Prognostic significance of body mass index in patients with localized renal cell carcinoma.

OBJECTIVE: To investigate the relationship between the pretreatment body mass index (BMI) and the clinical outcomes in patients with localized stage I - III renal cell carcinoma (RCC) surgically treated. MATERIALS AND METHODS: From January 2000 to December 2012, 798 patients with stage I - III RCC were recruited from First Affiliated Hospital and Cancer Center of Sun Yat - Sen University. Patients were divided into two groups of BMI < 25 kg / m2 or BMI ≥ 25 kg / m2 according to the World Health Organization classifications for Asian populations. The differences in the long-term survival of these two BMI groups were analyzed. RESULTS: The 5 - year failure - free survival rates for BMI < 25 kg / m2 and BMI ≥ 25 kg / m2 groups were 81.3% and 93.3%, respectively (P = 0.002), and the 5 - year overall survival rates were 82.5% and 93.8%, respectively (P = 0.003). BMI was a favored prognostic factor of overall survival and failure - free survival in a Cox regression model. CONCLUSIONS: Pretreatment body mass index was an independent prognostic factor for Chinese patients surgically treated, localized stage I - III RCC.

3D-image-guided HDR-brachytherapy versus 2D HDR - brachytherapy after external beam radiotherapy for early T-stage nasopharyngeal carcinoma.

BACKGROUND: Two-dimensional high-dose-rate brachytherapy (2D-HDR-BT) is an effective method of dose escalation for local tumor control in early T-stage nasopharyngeal carcinoma (NPC). Treatment outcomes for 3D-image-guided high-dose-rate brachytherapy (3D-image-guided-HDR-BT) after external beam radiotherapy (ERT) have not been examined in early T-stage NPC patients. The current study was designed to evaluate whether addition of 3D-HDR-BT to ERT showed further improvement in treatment outcomes in patients with early T-stage NPC when compared to 2D-HDR-BT after ERT. METHODS: The current study retrospectively analyzed and compared treatment outcomes for patients with nonmetastatic stage T1-2b NPC treated with 2D-HDR-BT (n =101) or 3D-HDR-BT (n =118) after ERT. Patients in both groups were treated with ERT at a mean dose of 60 Gy and a brachytherapy dose of 12Gy (8 ~ 20Gy), 2.5 ~ 5Gy per fraction under local anesthesia. RESULTS: Compared to patients treated with 2D-HDR-BT after ERT, patients treated with 3D-HDR-BT after ERT showed improvement in five-year actuarial local control survival rates (p = 0.024), local/regional relapse-free survival rates (p = 0.038), and disease-free survival rates (p = 0.021). Multivariate analysis showed that NPC patients treated with 3D-HDR-BT had improved local control survival (p = 0.042). The incidence rates of acute or chronic complications were similar between two groups. CONCLUSIONS: The current study showed that 3D-image-guided HDR-BT after ERT was an effective treatment modality for patients with stage T1-2 NPC with acceptable complications. The improvement in local tumor control and disease free survival is likely due to improved conformal dose distributions.

Establishment and Application of Novel Hypoxia-driven Dual-reporter Model to Investigate Hypoxic Impact on Radiation Sensitivity in Human Nasopharyngeal Carcinoma Xenografts.

