Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients.

This study is aimed to establish a new glioma prognosis model by integrating the aging-related lncRNA expression profiles and clinical parameters of glioma patients enrolled in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas. The aging-related lncRNAs were explored using Pearson correlation analysis (|R|> 0.6, P < 0.001), and the prognostic signature in glioma patients was screened using univariate cox regression and least absolute shrinkage/selection operator regression. Based on the fifteen lncRNAs screened out, we divided the glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients survived longer time than high-risk patients. Principal component analysis indicated that the signature of aging-related lncRNAs was clearly distinct between the high- and low-risk groups. We also found the fifteen lncRNAs were closely correlated with 119 genes by establishing a co-expression network. Kyoto Encyclopedia of Genes and Genomes analysis displayed that the high- and low-risk groups were enriched in different functions and pathways. Different missense mutations were observed in the two groups, and the most frequent variant types were single nucleotide polymorphism. This study demonstrates that the novel aging-related lncRNAs signature has an important prognosis prediction ability and may contribute to individualized treatment for glioma.

The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence-based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow-up of NPC, which aim to improve the management of NPC.

A novel nomogram for predicting locoregional recurrence risk in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy.

BACKGROUND: This study aimed to establish a nomogram for predicting locoregional recurrence (LRR) in breast cancer patients treated with neoadjuvant chemotherapy (NAC) and mastectomy. METHODS: A total of 2368 patients who received NAC and mastectomy between 2000 and 2014 from 12 grade A tertiary hospitals in China were analyzed retrospectively. The nomogram was developed based on the patients treated in three cancer hospitals (training set, n = 1629) and validated based on patients from the other nine general hospitals (validation set, n = 739). Factors identified from Fine and Gray's competing risk analysis were used to establish the nomogram. The predictive performance of the nomogram model was compared with the cTNM stage, ypTNM stage, and the Neo-Bioscore model by using the area under the time dependent receiver operating characteristic curves (tAUC), calibration curve, and decision curve analysis (DCA). RESULTS: The nomogram incorporated six risk factors derived from multivariable analysis of the training set including age, ypT stage, ypN stage, lymph node ratio, postmastectomy radiotherapy, and endocrine therapy. In the training set, the AUC of the nomogram was 0.792, which was higher than the values of the cTNM stage (0.582), ypTNM stage (0.737), and the Neo-Bioscore prognosis model (0.658). In the validation set, the AUC of the cTNM (0.619); ypTNM (0.636); and Neo-Bioscore staging system (0.584) were also significantly lower than the AUC of the nomogram (0.705). Both in the training and validation sets, the calibration curve showed good agreement between the nomogram-based predictions and the actual observations. CONCLUSION: The novel nomogram provides a more accurate evaluation of LRR for breast cancer patients treated with NAC and mastectomy.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Postmastectomy Radiation Therapy Based on Pathologic Nodal Status in Clinical Node-Positive Stage II to III Breast Cancer Treated with Neoadjuvant Chemotherapy.

PURPOSE: The present study aimed to evaluate the effect of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy in patients with node-positive stage II to III (cT1-4N1-2M0) breast cancer. METHODS AND MATERIALS: A total of 1813 patients from 12 institutions were retrospectively reviewed. Patients were classified into 1 of 3 groups based on the pathologic lymph node status after neoadjuvant chemotherapy: ypN0, ypN1, and ypN2-3. The role of PMRT was separately evaluated in each group. Locoregional control, disease-free survival, and overall survival (OS) were estimated using the Kaplan-Meier method. The effect of PMRT was assessed by propensity score-matched analyses and multivariate Cox analyses. RESULTS: With a median follow-up of 72.9 months, 5-year locoregional control, disease-free survival, and OS rates were 86.3%, 68.4%, and 83.1% for the entire cohort, respectively. There were 490 (27.0%), 567 (31.3%), and 756 (41.7%) patients in the ypN0, ypN1, and ypN2-3 groups, respectively. PMRT significantly improved 5-year OS in the ypN2-3 group (74.2% vs 55.9%; P < .001) but had no effect on 5-year OS in the ypN0 group (93.1% vs 95.5%; P = .517) and ypN1 group (88.4% vs 87.8%; P = .549). CONCLUSIONS: With modern systemic therapy, PMRT significantly improved OS in the ypN2-3 group but not in the ypN0 and ypN1 groups. Whether PMRT can be safely omitted in the ypN0 and ypN1 groups should be addressed prospectively.

