Altered DNA Methylation and Gene Expression Profiles in Radiation-Induced Heart Fibrosis of Sprague-Dawley Rats.

Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for thoracic tumors. Advanced myocardial fibrosis in the late phase of RIHD can lead to myocardial remodeling, heart function impairing and heart failure, resulting in serious clinical consequences, and its pathogenesis remains vague. DNA methylation is one of the important epigenetic mechanisms which often occurs in response to environmental stimuli and is crucial in regulating gene expression. We hypothesized DNA methylation may contribute to pathogenesis in radiation-induced heart fibrosis (RIHF) and altered DNA methylation patterns probably influenced the genes expression in RIHF. In present study, we found genome-wide differences in DNA methylation status and RNA expression were demonstrated and we screened out 44 genes whose altered expression maybe were regulated by CpG island methylation within the gene promoter in RIHF of Sprague-Dawley rat by employing gene expression arrays and human CpG island microarrays. Gene expression and CpG island methylation levels of several candidate genes were further validated. Our investigation provided a new dimension to reveal the specific mechanisms of RIHF and explore the potential therapeutic targets for it.

Survey and analysis of the nutritional status in hospitalized patients with malignant gastric tumors and its influence on the quality of life.

BACKGROUND/OBJECTIVES: The assessment of nutritional status and the quality of life in patients with gastric cancer has become one of the important goals of current clinical treatment. The purpose of this study was to assess the nutritional status in hospitalized gastric cancer patients by using patient-generated subjective global assessment (PG-SGA) and to analyze the influence of nutritional status on the patients' quality of life (QOL). METHODS: We reviewed the pathological diagnosis of gastric cancer for 2322 hospitalized patients using PG-SGA to assess their nutritional status and collected data on clinical symptoms, the anthropometric parameters (height, weight, body mass index (BMI), mid-arm circumference (MAC), triceps skin-fold thickness (TSF), and hand-grip strength (HGS). We also collected laboratory data (prealbumin, albumin, hemoglobin) within 48 h after the patient was admitted to the hospital. The 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) was used for QOL assessment in all patients. RESULTS: By using PG-SGA, we found 80.4% of the patients were malnourished (score ≥ 4) and 45.1% of the patients required urgent nutritional support (score ≥ 9). In univariate analysis, old age (> 65 years, p < 0.001), female (p = 0.007), residence in a village (p = 0.004), a lower level of education (p < 0.001), and self-paying (p < 0.001) were indicated as risk factors of patients with gastric cancer to be suffering from severe malnutrition. There was a negative correlation between PG-SGA and various nutritional parameters (p < 0.05). The quality of life was significantly different in gastric cancer patients with different nutritional status (p < 0.01). CONCLUSION: Malnutrition of hospitalized patients with gastric cancer in China is common and seriously affects the patients' quality of life. The nutritional status should be evaluated in a timely manner and reasonable nutritional intervention should be provided as soon as possible. The PG-SGA was fit for using as a clinical nutrition assessment method, being worthy of clinical application.

Locoregional Control and Mild Late Toxicity After Reducing Target Volumes and Radiation Doses in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy (IC) Followed by Concurrent Chemoradiotherapy: 10-Year Results of a Phase 2 Study.

PURPOSE: To evaluate the long-term locoregional control, failure patterns, and late toxicity after reducing the target volume and radiation dose in patients with locoregionally advanced nasopharyngeal carcinoma patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). METHODS AND MATERIALS: Previously untreated patients with locoregionally advanced nasopharyngeal carcinoma were recruited into this prospective study. All patients received 2 cycles of IC followed by CCRT. The gross tumor volumes of the nasopharynx (GTVnx) and the neck lymph nodes (GTVnd) were delineated according to the post-IC tumor extension and received full therapeutic doses (68 Gy and 62-66 Gy, respectively). The primary tumor shrinkage after IC was included in the high-risk clinical target volume (CTV1) with a reduced dose of 60 Gy. The locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. The location and extent of locoregional recurrences were transferred to pretreatment planning computed tomography for dosimetry analysis. RESULTS: There were 112 patients enrolled in this study. The average mean dose of post-GTVnx, post-GTVnd (left), post-GTVnd (right), post-CTV1, and post-low-risk clinical target volume (CTV2) was 75.24, 68.97, 69.16, 70.49, and 63.37 Gy, respectively. With a median follow-up of 125.95 months, the 10-year LRRFS, DMFS and OS were 89.0%, 83.3%, and 75.9%, respectively. There were 8 local recurrences and 6 regional recurrences in 12 patients. All 8 of the local recurrences were in-field; among the 6 regional recurrences, 4 were in-field, 1 was marginal, and 1 was out-field. The most common late toxicities were grade 1 to 2 subcutaneous fibrosis, hearing loss, and xerostomia. No grade 4 late toxicities were observed. CONCLUSIONS: Reduction of the target volumes according to the post-IC tumor extension and radiation dose to the post-IC tumor shrinkage could yield excellent long-term locoregional control with limited marginal and out-field recurrences and mild late toxicities.