Background: Tumor hypoxia has been frequently detected in nasopharyngeal carcinoma (NPC) and is intently associated with therapeutic resistance. The aim of the study is to establish a clonogenically stable hypoxia-inducible dual reporter model and apply it to investigate the effect of tumor hypoxia on DNA double strand break (DSB) and synergistic effect of irradiation in combination with chemotherapy or targeted therapy. Methods: The plasmid vector consisting of hypoxia response elements to regulate HSV1-TK and GFP genes, was constructed and stably transfected into human NPC cells. The expected clone was identified and validated by in vivo and in vitro assay. DSB repair was measured by γH2AX foci formation. Tumor growth delay assay and spatial biodistribution of various biomarkers was designed to investigate the anti-tumor effect. Results: The system has the propensity of high expression of reporter genes under hypoxia and low to no expression under normoxia. Intratumoral biodistributions of GFP and classic hypoxic biomarkers were identical in poor-perfused region. Upon equilibration with 10% O2, the xenografts showed higher expression of hypoxic biomarkers. Cisplatin radiosensitized SUNE-1/HRE cells under hypoxia by suppressing DSB repair while the addition of PI3K/mTOR inhibitor further enhanced the anti-tumoral therapeutic efficacy. Combination of IR, DDP and NVP-BEZ235 exhibited most effective anti-tumor response in vivo. These observations underline the importance of dual reporter model for imaging tumor hypoxia in therapeutic study. Conclusions: Our preclinical model enables the investigation of heterogeneous tumor hypoxic regions in xenograft tissues and explores the treatment efficacy of combinations of various therapeutic approaches to overcome hypoxia.

[Value of postoperative adjuvant chemotherapy in locally advanced rectal cancer patients with ypT1-4N0 after neo-adjuvant chemoradiotherapy].

OBJECTIVE: The purpose of this study was to investigate the value of postoperative chemotherapy for locally advanced rectal cancer patients who reached pathological ypT1-4N0 after neo-adjuvant chemoradiotherapy. METHODS: We performed a retrospective study of 104 patients treated with preoperative chemoradiotherapy followed by radical resection, who achieved pathological ypT1-4N0, between Mar 2003 and Dec 2010. There were 73 patients who received postoperative adjuvant chemotherapy, and the other 31 patients did not. The distribution of final pathologic stages for these patients was ypT1-2N0 in 39 cases and ypT3-4N0 in 65 cases. RESULTS: The median follow-up was 41 months. The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) for the whole group (ypT1-4N0) were 93.4% and 85.3%, respectively. The 3-year OS and RFS in the adjuvant chemotherapy group and non-adjuvant chemotherapy group were 95.5%, 88.6% and 88.6%, 77.2%, respectively. There were no significant differences in 3-year RFS (P = 0.108) and OS (P = 0.106) between the two groups. The 3-year local recurrence and distant metastasis rates in the adjuvant chemotherapy group were 4.1% (3/73) and 5.5% (4/73), while for the non-adjuvant chemotherapy group, the 3-year local recurrence rate and distant metastasis rate were 3.2% (1/31) and 16.1% (5/31), respectively. Significant difference was found in distant metastasis rates (P = 0.030) between the two groups, but not in local recurrence rates (P = 0.676).Further subgroup analysis indicated that for the ypT1-2N0 patients, there were no significant differences in 3-year OS (P = 0.296) and RFS (P = 0.939) between the adjuvant and non-adjuvant chemotherapy groups, while negative results displayed in 3-year local recurrence rates (P = 0.676) and distant metastasis rates (P = 0.414). However, for patients with ypT3-4N0, significant differences were showed in both the 3-year OS (P = 0.034) and RFS (P = 0.025), and further analysis revealed that the 3-year distant metastasis rate was significantly higher in the non-adjuvant chemotherapy group than in the adjuvant chemotherapy group (P = 0.010) , but with non-significant difference in the 3-year local recurrence (P = 0.548). CONCLUSIONS: Adjuvant chemotherapy may not improve survival for ypT1-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing distant metastasis rate. Further randomized controlled clinical trials are needed to confirm our results.

A support vector machine (SVM) for predicting preferred treatment position in radiotherapy of patients with breast cancer.