RIG-I promotes IFN/JAK2 expression and the endoplasmic reticulum stress response to inhibit chemoradiation resistance in nasopharyngeal carcinoma.

RIG-I is associated with the occurrence and development of many tumors. However, the role of RIG-I in radiotherapy and chemotherapy in NPC has not been reported to date. In our study, RIG-I expression was significantly reduced in chemoradiotherapy-resistant NPC tissues and cells compared with that in therapy-sensitive tissues and cells. RIG-I expression increased in nonresistant NPC cells, including CNE1 and CNE2, in a dose-dependent manner with increasing chemotherapy drug concentration or radiotherapy dose. RIG-I overexpression promoted radiotherapy and chemotherapy sensitivity in NPC cells, leading to cellular apoptosis and increased expression of the proapoptotic factors BAX and caspase-3. Similarly, RIG-I knockdown in NPC cells promoted chemoradiotherapy resistance and reduced apoptosis. Analysis of microarray data indicated that the expression of IFN/JAK2 and endoplasmic reticulum (ER) stress response markers, such as JAK2, STAT1, IRF9, IFNB1, IRF3, p-IRF3, XBP1, ATF6, IFIT2, and ISG15, was inhibited in chemoradiotherapy-resistant cells compared with that in sensitive cells. Conversely, activation of IFN/JAK2 and ER stress response pathways in NPC cells reduced paclitaxel resistance and increased apoptosis. RIG-I promotes IFN/JAK2 and ER stress response-mediated apoptosis to inhibit chemoradiation resistance in nasopharyngeal carcinoma.

Dosimetric Comparisons of Volumetric Modulated Arc Therapy and Tomotherapy for Early T-Stage Nasopharyngeal Carcinoma.

PURPOSE: To compare the dosimetric differences between volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) in treating early T-stage nasopharyngeal carcinoma (NPC). METHOD: Ten patients with early T-stage NPC who received tomotherapy using simultaneously integrated boost (SIB) strategies were replanned with VMAT (RapidArc of Varian, dual-arc). Dosimetric comparisons between the RapidArc plan and the HT plan included the following: (1) D98, homogeneity, and conformity of PTVs; (2) sparing of organs at risk (OARs); (3) delivery time and monitor units (MUs). RESULTS: (1) Compared with RapidArc, HT achieved better dose conformity (CI of PGTVnx + nd: 0.861 versus 0.818, P = 0.004). (2) In terms of OAR protection, RapidArc exhibited significant superiority in sparing ipsilateral optic nerve (Dmax: 27.5Gy versus 49.1Gy, P < 0.001; D2: 23.5Gy versus 48.2Gy, P < 0.001), contralateral optic nerve (Dmax: 30.4Gy versus 49.2Gy, P < 0.001; D2: 26.2Gy versus 48.1Gy, P < 0.001), and optic chiasm (Dmax: 32.8Gy versus 48.3Gy, P < 0.001; D2: 30Gy versus 47.6Gy, P < 0.001). HT demonstrated a superior ability to protect the brain stem (D1cc: 43.0Gy versus 45.2Gy, P = 0.012), ipsilateral temporal lobe (Dmax 64.5Gy versus 66.4 Gy, P = 0.015), contralateral temporal lobe (Dmax: 62.8Gy versus 65.1Gy, P = 0.001), ipsilateral lens (Dmax: 4.27Gy versus 5.24Gy, P = 0.009; D2: 4.00Gy versus 5.05Gy, P = 0.002; Dmean: 2.99Gy versus 4.31Gy, P < 0.001), contralateral lens (Dmax: 4.25Gy versus 5.09Gy, P = 0.047; D2: 3.91Gy versus 4.92Gy, P = 0.005; Dmean: 2.91Gy versus 4.18Gy, P < 0.001), ipsilateral parotid (Dmean: 36.4Gy versus 41.1Gy, P = 0.002; V30Gy: 54.8% versus 70.4%, P = 0.009), and contralateral parotid (Dmean: 33.4Gy versus 39.1Gy, P < 0.001; V30Gy: 48.2% versus 67.3%, P = 0.005). There were no statistically significant differences in spinal cord or pituitary protection between the RapidArc plan and the HT plan. (3) RapidArc achieved a much shorter delivery time (3.8 min versus 7.5 min, P < 0.001) and a lower MU (618MUs versus 5646MUs, P < 0.001). CONCLUSION: Our results show that RapidArc and HT are comparable in D98, dose homogeneity, and protection of the spinal cord and pituitary gland. RapidArc performs better in shortening delivery time, lowering MUs, and sparing the optic nerve and optic chiasm. HT is superior in dose conformity and protection of the brain stem, temporal lobe, lens, and parotid.