Predictive value of pancreatic dose-volume metrics on sarcopenia rate in gastric cancer patients treated with adjuvant chemoradiotherapy.

OBJECTIVE: To evaluate the relationship of sarcopenia with the pancreatic dose-volume histogram (DVH) in gastric cancer patients treated with adjuvant chemoradiotherapy (CRT) after radical gastrectomy. METHODS: A retrospective study was performed on the data in Zhongnan Hospital of Wuhan University from January 2008 to December 2016. Skeletal muscle index (SMI) was analyzed by cross-sectional areas of body composition at the level of third lumbar (L3) vertebrae, which was measured using single-slice computer tomograph (CT) prior to CRT, at 6 months and 12 months after CRT respectively. Logistic regression analysis was conducted to explore the potential clinical risk factors of sarcopenia in this patients cohort. Regarding the dosimetrics of pancreas, the sarcopenia rate was compared between the two groups divided according to the cut-off value determined by the receiver operating characteristic (ROC) curves. RESULTS: One hundred and fifty-three gastric cancer patients were eligible in this study. The median postoperative follow-up was 36 (7-115) months. The mean dose of pancreas was 4399.7 ± 396.0 cGy. The incidence of sarcopenia prior to CRT, at 6 months and 12 months later were 29.4% (45/153), 27.3% (35/128) and 37.0% (37/100). Both sarcopenia at 6 months (HR = 2.038, 95%CI = 1.084-3.833, P = 0.027) and sarcopenia at 12 months (HR = 2.216, 95%CI = 1.007-4.873, P = 0.048) were the independent prognostic factor of gastric cancer patients. V46 remained to be the only independent risk factor of sarcopenia at 6 months (OR = 3.889, 95%CI = 1.099-13.764, P = 0.035) and 12 months (OR = 6.067, 95%CI = 1.687-21.821, P = 0.006) in multivariate logistic regression analysis. Among the dosimetric parameters used for ROC analysis, the V46 showed the highest area under the curve (AUC = 0.707). Here is the relationship between sarcopenia rate and the cut-off value for V46. Higher sarcopenia rate at 6 months was noted in 42.6% patients with V46 ≥ 57% compared with 9% of patients with V46 < 57% (P < 0.001). The sarcopneia rate at 12 months was 52% with V46 ≥ 57% and 25% with V46 < 57% (P = 0.010). CONCLUSION: Gastric cancer with sarcopenia after adjuvant CRT had poorer survival. Higher dose and larger irradiated volume of pancreas correlated with higher risk of sarcopenia. Appropriated administration of pancreas dose-volume may be conducive to reduce the risk of sarcopenia and improve survival in gastric cancer patients treated with adjuvant CRT.

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

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

Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma.

PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells. Besides, LY294002 inhibited noncanonical PKR-like ER kinase (PERK)/elF2α/ATF4 pathway as well. Both siRNA and the small molecule inhibitor GSK2656157 against PERK/elF2α/ATF4 pathway can significantly inhibit the growth of ESCC. More importantly, GSK2656157 aggravated the inhibitory effect of LY294002 on cell growth, colony formation, and apoptosis induction of ESCC. In addition of dual high expression of PI3K and PERK pathways in the ESCC patients, the difference of overall survival (OS) was more significant than using PI3K alone. These results indicated that dual targeting of PI3K and PERK pathways might improve clinical prognosis and enhance the treatment of ESCC patients.