PURPOSE: NYU 05-181 protocol compared the CT simulation in both supine and prone positions for 400 patients with breast cancer (200 left-breast and 200 right-breast) to identify which setup is better at sparing heart and lung involvement in the treatment process. The results demonstrated that all right-breast patients benefited from the prone treatment position, while for left-breast patients, 85% were better treated prone and 15% were better treated supine. Using the clinical data collected from this protocol, the authors aimed at developing an automated tool capable of identifying which of the left-breast cancer patients are better treated supine without obtaining a second CT scan in the supine position. METHODS: Prone CT scans from 198 of the 200 left-breast cancer patients enrolled in NYU 05-181 protocol were deidentified and exported to a dedicated research planning workstation. Three-dimensional geometric features of the organs at risk and tumor bed were extracted. A two-stage classifier was used to classify patients into the prone class or the supine class. In the first stage, the authors use simple thresholding to divide the patients into two groups based on their in-field heart volume. For patients with in-field heart volume < or = 0.1 cc, the prone position was chosen as the preferred treatment position. Patients with in-field heart volume > 0.1 cc will be further classified in the second stage by a weighted support vector machine (SVM). The weight parameters of the SVM were adjusted to maximize the specificity [true-supine/(true-supine+false-prone)] at the cost of lowering but still maintaining reasonable sensitivity [true-prone/(true-prone+false-supine)]. The authors used K-fold cross validations to test the performance of the SVM classifier. A feature selection algorithm was also used to identify features that give the best classification performance. RESULTS: After the first stage, 49 of the 198 left-breast cancer patients were found to have > 0.1 cc of in-field heart volume. The three geometric features of heart orientation, distance between heart and tumor, and in-field lung were selected by the feature selection algorithm in the second stage of the two-stage classifier to give the best predefined weighted accuracy. The overall sensitivity and specificity of the proposed method were found to be 90.4% and 99.3%, respectively. Using two-stage classification, the authors reduced the proportion of prone-treated patients that need a second supine CT scan down to 16.3/170 or 9.6%, as compared to 21/170 or 12.4% when the authors use only the first stage (thresholding) for classification. CONCLUSIONS: The authors' study showed that a feature-based classifier is feasible for predicting the preferred treatment position, based on features extracted from prone CT scans. The two-stage classifier achieved very high specificity at an acceptable expense of sensitivity.

A robotic system for 18F-FMISO PET-guided intratumoral pO2 measurements.

An image-guided robotic system was used to measure the oxygen tension (pO2) in rodent tumor xenografts using interstitial probes guided by tumor hypoxia PET images. Rats with approximately 1 cm diameter tumors were anesthetized and immobilized in a custom-fabricated whole-body mold. Imaging was performed using a dedicated small-animal PET scanner (R4 or Focus 120 microPET) approximately 2 h after the injection of the hypoxia tracer 18F-fluoromisonidazole (18F-FMISO). The coordinate systems of the robot and PET were registered based on fiducial markers in the rodent bed visible on the PET images. Guided by the 3D microPET image set, measurements were performed at various locations in the tumor and compared to the corresponding 18F-FMISO image intensity at the respective measurement points. Experiments were performed on four tumor-bearing rats with 4 (86), 3 (80), 7 (162), and 8 (235) measurement tracks (points) for each experiment. The 18F-FMISO image intensities were inversely correlated with the measured pO2, with a Pearson coefficient ranging from -0.14 to -0.97 for the 22 measurement tracks. The cumulative scatterplots of pO2 versus image intensity yielded a hyperbolic relationship, with correlation coefficients of 0.52, 0.48, 0.64, and 0.73, respectively, for the four tumors. In conclusion, PET image-guided pO2 measurement is feasible with this robot system and, more generally, this system will permit point-by-point comparison of physiological probe measurements and image voxel values as a means of validating molecularly targeted radiotracers. Although the overall data fitting suggested that 18F-FMISO may be an effective hypoxia marker, the use of static 18F-FMISO PET postinjection scans to guide radiotherapy might be problematic due to the observed high variation in some individual data pairs from the fitted curve, indicating potential temporal fluctuation of oxygen tension in individual voxels or possible suboptimal imaging time postadministration of hypoxia-related trapping of 18F-FMISO.

Adenovirus-mediated expression of a dominant negative Ku70 fragment radiosensitizes human tumor cells under aerobic and hypoxic conditions.