Establishment and validation of M1 stage subdivisions for de novo metastatic nasopharyngeal carcinoma to better predict prognosis and guide treatment.

BACKGROUND: To better manage patients with de novo metastatic NPC (mNPC) including easily identifying individuals' survival outcomes and accurately choosing the most suitable treatment. MATERIALS AND METHODS: Three independent cohorts of mNPC patients (a training set of n = 462, an internal prospective validation set of n = 272 and an external prospective validation set of n = 243) were studied. The radiological characteristics of distant metastases, including number of metastatic locations, number of metastatic lesions and size of metastatic lesions, were carefully defined based on imaging data. These three factors and other potential prognostic factors were comprehensively analysed and were further integrated into new subdivisions of stage M1 using a Cox proportional hazards model. RESULTS: We successfully subdivided the M1 stage into three categories: M1a, oligo metastasis without liver involvement; M1b, multiple metastases without liver involvement; and M1c, liver involvement irrespective of metastatic lesions. The 3-year overall survival ranged from 54.5% to 72.8%, from 34.3% to 41.6% and from 22.6.0%-23.6% for M1a, M1b and M1c, respectively (P < 0.001). Systemic chemotherapy combined with radical loco-regional radiotherapy may benefit patients in M1a and M1b, not in M1c. Further aggressive treatment of metastatic lesions based on systemic chemotherapy and definitive loco-regional radiotherapy showed no survival benefit, even for patients in M1a (P > 0.05). CONCLUSION: The subdividing of M1 provided promising prognostic value and could aid clinicians in choosing the most suitable treatment for de novo mNPC patients.

Prognostic value and predictive threshold of tumor volume for patients with locally advanced nasopharyngeal carcinoma receiving intensity-modulated radiotherapy.

BACKGROUND: Gross target volume of primary tumor (GTV-P) is very important for the prognosis prediction of patients with nasopharyngeal carcinoma (NPC), but it is unknown whether the same is true for locally advanced NPC patients treated with intensity-modulated radiotherapy (IMRT). This study aimed to clarify the prognostic value of tumor volume for patient with locally advanced NPC receiving IMRT and to find a suitable cut-off value of GTV-P for prognosis prediction. METHODS: Clinical data of 358 patients with locally advanced NPC who received IMRT were reviewed. Receiver operating characteristic (ROC) curves were used to identify the cut-off values of GTV-P for the prediction of different endpoints [overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS)] and to test the prognostic value of GTV-P when compared with that of the American Joint Committee on Cancer T staging system. RESULTS: The 358 patients with locally advanced NPC were divided into two groups by the cut-off value of GTV-P as determined using ROC curves: 219 (61.2%) patients with GTV-P ≤46.4 mL and 139 (38.8%) with GTV-P >46.4 mL. The 3-year OS, LRFS, DMFS, and DFS rates were all higher in patients with GTV-P ≤46.4 mL than in those with GTV-P > 46.4 mL (all P < 0.05). Multivariate analysis indicated that GTV-P >46.4 mL was an independent unfavorable prognostic factor for patient survival. The ROC curve verified that the predictive ability of GTV-P was superior to that of T category (P < 0.001). The cut-off values of GTV-P for the prediction of OS, LRFS, DMFS, and DFS were 46.4, 57.9, 75.4 and 46.4 mL, respectively. CONCLUSION: In patients with locally advanced NPC, GTV-P >46.4 mL is an independent unfavorable prognostic indicator for survival after IMRT, with a prognostic value superior to that of T category.