Optimal postoperative nutrition support for patients with gastrointestinal malignancy: A systematic review and meta-analysis.

OBJECTIVE: To improve clinical outcomes, parenteral nutrition, standard enteral nutrition and immuno-enhanced nutrition are widely used in the gastrointestinal tumor patients undergoing surgery, but the optimal management of postoperative nutrition support remains uncertain. METHODS: We systematically searched the PUBMED, EMBASE and CNKI to identify latent studies which the effects of standard EN compared with PN or IEN on gastrointestinal tumor patients until the end of November, 2015. The quality of included trials was assessed according to the handbook for Cochrane reviewer. Statistical analysis was carried out by RevMan5.1 software. RESULTS: 30 randomized controlled trials containing 3854 patients were contained in our meta-analysis, the results indicated that postoperative SEN could absolutely reduce the incidence of postoperative infectious (P < 0.00001) and non-infectious complications (P = 0.0003), together with its positive effect on the length of hospital stay (P < 0.00001). Additionally, enteral nutrition enhanced with immune stimulation was confirmed to be better, with a significant difference between groups in terms of total infectious (P < 0.00001) and non-infectious complications (P = 0.04), and IEN could also significantly shorten the length of hospital stay (P < 0.00001). CONCLUSION: Early use of Enteral nutrition in digestive tumor patients after surgery could significantly reduce the postoperative complications and shorten the length of hospital stay, IEN should be the optimal management, while the use of parenteral nutrition should be restrict to few patients with severe intolerance to enteral nutrition.

Chinese expert consensus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies.

Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis (PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of < 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases I, II and III clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.

MicroRNA-320 regulates the radiosensitivity of cervical cancer cells C33AR by targeting ß-catenin.

Cervical cancer is the second most common malignancy in women worldwide and always has recurrence owing to radioresistance. MicroRNA (miRNA or miR) has been identified to relate to the sensitivity of cancer radiotherapy. Here, we investigated the potential of miRNA-320 as a biomarker for radiosensitivity by targeting ß-catenin in cervical cancer. A radioresistant cervical cancer cell line, C33AR, was established, and the radioresistance of C33AR cells was confirmed by a colony-formation assay. The expression of miRNA-320 was detected by reverse transcription-quantitative polymerase chain reaction, and compared between C33A and C33AR. ß-catenin, the target of miRNA-320, was determined at the protein level by western blotting after transfecting the inhibitor of miRNA-320. The expression of miRNA-320 was markedly decreased in C33AR cells, which appeared to be more radioresistant, compared with its parental cell line C33A. Target prediction suggested that miRNA-320 negatively regulated the expression of ß-catenin. Knockdown of ß-catenin increased C33AR radiosensitivity, which revealed that the inhibition of ß-catenin could rescue the miRNA-320-mediated cell radioresistance. On the other hand, overexpressing miRNA-320 increased C33AR radiosensitivity. In conclusion, miRNA-320 regulated the radiosensitivity of C33AR cells by targeting ß-catenin. This finding provides evidence that miRNA-320 may be a potential biomarker of radiosensitivity in cervical cancer.

Complete sequence of a cholangiocarcinoma inbred Sprague-Dawley rat model mitochondrial genome.

In the present work we undertook the complete mitochondrial genome sequencing of an important cholangiocarcinoma model inbred rat strain for the first time. Its mitogenome was 16,312 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. A total of 96 SNPs were examined when compared to reference BN sequence.

Expression of various protection of telomeres 1 variants is associated with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells in vitro.

Protection of telomeres 1 (POT1) is a telomere-binding protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Different POT1 mRNA variants were examined and compared with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells. POT1 production and telomere lengths were assessed using 10 human cancer cell lines by quantitative polymerase chain reaction (qPCR). POT1 mRNA levels, which were relatively stable, were significantly correlated with telomere length in gastric cancer cells and colon cancer cells, except for HT29 (P<0.01). POT1 v5 indexes were closely associated with radiosensitivity in colon cancer cells and gastric cancer cells (P<0.05). In conclusion, POT1 may be a good marker for the examination of cell-specific telomere length and radiosensitivity.