Ku70 is one component of a protein complex, the Ku70/Ku80 heterodimer, which binds to DNA double-strand breaks and activates DNA-dependent protein kinase (DNA-PK), leading to DNA damage repair. Our previous work has confirmed that Ku70 is important for DNA damage repair in that Ku70 deficiency compromises the ability of cells to repair DNA double-strand breaks, increases the radiosensitivity of cells, and enhances radiation-induced apoptosis. Because of the radioresistance of some human cancers, particularly glioblastoma, we examined the use of a radio-gene therapy paradigm to sensitize cells to ionizing radiation. Based on the analysis of the structure-function of Ku70 and the crystal structure of Ku70/Ku80 heterodimer, we designed and identified a candidate dominant negative fragment involving an NH(2)-terminal deletion, and designated it as DNKu70. We generated this mutant construct, stably overexpressed it in Rat-1 cells, and showed that it has a dominant negative effect (i.e., DNKu70 overexpression results in decreased Ku-DNA end-binding activity, and increases radiosensitivity). We then constructed and generated recombinant replication-defective adenovirus, with DNKu70 controlled by the cytomegalovirus promoter, and infected human glioma U-87 MG cells and human colorectal tumor HCT-8 cells. We show that the infected cells significantly express DNKu70 and are greatly radiosensitized under both aerobic and hypoxic conditions. The functional ramification of DNKu70 was further shown in vivo: expression of DNKu70 inhibits radiation-induced DNA-PK catalytic subunit autophosphorylation and prolongs the persistence of gamma-H2AX foci. If radiation-resistant tumor cells could be sensitized by down-regulating the cellular level/activity of Ku/DNA-PK, this approach could be evaluated as an adjuvant to radiation therapy.

Association between Pretreatment Serum High-density Lipoprotein Cholesterol and Treatment Outcomes in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma Treated with Chemoradiotherapy: Findings from a Randomised Trial.

Background: To investigate the relationship between the pretreatment serum lipid concentrations and the clinical outcomes in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) who were treated with a combination of chemotherapy and radiotherapy. Methods: From August 2002 to April 2005, 400 patients with stage III or stage IVa nasopharyngeal carcinoma were recruited for a randomised clinical trial of induction chemotherapy combined with radiotherapy or concurrent chemoradiotherapy. Pretreatment serum lipid concentrations were examined in 342 patients. Both univariate and multivariate analyses were conducted to investigate the association of serum lipid levels with different treatment outcomes. Results: The 5-year failure-free survival rate for the low- high-density lipoprotein cholesterol (HDL-C) and high-HDL-C groups was 52.1% and 65.5%, respectively (p=0.017), and the 5-year overall survival rate was 64.7% and 72.5%, respectively (p=0.094). The pretreatment serum level of HDL-C was a favourable prognostic factor of overall survival and failure-free survival in a Cox regression model with HR 0.65 (95% CI 0.43-0.97; p=0.036) and 0.60 (95% CI 0.41-0.88; p =0.008). No significant correlation was observed between the prognosis of patients with NPC and serum levels of total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C). Conclusions: The pretreatment serum level of HDL-C was an independent prognostic factor for patients with locoregionally advanced nasopharyngeal carcinoma who were treated with chemoradiotherapy.

Imaging hypoxia in orthotopic rat liver tumors with iodine 124-labeled iodoazomycin galactopyranoside PET.