Clinical utility of microRNA-378 as early diagnostic biomarker of human cancers: a meta-analysis of diagnostic test.

A meta-analysis was performed to evaluate the diagnostic value of miR-378 for detecting human cancers. Systematic electronic searches were conducted in PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang from the inception to January 15, 2016. We used the bivariate mixed effects models to estimate the combined sensitivity, specificity, PLRs (positive likelihood ratios), NLR (negative likelihood ratios), DORs (diagnostic odds ratios) and their 95% CI (confidence intervals) for assessing the diagnostic performance of miR-378 for cancers. Twelve studies were included in the meta-analysis, with a total number of 1172 cancer patients and 809 health controls. The overall estimated sensitivity and specificity were 0.75 and 0.74. The pooled PLR was 2.91, NLR was 0.34, DOR was 8.50, and AUC (Area Under the Curve) was 0.81. The subgroup analyses suggested that AUC for plasma-based is higher than serum-based. The overall diagnostic values of miR-378 in the present meta-analyses are moderate accurate for human cancers; The source of specimen has an effect on the diagnostic accuracy. The diagnostic value of serum-based was higher than that of plasma-based.

MiR-129-2 functions as a tumor suppressor in glioma cells by targeting HMGB1 and is down-regulated by DNA methylation.

MicroRNA (miRNA) dysregulation is causally related to cancer development and progression, and recent reports have revealed that DNA methylation constitutes an important mechanism for miRNA deregulation in cancer. MiR-129-2 has been reported to be down-regulated and functions as a tumor suppressor in a few human cancers. However, the involvement of miR-129-2 in the pathology of glioma and the mechanism underlying miR-129-2 regulation in glioma cells remain unclear. In this study, we performed quantitative PCR to investigate the level of miR-129-2 in 21 pairs of glioma tumors and matched adjacent tissues and found that miR-129-2 is down-regulated in glioma tumors. In vitro cell growth, apoptosis, cell migration, and invasion assays revealed that miR-129-2 functions as a tumor suppressor in glioma cells. Luciferase reporter assay found that miR-129-2 could directly target high-mobility group box 1 (HMGB1) and inhibit its expression in glioma cells. Methylation-specific PCR found that DNA methylation in upstream regions of miR-129-2 occured more frequently in cancer tissues than in adjacent tissues. Demethylation of miR-129-2 by 5-aza-2'-deoxycytidine treatment and quantitative PCR analysis revealed that miR-129-2 expression is epigenetically regulated in glioma cells. Taken together, our data suggested that miR-129-2 functions as a tumor suppressor in glioma cells by directly targeting HMGB1 and is down-regulated by DNA methylation, which may provide a novel therapeutic strategy for treatment of glioma.

Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma.

The aim of this study was to investigate the association of CD147 and GLUT-1, which play important roles in glycolysis in response to radiotherapy and clinical outcomes in patients with locally advanced cervical squamous cell carcinoma (LACSCC). The records of 132 female patients who received primary radiation therapy to treat LACSCC at FIGO stages IB-IVA were retrospectively reviewed. Forty-seven patients with PFS (progression-free survival) of less than 36 months were regarded as radiation-resistant. Eighty-five patients with PFS longer than 36 months were regarded as radiation-sensitive. Using pretreatment paraffin-embedded tissues, we evaluated CD147 and GLUT-1 expression by immunohistochemistry. Overexpression of CD147, GLUT-1, and CD147 and GLUT-1 combined were 44.7%, 52.9% and 36.5%, respectively, in the radiation-sensitive group, and 91.5%, 89.4% and 83.0%, respectively, in the radiation-resistant group. The 5-year progress free survival (PFS) rates in the CD147-low, CD147-high, GLUT-1-low, GLUT-1-high, CD147- and/or GLUT-1-low and CD147- and GLUT-1- dual high expression groups were 66.79%, 87.10%, 52.78%, 85.82%, 55.94%, 82.90% and 50.82%, respectively. CD147 and GLUT-1 co-expression, FIGO stage and tumor diameter were independent poor prognostic factors for patients with LACSCC in multivariate Cox regression analysis. Patients with high expression of CD147 alone, GLUT-1 alone or co-expression of CD147 and GLUT-1 showed greater resistance to radiotherapy and a shorter PFS than those with low expression. In particular, co-expression of CD147 and GLUT-1 can be considered as a negative independent prognostic factor.