Elevated expression of USP9X correlates with poor prognosis in human non-small cell lung cancer.

BACKGROUND: The aim of this study was to investigate the expression of ubiquitin-specific peptidase 9, X-linked (USP9X) in non-small cell lung cancer (NSCLC) patients and to evaluate the relevance of USP9X expression to tumor prognosis. METHODS: Ninety-five patients who underwent surgical resection for clinical stage I-IIIA NSCLC between July 2008 and July 2011 were included in this study. Immunohistochemical analysis of USP9X expression was performed on 95 NSCLC tissues and 32 adjacent normal lung parenchymal tissues from these patients. The Chi-squared test was used to compare the clinicopathological characteristics between different groups. Kaplan-Meier analysis and a Cox regression model were used to determine the independent prognostic factors. A P value <0.05 was considered to be significant. RESULTS: The expression of USP9X was found to be significantly higher in NSCLC tissue (44.2%) than in adjacent normal lung parenchymal tissue (6.3%) (P<0.001). High USP9X expression was significantly associated with positive lymph node metastasis (P<0.001), clinical stage (P<0.001) and a reduced overall survival rate (P=0.001) in patients with NSCLC. Based on the multivariate analysis, the elevated expression of the USP9X protein was a significant predictor of poor prognosis for NSCLC patients (HR =2.244, P=0.028). CONCLUSIONS: The current study demonstrated that the expression of USP9X in NSCLC tissue was significantly higher than that in normal lung tissue and that this elevated expression level of USP9X was associated with poor prognosis among NSCLC patients, suggesting that USP9X might serve as a prognostic biomarker for NSCLC.

Regulatory effects of WRAP53 on radiosensitivity of laryngeal squamous cell carcinoma cells.

BACKGROUND: Telomere length is closely associated with cellular radiosensitivity and WRAP53 is required for telomere addition by telomerase. In this research we assessed radiosensitivity of laryngeal squamous cell carcinoma Hep-2 cell lines after WRAP53 inhibition, and analyzed the molecular mechanisms. MATERIALS AND METHODS: phWRAP53-siRNA and pNeg-siRNA were constructed and transfected into Hep-2 cells with lipofectamine. Expression of WRAP53 was analyzed by RT-PCR and Western-blottin, radiosensitivity of Hep-2 cells was assessed colony formation assay, and the relative length of telomeres was measured by QPCR. RESULTS: The data revealed that the plasmid of phWRAP53-siRNA was constructed successfully, and the mRNA and protein levels of WRAP53 were both obviously reduced in the Hep-2 cell line transfected with phWRAP53-siRNA. After Hep-2 cells were irradiated with X-rays, the D0 and SF2 were 2.481 and 0.472, respectively, in the phWRAP53-siRNA group, much lower than in the control group (D0 and SF2 of 3.213 and 0.592) (P<0.01). The relative telomere length in the phWRAP53-siRNA group was 0.185±0.01, much lower than in the untreated group (0.523±0.06) and the control group (0.435±0.01). CONCLUSIONS: Decreasing the expression of WRAP53 using RNA interference technique can enhance the radiosensitivity of Hep-2 cell lines by influencing the telomere length. WRAP53 is expected to be a new target to regulate the radiosensitization of tumor cells.

Involvement of cdc25c in cell cycle alteration of a radioresistant lung cancer cell line established with fractionated ionizing radiation.

Cancer patients often suffer from local tumor recurrence after radiation therapy. Cell cycling, an intricate sequence of events which guarantees high genomic fidelity, has been suggested to affect DNA damage responses and eventual radioresistant characteristics of cancer cells. Here, we established a radioresistant lung cancer cell line, A549R , by exposing the parental A549 cells to repeated γ-ray irradiation with a total dose of 60 Gy. The radiosensitivity of A549 and A549R was confirmed using colony formation assays. We then focused on examination of the cell cycle distribution between A549 and A549R and found that the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased. When A549 and A549R cells were exposed to 4 Gy irradiation the total differences in cell cycle redistribution suggested that G2-M cell cycle arrest plays a predominant role in mediating radioresistance. In order to further explore the possible mechanisms behind the cell cycle related radioresistance, we examined the expression of Cdc25 proteins which orchestrate cell cycle transitions. The results showed that expression of Cdc25c increased accompanied by the decrease of Cdc25a and we proposed that the quantity of Cdc25c, rather than activated Cdc25c or Cdc25a, determines the radioresistance of cells.

Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Mitochondrial dysfunction has been postulated to render cancer cells resistant to apoptosis based on the Warburg hypothesis. However, few studies have investigated the prognostic value of mitochondrial DNA (mtDNA) content and G10398A polymorphism in NSCLC patients. mtDNA copy number and G10398A polymorphism in 128 NSCLC tissue samples were assessed by real-time PCR (RT-PCR) and PCR-RFLP respectively, and their relationship to prognosis were analyzed by survival analysis and Cox proportional hazards model. In vitro, an mtDNA deletion A549 ρ(0) cell model was utilized to assess the function of mtDNA on radiosensitivity. Cell cycle distribution and reactive oxygen species (ROS) were analyzed to elucidate the potential mechanisms. For the whole group, the median follow-up time and overall survival time were 22.5 and 23.4 months, respectively. Patients with high mtDNA content had a marginally longer survival time than patients with low mtDNA content (P=0.053). Moreover, patients with high mtDNA content plus 10398G had a significantly longer overall survival time compared with those having low mtDNA content plus 10398A (47 vs. 27 months, P<0.05). In addition, multivariate analysis showed that stage and low mtDNA content plus 10398A were the two most independent prognostic factors. In vitro, the A549 ρ(0) cells showed more resistance to radiation than ρ(+) cells. Following radiation, ρ(0) cells showed delayed G2 arrest and lower ROS level as compared to ρ(+) cells. In conclusion, the present study suggests that in patients with NSCLC, low mtDNA content plus 10398A could be a marker of poor prognosis which is associated with resistance to anticancer treatment caused by low mtDNA content plus 10398A polymorphism resulting in mitochondrial dysfunction.

Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer: a prospective randomized study.

This prospective randomized study is to evaluate the locoregional failure and its impact on survival by comparing involved field radiotherapy (IFRT) with elective nodal irradiation (ENI) in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer. It appears that higher dose could be delivered in IFRT arm than that in ENI arm, and IFRT did not increase the risk of initially uninvolved or isolated nodal failures. Both a tendency of improved locoregional progression-free survival and a significant increased overall survival rate are in favor of IFRT arm in this study.

Suppression of Ku80 correlates with radiosensitivity and telomere shortening in the U2OS telomerase-negative osteosarcoma cell line.

Ku70/80 heterodimer is a central element in the nonhomologous end joining (NHEJ) DNA repair pathway, Ku80 playing a key role in regulating the multiple functions of Ku proteins. It has been found that the Ku80 protein located at telomeres is a major contributor to radiosensitivity in some telomerase positive human cancer cells. However, in ALT human osteosarcoma cells, the precise function in radiosensitivity and telomere maintenance is still unknown. The aim of this study was to investigate the effects of Ku80 depletion in the U2OS ALT cell line cell line. Suppression of Ku80 expression was performed using a vector-based shRNA and stable Ku80 knockdown in cells was verified by Western blotting. U2OS cells treated with shRNA-Ku80 showed lower radiobiological parameters (D0, Dq and SF2) in clonogenic assays. Furthermore, shRNA-Ku80 vector transfected cells displayed shortening of the telomere length and showed less expression of TRF2 protein. These results demonstrated that down-regulation of Ku80 can sensitize ALT cells U2OS to radiation, and this radiosensitization is related to telomere length shortening.

Phase II trial of neoadjuvant docetaxel and cisplatin followed by intensity-modulated radiotherapy with concurrent cisplatin in locally advanced nasopharyngeal carcinoma.