PURPOSE: To evaluate iodine 124 (124I)-labeled iodoazomycin galactopyranoside (IAZGP) positron emission tomography (PET) in the detection of hypoxia in an orthotopic rat liver tumor model by comparing regions of high (124)I-IAZGP uptake with independent measures of hypoxia and to determine the optimal time after injection to depict hypoxia. MATERIALS AND METHODS: The institutional animal care and use committee approved this study. Morris hepatoma tumors were established in the livers of 15 rats. Tumor oxygenation was measured in two rats with a fluorescence fiberoptic oxygen probe. (124)I-IAZGP was coadministered with the established hypoxia markers pimonidazole and EF5 in nine rats; 12-hour PET data acquisition was performed 24 hours later. Tumor cryosections were analyzed with immunofluorescence and autoradiography. In the four remaining rats, serial 20- and 60-minute PET data acquisition was peformed up to 48 hours after tracer administration. RESULTS: Oxygen probe measurements showed severe hypoxia (<1 mm Hg) distributed evenly throughout tumor tissue. Analysis of cryosections showed diffuse homogeneous uptake of (124)I-IAZGP throughout all tumors. The (124)I-IAZGP distribution correlated positively with pimonidazole (r = 0.78) and EF5 (r = 0.76) distribution. Tracer uptake in tumors was detectable with PET after 24 hours in seven of nine rats. In rats that underwent serial PET, tumor-to-liver contrast was sufficient to enable detection of hypoxia between 6 and 48 hours after tracer administration. The optimal ratio between signal intensity and tumor-to-liver contrast occurred 6 hours after tracer administration. CONCLUSION: Regions of high (124)I-IAZGP uptake in orthotopic rat liver tumors are consistent with independent measures of hypoxia; visualization of hypoxia with (124)I-IAZGP PET is optimal 6 hours after injection.

Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic 18F-MISO and 124I-IAZG PET in the same study cohort.

PURPOSE: The purpose of this paper is to compare the uptake of two clinically promising positron emission tomography (PET) hypoxia targeting agents, (124)I-iodoazomycin galactopyranoside ((124)I-IAZG) and (18)F-fluoromisonidazole ((18)F-FMISO), by dynamic microPET imaging, in the same rats bearing liver tumors and peritoneal metastasis. METHODS: Morris hepatoma (RH7777) fragments were surgically implanted into the livers of four nude rats. Tumors formed in the liver and disseminated into the peritoneal cavity. Each rat had a total of two to three liver tumors and peritoneal metastasis measuring 10-15 mm in size. Animals were injected with (18)F-FMISO, followed on the next day (upon complete (18)F decay) by (124)I-IAZG. The animals were imaged in list mode on the microPET system from the time of injection of each tracer for 3 h and then again at 6 h and 24 h for the long-lived (124)I-IAZG tracer (4.2-day half-life). Micro computed tomography (CT) scans of each rat were performed for co-registration with the microPET scans acquired with a liver contrast agent, allowing tumor identification. Regions of interest (ROIs) were drawn over the heart, liver, muscle, and the hottest areas of the tumors. Time-activity curves (TACs) were drawn for each tissue ROI. RESULTS: The (18)F-FMISO signal increased in tumors over the 3-h time course of observation. In contrast, after the initial injection, the (124)I-IAZG signal slowly and continuously declined in the tumors. Nevertheless, the tumor-to-normal-tissue ratios of (124)I-IAZG increased, but more slowly than those of (18)F-FMISO and as a result of the differentially faster clearance from the surrounding normal tissues. These pharmacokinetic patterns were seen in all 11 tumors of the four animals. CONCLUSIONS: (18)F-FMISO localizes in the same intra-tumor regions as (124)I-IAZG. The contrast ratios (tumor/background) reach similar values for the two hypoxia tracers, but at later times for (124)I-IAZG than for (18)F-FMISO and, therefore, with poorer count statistics. As a consequence, the (18)F-FMISO images are of superior diagnostic image quality to the (124)I-IAZG images in the Morris hepatoma McA-R-7777 tumor model.

Comparison of Helzel and OxyLite systems in the measurements of tumor partial oxygen pressure (pO2).

