needed.

Relationship between EGFR over-expression and clinicopathologic characteristics in squamous cell carcinoma of the esophagus: a meta-analysis.

Over-expression of epidermal growth factor receptor (EGFR) has been identified as a common feature associated with clinical outcome in many types of cancer, including squamous cell carcinoma of the oesophagus (SCCO). However, the clinical importance of EGFR over-expression in SCCO remains unsettled as conflicting results exist. Therefore we carried out the present meta-analysis of published studies for clarification. A total of 13 studies including 1,150 patients were enrolled. EGFR over-expression was positive in 722 of these cases. With EGFR over-expression, patients had higher depth of invasion, vascular invasion, and poor prognosis. However, expression had no relation with degree of differentiation, histological grade, lymph node metastasis, clinical stage or lymphatic invasion. EGFR over-expression is probably a valuable predictor for the T stage, vascular invasion and OS, and it could be used as a poor prognosis indicator for the esophageal SCC patients. Targeting therapy to EFGR should be considered to the combined treatment in SCCO.

miR­210 regulates esophageal cancer cell proliferation by inducing G2/M phase cell cycle arrest through targeting PLK1.

micro (mi)RNAs are short regulatory RNAs that negatively modulate protein expression at the post­transcriptional level, and are being considered as novel therapeutic targets for the treatment of cancer. In the present study, an elevated expression level of circulating miR­210 was observed in patients with esophageal squamous cell carcinoma (ESCC) for the first time, to the best of our knowledge, and the induction of miR­210 under hypoxic conditions in ESCC was confirmed. Cell counting kit­8 assay and bromodeoxyuridine incorporation assay indicated that miR­210 markedly inhibited the proliferation of ESCC cells. In addition, the effect of miR­210 on the cell cycle was examined. Transfection of miR­210 resulted in a significant increase in the proportion of cells in G2/M phase. Polo­like kinase 1 (PLK1) was investigated as a candidate target of miR­210, which is a critical regulator of cell cycle transmission at multiple levels. It was demonstrated that miR­210 reduced the levels of PLK1 protein by binding the 3' untranslated region of its mRNA. The results of the present study demonstrated that miR­210 inhibited the proliferation of ESCC cells by inducing G2/M phase cell cycle arrest, and these effects of miR­210 were mediated by the targeting of PLK1.

Interactions between filamin A and MMP-9 regulate proliferation and invasion in renal cell carcinoma.

This study aimed to analyze the expression, clinical significance of filamin A (FLNA) in renal cell carcinoma (RCC) and biological effects in a cell line by regulating FLNA expression. Immunohistochemistry and Western blotting were used to analyze FLNA protein expression in 70 cases of RCC and normal tissues to study the relationship with clinical factors. FLNA lentiviral and empty vectors were transfected into RCC to study the influence of up-regulated expression of FLNA. FLNA siRNA was transiently transfected into ACHN kidney carcinoma cells by a liposome-mediated method and protein was detected by Western blotting. The level of expression was found to be significantly lower in RCC than normal tissues (p<0.05). No correlation was noted with gender, age, tumor size or pathological types (p>0.05), but links with lymph node metastasis, clinic stage and histological grade were noted (p<0.05). Loss of FLNA expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (p<0.05). Results for biological function showed that ACHN cells transfected with FLNA had a lower survival fraction, significant decrease in migration and invasion, higher cell apoptosis, higher percentage of the G0/G1 phases, and lower MMP-9 protein expression compared with ACHN cells untransfected with FLNA (p<0.05). However, renal 786-0 cells transfected with FLNA siRNA had a higher survival fraction, significant increase in migration and invasion, and higher MMP-9 protein expression compared (p<0.05). In conclusion, FLNA expression was decreased in RCC and correlated significantly with lymph node metastasis, clinic stage, histological grade and poor overall survival, suggesting that FLNA may play important roles as a a tumor suppressor in RCC by promoting degradation of MMP-9.

Inhibiting UHRF1 expression enhances radiosensitivity in human esophageal squamous cell carcinoma.

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel nuclear protein which is overexpressed in various cancers but not yet examined in esophageal squamous cell carcinoma (ESCC). The correlation between UHRF1 and the radioresistance in ESCC is still unclear. In the present study, the expression of UHRF1 was examined by immunohistochemistry in specimens of ESCC patients treated with radiotherapy. The results showed that UHRF1 was significantly overexpressed in ESCC specimens. Overexpression of UHRF1 correlated significantly with advanced T-stage, positive lymph node metastasis and poor differentiation. In addition, UHRF1 was associated with radiotherapy response, in which overexpression of UHRF1 was observed more frequently in the radioresistant group than in the effective group. At the molecular level, inhibition of UHRF1 by lentivirus-mediated shRNA targeting UHRF1 increased the radiosensitivity and apoptosis, while decreased radiation-induced G2/M phase arrest in TE-1 cells. Moreover, inhibition of UHRF1 resulted in higher residual γH2AX expression after irradiation, but not initial γH2AX. Further study showed that inhibition of UHRF1 down-regulated the endogenous expressions of DNA repair protein Ku70 and Ku80 in TE-1 cells, and significantly inhibited the increase of these proteins after irradiation. Above all, our data suggested that UHRF1 might play an important role in radioresistance of ESCC, and inhibition of UHRF1 can increase the radiosensitivity of TE-1 cells by altering cell cycle progression, enhancing apoptosis, and decreasing DNA damage repair capacity.