PURPOSE: To evaluate the feasibility and efficacy of neoadjuvant chemotherapy involving docetaxel and cisplatin followed by intensity-modulated radiotherapy (IMRT) with concurrent cisplatin in patients with newly diagnosed stage III to IVB nasopharyngeal carcinoma (NPC). METHODS: Docetaxel (75 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered on a 3-week cycle for 2 courses, followed by radical IMRT (72 Gy/33F/6.5-7 W) with concurrent cisplatin (75 mg/m(2), on day 1) every 3 weeks for 2 cycles. RESULTS: From June 2008 to October 2010, forty-six patients were recruited in this trial. Forty-five patients completed neoadjuvant setting, and all patients completed planned concurrent chemoradiotherapy (CCRT). The complete and partial response rates were 28.3 and 56.5 % after neoadjuvant chemotherapy, and 91.3, 8.7 % after CCRT, respectively. After median follow-up of 26 months (range 12-39 months), one patient experienced local recurrence and 4 patients developed distant metastasis. The 3-year overall survival and progression-free survival rate were 94.1 and 72.7 %, respectively. Neutropenia (37.0 %) and vomiting (28.3 %) were the most common Grade 3-4 adverse effects during neoadjuvant course, while mucositis (30.4 %), xerostomia (30.4 %) and radiodermatitis (21.7 %) were the most common Grades 3 acute toxicities during CCRT. Xerostomia (73.9 %), dysphagia (56.5 %), hear loss (30.4 %) and skin reaction (21.7 %) were the common Grade 1-2 late effects. There were no Grades 3-4 late toxicities. CONCLUSIONS: The protocol of neoadjuvant docetaxel and cisplatin followed by IMRT with concurrent cisplatin was well tolerated, with outstanding compliance and efficacy in locally advanced NPC, which deserved further follow-up.

Frizzled-8 as a putative therapeutic target in human lung cancer.

Lung cancer is the leading cause of cancer related deaths worldwide. It is necessary to better understand the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this disease. Recent reports have shown that Wnt signaling pathway is important in a number of cancer types including lung cancer. However, the role of Frizzled-8 (Fzd-8), one of the Frizzled family of receptors for the Wnt ligands, in lung cancer still remains to be elucidated. Here in this study we showed that Fzd-8 was over-expressed in human lung cancer tissue samples and cell lines. To investigate the functional importance of the Fzd-8 over-expression in lung cancer, we used shRNA to knock down Fzd-8 mRNA in lung cancer cells expressing the gene. We observed that Fzd-8 shRNA inhibited cell proliferation along with decreased activity of Wnt pathway in vitro, and also significantly suppressed A549 xenograft model in vivo (p<0.05). Furthermore, we found that knocking down Fzd-8 by shRNA sensitized the lung cancer cells to chemotherapy Taxotere. These data suggest that Fzd-8 is a putative therapeutic target for human lung cancer and over-expression of Fzd-8 may be important for aberrant Wnt activation in lung cancer.

Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer.

OBJECTIVE: To evaluate the efficacy and safety of nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) and to investigate the association of the status of KRAS gene mutation and epidermal growth factor receptor (EGFR) genotype with clinical outcome. METHODS: Twenty-eight patients with advanced NSCLC were enrolled in this single center, uncontrolled pilot clinical study. All the patients developed drug resistance or disease progression after first-line chemotherapy of either a docetaxel + cisplatin regimen or a vinorelbine + cisplatin regimen and then received nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy. Eight cases were stage IIIB and 20 were stage IV. An i.v. dosage regimen of 200 mg of nimotuzumab was given as a single dose, injected into the patient at days 1, 8 and 15; i.v. gemcitabine was injected at a dose of 1000 mg/m2 at days 1 and 8 and cisplatin (25 mg/m2 i.v.) at days 1, 2 and 3. Each patient received four or more therapeutic cycles. The efficacy and toxic reactions were evaluated, as well as time to progression and overall survival. RESULTS: In total, 28 patients with advanced NSCLC received 101 therapeutic cycles. The mean cycle number was 3.6. Median time to progression was 4.9 (2.5-6.5) months; median overall survival and 1-year survival rate were 9.8 months and 48.5%, respectively. There was one case of complete response, six cases of partial response, 11 cases of stable disease and 10 cases of progressive disease. Response rate was 25%, and clinical benefit rate was 64.3%. Major toxic reactions were bone marrow suppression and gastrointestinal reaction. Only one patient developed grade I acneiform eruption. CONCLUSION: Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced NSCLC was active and well-tolerated in this setting. Patients with EGFR amplification and KRAS gene wild type had a better prognosis. Prospective, randomized, controlled, large-scale clinical studies are needed to confirm the results.