Wen, B., Urano, M., Humm, J. L., Seshan, V. E., Li, G. C. and Ling, C. C. Comparison of Helzel and OxyLite Systems in the Measurements of Tumor Partial Oxygen Pressure (pO(2)). Radiat. Res. 168, 67-75 (2008). It has been demonstrated in both experimental and human malignancies that hypoxic tumor cells are linked with aggressive disease phenotype. One of the methods to identify these cells is by direct physical measurement of tumor pO(2). This study compared pO(2) values measured with two systems, the Helzel Hypoximeter (successor of the polarographic Eppendorf electrode) and the Oxford-Optronix OxyLite (fiber-optic probe), in R3327-AT and R3327-AT/tkeGFP tumors. Partial oxygen pressure was measured in individual tumors with either system or in the same tumor with both systems. The similarities and discrepancies in pO(2) measurements between the two systems were also investigated when tumor-bearing animals were breathing pure oxygen. Our data showed a considerable heterogeneity in pO(2) values in each tumor using both the Helzel and OxyLite systems. Similar results were obtained with both systems for the mean and median pO(2) values, and the distributions of pO(2) values within the interval 0 < pO(2) < 40 mmHg (the range important for defining tumor hypoxia) were found to be statistically equivalent. However, the frequencies of high pO(2) values (>40 mmHg) and zero values measured by the two systems were statistically significantly different.

Post-radiation CT changes and recurrent nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is endemic in Southern Asia. Radiation therapy remains the mainstay of treatment strategies for NPC. Although approximately 19% - 56% of patients develop a recurrent disease 5 years after their primary treatment, recognition of post-radiation changes and early detection of relapse are important in improving the outcome of NPC. Our aim was to analyze the post-radiation changes and recurrent diseases related to NPC using computed tomography (CT) scans and to investigate their relationship. METHODS: CT scans of 510 pathologically proven NPC patients who have been followed up for more than 2 years after radiation were reviewed. The tumor's response to the radiation therapy and its relevance to recurrence were evaluated. RESULTS: For patients who were followed up for more than 2 years, their CT scans-obtained within 3 months, during the 4th to the 6th month, and beyond 7 months after radiation therapy, showed a normal nasopharyngeal cavity with a slight thickening in the wall in 93.5%, 95.0% and 84.8% of the patients respectively. The degree of tumor regression had no significant relevance to the risk of recurrence within the initial 3 months (P = 0.094). During this term, the relapse rates in the cases in which the nasopharyngeal walls were displayed as normal, slightly or moderately thickening, or with obvious residual masses on CT scans were 7.1%, 11.7%, 23.5% and 23.1% respectively. The degree of tumor regression beyond 3 months after radiation therapy had a considerable reverse relevance to the risk of recurrence (P = 0.000). The relapse rates were 13.2%, 14.1%, 10.2% and 2.1%, respectively, in the cases with a normal and a slightly thickening nasopharyngeal wall during the 4th to the 6th month, the 7th to the 12th month, the 13th to the 24th month, and beyond 25 months after radiation. In contrast, the percents in cases with moderate or more aggressive thickening walls in the corresponding periods were 62.5%, 88.9%, 100% and 100%. Within 6 months after radiation therapy, shown by CT scans, the metastatic lymph nodes disappeared, markedly decreased, slightly decreased, or enlarged in 37.4%, 51.8%, 4.7%, and 0.4%, respectively, of the patients. During 6 to 12 months after radiation therapy, the proportions were 78.5%, 19.2%, 0.6% and 1.7% correspondingly. Beyond 12 months, the proportions were 83.7%, 7.9%, 0%, and 8.4%. The regression degree of the malignant nodes after radiation therapy showed a remarkable reverse relevance to the risk of recurrence in lymph nodes (P = 0.000). In the cases with disappearing, markedly decreased, slightly decreased, or enlarged malignant nodes within six months after radiation, the relapse rates were 2.9%, 4.5%, 12.5% and 100%, respectively. CONCLUSIONS: If the nasopharyngeal walls are shown to remain moderately thick on a CT scan beyond 6 months after radiotherapy, the risk of relapse will increase. The baseline images taken within 3 months after radiotherapy and regular follow-up studies are the key to pick up the tumor recurrences in an earlier stage.

Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model.