Characteristics of recurrence after radical esophagectomy with two-field lymph node dissection for thoracic esophageal cancer.

Postoperative radiotherapy has shown positive efficacy in lowering the recurrence rate and improving the survival rate in cases involving lymph node (LN) metastasis. However, the radiotherapy target volume remains controversial. Certain published studies have paid more attention to LNs found to be affected during surgery, while little effort has been made to study the LN metastatic pattern following surgery and its influence on the determination of the target volume of postoperative radiotherapy. In this study, the locoregional recurrence of esophageal squamous cell cancer was examined in 134 patients receiving radical surgery with two-field lymph node dissection from 2004 to 2009. In the 134 cases of recurrence, LN metastasis occurred in 126 patients (94.0%) while 13 patients (9.7%) developed anastomotic recurrence and 5 patients (3.7%) experienced tumor bed recurrence. The difference among the groups was statistically significant (P= 0.000). In the 126 cases with lymph node metastasis, the mediastinal metastasis rate (80.2%) was significantly higher compared with the rate of supraclavicular metastasis and abdominal metastasis (P= 0.000). A significant difference was identified between right and left supraclavicular LN metastasis (31.7% vs 16.7%, P= 0.005). Furthermore, the difference between the metastatic rates in the upper (73.8%), middle (39.7%) and lower mediastinum (1.6%) was statistically significant (P=0.000). Nevertheless, no significant correlation between the rate of LN metastasis was observed in the supraclavicular, mediastinal and abdominal regions for upper, middle and lower thoracic carcinomas (P= 0.404, P= 0.718 and P= 0.169, respectively). Based on our data, LN metastasis is the major locoregional recurrence pattern for esophageal squamous cell cancer following radical surgery. The high-risk lymphatic drainage areas include the supraclavicular nodes, recurrent laryngeal nerve nodes, azygos nodes and subcarinal nodes.

HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression.

Hypoxia-inducible factor-1α (HIF-1α) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF-1α in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1α, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1α on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1α, E-cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1α protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF-1α mRNA showed no significant change. SiRNA could block HIF-1α effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1α was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1α inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line.

LMO4 inhibits p53-mediated proliferative inhibition of breast cancer cells through interacting p53.

AIMS: The LIM domain only proteins (LMOs) which consist of four members (LMO1-LMO4) are a family of nuclear transcription coregulators that are characterized by the exclusive presence of two tandem LIM domains and no other functional domains. They regulate gene transcription by functioning as "linker" or "scaffolding" proteins by virtue of their LIM domains and are involved in the formation of multiprotein complexes with several DNA-binding factors and transcriptional regulatory proteins. In the present study, we tried to find the physical interaction between p53 and LMO4, and the effect of LMO4 on p53-mediated proliferative inhibition of breast cancer cells. MAIN METHODS: FCM analysis was developed to detect the apoptosis of breast cancer cells after adriamycin (ADR) treatment. RT-PCR and Western blot analysis were performed to detect the expression of LMO4 and p53-related genes and proteins. Immunoprecipitation assay was used to detect the interaction between LMO4 and p53. Colony formation assay was developed to detect the proliferation of breast cancer cells. KEY FINDINGS: We found that p53 was induced, but LMO4 was down-regulated in response to ADR. We also found that enforced expression of p53 inhibited the expression of LMO4, suggesting that LMO4 is a direct transcriptional target of p53. Furthermore, LMO4 can interact with p53 and inhibit p53-mediated inhibition of colony formation of breast cancer MDA-MB-453 cells. SIGNIFICANCE: The present study showed that LMO4 is a direct target of p53 and inhibits p53-mediated proliferative inhibition of breast cancer cells through interacting p53.

Prognostic analysis of limited-stage small cell lung cancer after chemoradiotherapy.

BACKGROUND: Chemotherapy (CT) in combination with thoracic radiotherapy (RT) can improve the survival of patients with limited-stage small cell lung cancer (LSSCLC). In the current study, we evaluated the prognostic factors, especially the effect of the therapy integration and the timing of RT, on survival. PATIENTS AND METHODS: We retrospectively studied 142 patients with LS-SCLC. All patients received thoracic RT and 126 patients received at least 2 cycles of CT; 38 patients received RT following CT cycles, 32 received RT between CT cycles, and 56 received RT concurrently with CT. RESULTS: For all patients, the 1-, 3-, and 4-year overall survival (OS) rates were 68.3, 31.2, and 28.6%, respectively. In univariate analyses, the volume of the primary tumor, T classification, CT, the target volume, the RT dose, and the treatment response were significantly associated with OS. The multivariate analysis showed that CT, the timing of RT, and RT dose were independent factors influencing the OS. CONCLUSION: Concurrent chemoradiotherapy could result in high survival rates, and early integration of thoracic RT was associated with a better outcome. A radiation dose-response relationship was observed in our study.