Outcomes and prognostic factors of conformal radiotherapy versus intensity-modulated radiotherapy for nasopharyngeal carcinoma.

INTRODUCTION: This study retrospectively compared outcomes and prognostic factors of nasopharyngeal carcinoma (NPC) treated with conformal radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: The treatment records of 182 patients treated with IMRT and 198 patients treated with CRT from April 2005 to December 2007 in our hospital were reviewed. The clinical characteristics, treatment outcomes (including survival analysis and acute and late toxicity), and prognostic factors of the two groups were compared. RESULTS: The 4-year local-regional control (LRC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of the IMRT and CRT groups were 93.6 and 85.3 %, 79.1 and 73.6 %, 74.7 and 65.0 %, and 83.5 and 72.1 %, respectively. The acute radiation dermatitis and xerostomia of the two groups were significantly different (P < 0.05). In the IMRT group, OS between different T stages could not be well separated. Multivariate analysis revealed that, in the CRT group, the clinical stage and T and N stages were significant prognostic factors for OS, DMFS, and DFS and that T stage was a significant prognostic factor for LRC. In the IMRT group, T and N stages had no predictive value for outcomes. CONCLUSIONS: Compared with CRT, IMRT has a better prognosis and less adverse effects. For IMRT, T stage was not a significant prognostic factor for LRC, DMFS, DFS, or OS. An effective treatment strategy is needed for distant control. With the increasing use of IMRT and continued modulation of treatment strategies for NPC, the current staging system faces great challenges.

The superparamagnetic nanoparticles carrying the E1A gene enhance the radiosensitivity of human cervical carcinoma in nude mice.

To explore the effects of early region 1A (E1A) carried by superparamagnetic dextran iron oxide nanoparticles (SDION) on the radiosensitivity of human cervical cancer. The xenograft mice with cervical cancer received weekly intratumoral SDION-E1A injection and a subsequent 50-Gy irradiation. The weekly relative tumor volume and the final tumor volume were compared among different experimental groups. p53 and human epidermal growth factor receptor-2 (HER-2)/Neu expression in final tumor tissue was detected by reverse transcription-PCR and Western blot. The relative tumor volume and the final tissue volume in the SDION-E1A group was significantly smaller than that in Sham and SDION-Vector groups at each time points after irradiation (P < 0.05). Exogenous E1A expression by SDION delivery significantly increased p53 expression, but inhibited HER-2/Neu expression in tumor tissue (P < 0.05). The intratumoral delivery of exogenous E1A carried by SDION increases p53 expression but inhibits HER-2/neu expression, and enhances the radiosensitivity of human cervical cancer in xenograft mice.

Profiling protein markers associated with the sensitivity to concurrent chemoradiotherapy in human cervical carcinoma.

