Wen-Jie Guo

HMGA2 is associated with epithelial–mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma

Objective High-mobility group protein 2 (HMGA2) and epithelial–mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis. However, the clinical significance of HMGA2 and its relationship with EMT markers in nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the clinicopathological significance and prognostic value of HMGA2, E-cadherin, and vimentin in NPC. Methods Using immunohistochemistry, HMGA2, E-cadherin, and vimentin expression levels were evaluated in NPC (n=124) and non-tumoral inflammatory nasopharynx (n=20) tissues. The association of HMGA2 and EMT markers with clinicopathological characteristics and relationships between the protein levels and overall survival were analyzed. Results Compared with non-tumorous tissues, HMGA2 and vimentin levels were markedly increased in NPC tissues, whereas decreased E-cadherin levels were observed (P<0.001). Moreover, HMGA2 expression was positively correlated with vimentin levels (r=0.431, P<0.001) and negatively correlated with E-cadherin amounts (r=−0.413, P<0.001) in NPC tissues. The expression of all three proteins correlated significantly with tumor N stage, TNM stage, and 2-year metastasis. Furthermore, significant correlations were found for T stage, N stage, TNM stage, HMGA2, E-cadherin, and vimentin (all P<0.013) with poor prognosis (univariate analysis). However, multivariate analyses showed that only HMGA2 (hazard ratio [HR]: 2.683, 95% confidence interval [CI]: 1.185–6.077, P=0.018) and N stage (HR: 7.892, 95% CI: 2.731–22.807, P<0.001) were independent predictors of poor prognosis. Conclusion These results demonstrated that HMGA2, an independent prognostic factor, may promote NPC progression and metastasis, and is significantly associated with EMT proteins. Therefore, HMGA2 may be considered a potential therapeutic target in NPC.

Downregulating HMGA2 attenuates epithelial-mesenchymal transition-induced invasion and migration in nasopharyngeal cancer cells.

BACKGROUND Epithelial-mesenchymal transition (EMT) is associated with invasion and metastasis of cancer cells. High-mobility group AT-hook 2 (HMGA2) has been found to play a critical role in EMT in a number of malignant tumors. However, whether HMGA2 regulates the EMT in human nasopharyngeal carcinoma (NPC) is unclear. OBJECTIVE The aim of this study was to investigate the effect and mechanism of HMGA2 in inducing invasion and migration in NPC. METHODS In NPC tissues samples, the association of HMGA2 mRNA expression with clinicopathological characteristics were estimated by real-time quantitative RT-PCR(qRT-PCR). In vitro, following the silencing of HMGA2 in CNE-1 and CNE-2 cell lines, the viability and metastatic ability were analyzed using Cell Counting Kit-8 (CCK8), colony formation assay, and transwell assay. EMT and transforming growth factor-beta (TGFβ)/Smad3 signaling pathway-related protein expression changes were evaluated using western blot. RESULTS HMGA2 was upregulated in NPC cell lines and clinical specimens (P < 0.01), and HMGA2 expression correlated significantly with metastasis (P = 0.02) and disease-free survival of NPC (hazard ratio: 3.52; 95% confidence interval: 1.34-7.79; P = 0.01). In addition, following in vitro knockdown of HMGA2, the aggressiveness of cells was markedly inhibited, Vimentin and Snail level was downregulated and E-cadherin expression was upregulated. Moreover, the expression of key proteins TGFβRII and p-Smad3 of the TGFβ/Smad3 signaling pathway was inhibited by the downregulation of HMGA2. CONCLUSION HMGA2 might maintain EMT-induced invasion and migration through the TGFβ/Smad3 signaling pathway in NPC cell lines.

Concurrent chemoradiotherapy with nedaplatin plus paclitaxel or fluorouracil for locoregionally advanced nasopharyngeal carcinoma: Survival and toxicity.

The purpose of this study was to review the survival and toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiation therapy (IMRT) and concurrent nedaplatin plus paclitaxel or fluorouracil (NP or NF).