Concurrent chemoradiotherapy (CCRT) is recently recommended as the primary and standard treatment modality for cervical cancer. The aim of this study is to investigate the protein biomarkers associated with CCRT sensitivity, so as to better understand the mechanisms underlying CCRT resistance. Fresh tumor tissues from five cases for each group of CCRT-highly sensitive (CCRT-HS) and CCRT-lowly sensitive (CCRT-LS) were analyzed by 2-D electrophoresis coupled with MALDI-TOF-MS, followed by Western blot for four candidate proteins including S100A9, galectin-7, nuclear matrix protein-238 (NMP-238), and heat shock protein-70 (HSP-70). In randomly selected CCRT-HS (n = 60) and CCRT-LS (n = 35) cases, these four differentially expressed proteins were detected by tissue microarray with immunohistochemistry staining to explore the association between these interested proteins and CCRT sensitivity. Nineteen proteins differentially expressed more than four times between two groups were identified. An association was revealed between CCRT sensitivity and increased S100A9 and galectin-7, but decreased NMP-238 and HSP-70 expression (p < 0.001, respectively). Although none of these four protein markers could be used as an independent predictive factor, a recurrence prediction model was generated by combining S100A9, galectin-7, NMP-238, and HSP-70 as a full predictive factor. The proteomic analysis combined with tissue microarray provides us a dramatic tool in predicting CCRT response. The increased expression of S100A9 and galectin-7, but decreased expression of NMP-238 and HSP-70, suggests a significantly increased sensitivity to CCRT in cervical cancer.

[Molecular mechanism of proliferation of human breast cancer cell MCF-7 inhibited by E1A gene].

OBJECTIVE: To explore the molecular mechanism of proliferation inhibition of human breast cancer cell MCF-7 regulated by E1A gene. METHODS: E1A gene was transfected into MCF-7 cells by liposome reagents. RT-PCR and Western blot were used to detect E1A mRNA and protein expression and HER-2 mRNA in MCF-7. The proliferation and colony formation of MCF-7 were measured by 3-(4,5-dinmethylthiahiazo-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and soft agar formation assay. The apoptosis of MCF-7 cells regulated by E1A expression was examined by flow cytometry. RESULTS: E1A was not endogenously expressed in MCF-7. E1A expression in MCF-7 could significantly decrease HER-2 mRNA and protein expression. Flow cytometry indicated that the apoptosis of MCF-7 could be induced by E1A. Meanwhile, E1A gene could significantly inhibit MCF-7 proliferation and colony formation in soft agar. CONCLUSION: E1A gene can decrease HER-2 expression and induce the apoptosis of human breast cancer cell MCF-7, and inhibit the proliferation and colony formation of MCF-7.

[Screening concurrent chemoradiotherapy sensitivity-associated proteins in intermediate stage and advanced cervical carcinoma].

BACKGROUND & OBJECTIVE: Concurrent chemoradiotherapy is a new therapy for intermediate stage and advanced cervical carcinoma, but no valid index for prediction of concurrent chemoradiotherapy sensitivity is available. This study was to screen concurrent chemoradiotherapy sensitivity-associated proteins in intermediate stage and advanced cervical carcinoma. METHODS: Biopsy samples of 10 cervical carcinoma patients were collected before treatment. According to their responses to concurrent chemoradiotherapy (WHO standard), the patients were classified into high sensitivity (HS) group (5 patients) and low sensitivity (LS) group (5 patients). Total protein were extracted from the biopsy samples. Differential proteins were detected by two-dimensional gel electrophoresis (2-DE) and confirmed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Two differentially expressed proteins were further detected by immunohistochemistry in 95 specimens of cervical carcinoma, including 60 high sensitive cases and 35 low sensitive cases. RESULTS: Nineteen differentially expressed proteins were identified: 9 were highly expressed and 10 were lowly expressed in high sensitive group as compared with those in low sensitive group. According to immunohistochemical results, the expression intensity of heat shock protein 70 (HSP70) was higher and that of S100A9 protein was lower in HS group than in LS group; the positive rate of S100A9 was significantly higher and that of HSP70 was significantly lower in HS group than in LS group (88.3% vs. 28.6%, chi2=35.34, P<0.001; 21.7% vs. 85.7%, chi2=36.59, P<0.001). CONCLUSIONS: Differentially expressed proteins that related to concurrent chemoradiotherapy sensitivity of cervical carcinoma are identified. They may be candidate biomarkers for prediction of concurrent chemoradiotherapy sensitivity.

[Effect of radiotherapy on the thyroid of patients with nasopharyngeal cancer].