Cetuximab in combination with chemoradiation after induction chemotherapy of locoregionally advanced nasopharyngeal carcinoma: preliminary results

AIM This article aimed to determine treatment compliance, acute toxicities and the short-term curative effects of combining cetuximab with chemoradiation following induction chemotherapy of locoregionally advanced nasopharyngeal carcinoma (NPC). MATERIALS & METHODS A total of 21 patients with locoregionally advanced NPC were scheduled to receive one cycle of induction chemotherapy followed by intensity-modulated radiotherapy, weekly administration of cetuximab and concurrent chemotherapy (at least two cycles with a limit of six). RESULTS All 21 patients completed the planned radiotherapy, 14 patients (67%) without treatment breaks, and 20 patients (95.2%) completed the planned cetuximab therapy. Grade 4 toxicities included leukopenia (seven patients; 33.4%), neutropenia (three patients; 14.3%), thrombocytopenia (one patient; 4.8%) and acneiform rash (one patient; 4.8%). Over a median follow-up period of 13 months (range: 3-23 months), the local, regional and distant control rates were 100, 100 and 95.2%, respectively. CONCLUSION Cetuximab in combination with intensity-modulated radiotherapy and chemoradiation is a feasible strategy against locoregionally advanced NPC. Preliminary survival data are encouraging compared with historic data.

A new index comparable to BED for evaluating the biological efficacy of hypofractionated radiotherapy schemes on early stage non-small cell lung cancer: Analysis of data from the literature

BACKGROUND AND PURPOSE Hypofractionated radiotherapy has been the principal curative treatment option for early stage NSCLC patients who are medically inoperable or those who refuse surgery and achieved favorable clinical outcomes. Evidence demonstrated that the linear quadratic model widely used in normally fractionated radiotherapy cannot work well to fit outcome data by use of BED to predict the effect of hypofractionation schemes. New models and the related metrics need to be developed to quantify the effect of high-dose ablative regimens for early stage NSCLC. PATIENTS AND METHODS Trials using hypofractionated radiotherapy without chemotherapy to treat early stage (T1 or T2N0M0) primary NSCLC and providing information on patient numbers, age, T stage and local control rates were eligible. The endpoint was local relapse and the covariates analyzed were total radiotherapy dose, dose per fraction or combinations of the two parameters, treatment duration, T stage and median age of patients within the trial. The model used was a multivariate logistic regression. RESULTS 19 trials were included (767 patients) in which 90 patients suffered local relapse. Only total dose × dose per fraction (D × d) and stage T had statistically significant effect on local control. Smaller T stage (p=0.000) and increasing D × d (p=0.006) were associated with improved probability of local control. In contrast, BED10 had no significant impact on local control, which probably indicated that D × d might be a more effective metric than BED10 to predict tumor control rate and assess the efficacy of the large dose fractionation schemes for early stage NSCLC. CONCLUSIONS BED was not an ideal metric to estimate the effect of the schemes of high-dose ablative radiotherapy for early stage NSCLC, and total dose × fraction dose could be considered as a comparable index, though the result need to be further validated.

Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center

OBJECTIVES Intensity-modulated radiotherapy (IMRT) has been applied in nasopharyngeal carcinoma (NPC) for nearly twenty years, while little is known about the ten-year survival outcomes. This study aimed at evaluating the 10-year survival outcomes for patients with NPC receiving IMRT. MATERIALS AND METHODS Data on 614 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2004 and 2008 were retrospectively reviewed. Survival outcomes stratified by tumor stage were compared. RESULTS The median follow-up duration was 112.7months (range, 7.6-156.8months) for the entire cohort. The 10-year local relapse-free survival rates for T1, T2 and T3 were 94.2%, 92.5% and 91.4% (P>0.05), respectively, and significantly higher than that of T4 disease (79.3%, P<0.05 for all rates). As N category increased from N0 to N3, the 10-year distant metastasis-free survival rates significantly decreased accordingly (P<0.01 for all rates). Furthermore, the 10-year overall survival rates were 100%, 87.1%, 75.5% and 55.6% for stage I, II, III and IV, respectively (P<0.05 except stage I and II). Multivariate analysis established tumor stage and age as independent prognostic factors. Late toxicities were assessable for 495 (80.6%) patients and most were Grade I/II damages. Xerostomia (387 of 489, 79.1%) and hearing impairment (212 of 495, 42.8%) remained the most troublesome. CONCLUSION IMRT could achieve satisfactory survival outcomes for NPC patients with acceptable late toxicities. However, distant control still remains poor, especially for patients with N3 disease.

A comparative study of locoregionally advanced nasopharyngeal carcinoma treated with intensity modulated irradiation and platinum-based chemotherapy

PURPOSE To investigate the prognosis of three subgroups of locoregionally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy and platinum-based chemotherapy. PATIENTS AND METHODS Hundred and eighty-one consecutive patients with locoregionally advanced untreated nasopharyngeal carcinoma were retrospectively divided into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and the mixed group (T3-4N2-3M0). They were all treated with definitive intensity-modulated radiotherapy and platinum-based chemotherapy. Their prognosis were investigated and compared. Multivariate analysis was applied to identify the independent risk factors of study endpoints. RESULTS The 3-year locoregional control rates for locally advanced group, regionally advanced group, and the mixed group were 91.5%, 90.6% and 84.3% respectively, no significant difference was observed (P=0.656, P=0.429). The 3-year distant metastasis-free survival rates were 89.6%, 75.7% and 76.3%, respectively. The distant metastasis-free survival rate of the locally advanced group was significantly higher than the other two subgroups (P=0.028, P=0.028). The 3-year progression-free survival rates were 85.5%, 67.9% and 67.1% respectively with significance also favoring the locally advanced group (P=0.043, P=0.023). Nodal stage and the performance status were the independent risk factors of distant metastasis in the observed period. CONCLUSIONS In the context of intensity-modulated radiotherapy and platinum-based chemotherapy, the locally advanced group had a better prognosis compared with the regionally advanced group and the mixed group. Treatment stratification may be based on nodal stage.

Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma.

Background N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC) patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT). Patients and Methods Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67) or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61). Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy. Results With a median follow-up of 60 months, the 5-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212) and LRRFS rates (89.0% vs. 86.3%, P = 0.664) was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046) and DMFS (75.1% vs. 89.0%, P = 0.042) rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3–4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003), and both liver and renal dysfunction (χ2 = 5.206, P = 0.023) compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups. Conclusion IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute toxicity rate.

HAP1 gene expression is associated with radiosensitivity in breast cancer cells

OBJECTIVES The purpose of this study was to investigate the relationship between huntingtin-associated protein1 (HAP1) gene and radiation therapy of breast cancer cells. METHODS HAP1 gene was transfected into breast cancer MCF-7 cells, which was confirmed by quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) and Western blot in vitro. The changes of cell radiosensitivity were assessed by colony formation assay. Apoptosis were examined by flow cytometry. The expressions of two radiation-induced genes were evaluated by Western blot. Tumor growth was investigated in nude mice xenograft models in vivo. RESULTS Our data showed that HAP1 gene expression was significantly increased in HAP1-transfected MCF-7 cells in comparison with the parental cells or negative control cells. The survival rate in MCF-7/HAP1 cells was significantly decreased after irradiation (0, 2, 4, 6, 8Gy), compared to cells in MCF-7 and MCF-7/Pb groups in vitro. HAP1 gene increased apoptosis in MCF-7 cells after irradiation. Additionally, the tumor volume and weight in MCF-7/HAP1+RT group were observably lower than in MCF-7/HAP1 group and MCF-7/Pb+RT group. CONCLUSION The present study indicated that HAP1 gene expression was related to the radiosensitivity of breast cancer cells and may play an important role in the regulation of cellular radiosensitivity.

Comparing the efficacy of induction-concurrent with concurrent-adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: a propensity score matching analysis

Purpose This study aimed to compare the efficacy of induction-concurrent (IC-CCRT) with concurrent-adjuvant (CCRT-AC) chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated by intensity-modulated radiotherapy (IMRT). Materials and Methods Data on 834 patients with newly diagnosed, non-metastatic stage III-IVA (except T3N0) NPC receiving either IC-CCRT or CCRT-AC between July, 2004 and December, 2014 were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between IC-CCRT and CCRT-AC were compared. Results The median follow-up duration is 45.2 months (range, 1.07–145.4 months). Overall, 309 pairs were selected by PSM. Univariate analysis revealed the CCRT-AC group achieved significantly higher 3-year DFS (83.9% vs. 78.7 %; P = 0.014) and OS (87.6% vs. 87.0%; P = 0.031). Multivariate analysis also identified treatment group (IC-CCRT vs. CCRT-AC) as an independent prognostic factor for 3-year DFS (HR, 1.546; 95% CI, 1.113–2.149; P = 0.009) and OS (HR, 1.487; 95% CI, 1.035–2.136; P = 0.032). Subgroup analysis revealed IC-CCRT was a protective factor for DMFS (HR, 0.145; 95% CI, 0.043–0.488; P = 0.002) in stage III disease; however, it could adversely affected DFS (HR, 2.009; 95% CI, 1.316–3.065; P = 0.001), OS (HR, 1.671; 95% CI, 1.060–2.636; P = 0.027) and DMFS (HR, 1.986; 95% CI, 1.155–3.416; P = 0.013) in stage IVA disease. Conclusions CCRT-AC may be a more effective treatment modality in patients with stage IVA NPC disease, while IC-CCRT was superior in stage III disease.