OBJECTIVE: To determine the effect of radiotherapy on the thyroid of patients with nasopharyngeal cancer. METHODS: Thyroid dynamic imaging was performed on 51 patients with nasopharyngeal cancer who had the metastasis of the jugular lymph node before and after the radiotherapy. The peak time of the thyroid artery perfusion and the constant K were obtained. The levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) in the blood serum were measured at the same time. RESULTS: The peak time of the left and right thyroid artery perfusion before the radiotherapy was (14.5+/-2.1)s and (15.1+/-1.9)s, respectively, while that after the radiotherapy was (19.3+/-3.2)s and (20.2+/-3.5)s, respectively. There was significant difference between the pre- and post-radiotherapy (P<0.001). The constant K of the left and right thyroid before the radiotherapy was significantly higher than that after the radiotherapy (0.0265+/-0.0074 vs. 0.0173+/-0.0062; 0.0249+/-0.0065 vs. 0.0167+/-0.0053, P<0.001, respectively). The level of FT3 and FT4 was significantly higher than that after the radiotherapy, but the TSH level had no obvious change[(4.76+/-0.95) pmol/L vs. (3.85+/-0.71) pmol/L,P<0.001; (18.63+/-3.84) pmol/L vs. (15.69+/-3.27) pmol/L,P<0.001; (1.17+/-0.52) mU/L vs. (1.22+/-0.76)mU/L ,P>0.05, respectively]. CONCLUSION: The peak time of the thyroid artery perfusion and the constant K which reflect blood stream status after the radiotherapy are all damaged in patients with nasopharyngeal cancer. The level of FT3 and FT4 in the blood serum is dropped but the TSH level has no obvious change.

[Effect of diameter of adriamycin polybutylcyanoacrylate nanoparticles on liver targeting].

OBJECTIVE: To observe the different tissue distributions of the adriamycin polybutylcyanoacrylate nanoparticle (ADM-PBCA-NP) in the mice body after the injection via lateral tail vein, and to study the liver targeting effects of ADM-PBCA-NP in different diameters on normal mice livers. METHODS: One hundred and eighty mice were randomly divided into 6 groups with 30 mice in each group: non-conjugated free ADM (Group 1); (22.3+/-6.2) nm in diameter ADM-PBCA-NP group (Group 2); (48.6+/-9.2) nm ADM-PBCA-NP group (Group 3); (101.9+/-20.3) nm ADM-PBCA-NP group (Group 4); (143.5+/-23.5) nm ADM-PBCA-NP group (Group 5), and (194.2+/-28.4) nm ADM-PBCA-NP group (Group 6). A single dose of either conjugated or free adriamycin equaled 2 mg/kg of body weight was delivered via the tail vein. Five mice in each trail were sacrificed at 5, 15, 30 minutes, 1, 5 and 12 hours after the injection, respectively. The adriamycin concentrations in the collected livers, kidneys, spleens, hearts, lungs and plasma were demonstrated using a high performance liquid chromatography with fluorescence detector. RESULTS: Compared with that of the control group, adriamycin was hardly detected in the heart muscles of the treatment groups (P<0.05). The nanoparticle-conjugated adriamycin was cleaned up quickly from the kidney tissues. The adriamycin concentrations of the mice liver and spleen in the experimental groups was significantly higher than those in the control group, except for the group with the nanoparticles diameters of (22.3+/-6.2) nm (P<0.05). The ADM-PBCA-NP in (101.9+/-20.3) nm diameter had the highest liver distribution, and the second highest adriamycin distribution in the liver was the group of (143.5+/-23.5) nm diameter (P<0.05). Adriamycin was released slowly in the liver during the detection period in the experimental groups. ADM-PBCA-NP in (22.3+/-6.2) nm diameter was not distributed in the tissues of the livers, kidneys, hearts, spleens, and lungs. CONCLUSION: ADM-PBCA-NP with a 100 - 150 nm diameter range has the best liver targeting with slow medicine release. It also decreases the medicine distribution in the heart and other organs. In the treatment of liver cancer, the polybutylcyanoacrylate nanoparticle system has a good liver targeting ability, which increases the anticancer activity and markedly decreases the toxicity of adriamycin.