The purpose of this study was to monitor hypoxia in an orthotopic liver tumor model using a hypoxia-sensitive reporter imaging system and to image enhanced gene expression after clamping the hepatic artery. C6 and RH7777 Morris hepatoma cells were transduced with a triple reporter gene (HSV1-tk/green fluorescent protein/firefly luciferase-triple fusion), placed under the control of a HIF-1-inducible hypoxia responsive element (HRE). The cells showed inducible luciferase activity and green fluorescent protein expression in vitro. Isolated reporter-transduced Morris hepatoma cells were used to produce tumors in livers of nude rats, and the effect of hepatic artery clamping was evaluated. Tumor hypoxia was shown by immunofluorescence microscopy with the hypoxia marker EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl acetamide)] and the fluorescent perfusion marker Hoechst 33342, and by pO(2) electrode measurements. For tumor hypoxia imaging with the HRE-responsive reporter, both luciferase bioluminescence and [(18)F]2'-fluoro-2'-deoxyarabinofuranosyl-5-ethyluracil positron emission tomography was done, and the presence of hypoxia in Morris hepatoma tumors were successfully imaged by both techniques. Transient clamping of the hepatic artery caused cessation of tumor perfusion and severe hypoxia in liver tumors, but not in adjacent liver tissue. These results show that the orthotopic reporter-transduced RH7777 Morris hepatomas are natively hypoxic and poorly perfused in this animal model, and that the magnitude of hypoxia can be monitored using a HRE-responsive reporter system for both bioluminescence and positron emission tomography imaging. However, the severity of tumor ischemia after permanent ligation of the hepatic artery limits our ability to image severe hypoxia in this animal model.

Prognostic implications of circulating Epstein-Barr virus DNA for extranodal natural killer/T-cell lymphoma, nasal type: a meta-analysis.

INTRODUCTION: To evaluate the prognostic value of circulating Epstein-Barr virus DNA for extra-nodal natural killer/T-Cell lymphoma, nasal type (ENKTL), we performed a meta-analysis of published studies that provided survival information with pre-/post-treatment circulating EBV DNA. METHODS: Eligible studies that discussed prognostic significance of circulating EBV DNA in ENKTL were included. Random effects models were applied to obtain the estimated hazard ratios and 95% confidence intervals to evaluate prognostic significance (OS and DFS/PFS). Eleven studies covering a total of 562 subjects were included in this analysis. RESULTS: The summary HRs and 95% CIs of pre-treatment EBV DNA for OS and PFS/DFS were 4.43 (95% CI 2.66-7.39, P<0.00001) and 3.12 (95% CI 1.42-6.85, P=0.005), respectively. The corresponding HRs and 95% CIs of post-treatment EBV DNA for OS and PFS/DFS were 6.28 (95% CI 2.75-14.35, P<0.0001) and 6.57 (95% CI 2.14-20.16, P=0.001). Subgroup analyses indicated a strong trend of prognostic powers with pre-/post-treatment EBV DNA. CONCLUSION: With the present evidence, circulating EBV DNA consistently correlated with poorer prognosis in patients with ENKTL which need further investigation in large-scale clinical studies.

Exploration of the optimal treatment regimes for Esthesioneuroblastoma: a single center experience in China.

BACKGROUND: Esthesioneuroblastoma (ENB) is an uncommon neoplasm arising from the olfactory mucosa. The optimal treatment regimen for ENB remains unclear. This study aims to evaluate its clinical features, long-term outcomes and explore optimal treatment patterns. METHODS: Clinical data of consecutive 44 ENB patients were reviewed retrospectively. The correlation between clinical features and treatment approaches were analyzed, with several prognostic factors explored meanwhile. RESULTS: The age of onset of ENB showed a bimodal distribution, with peaks at 10~20 and 50~60 years. The median follow-up time was 84 months (range, 27~198 months).The 5-year overall and progression free survival rates were 42.7% and 39.1%, respectively, with 10-year rates of 28.9% and 21.7% respectively. Overall, 19 patients developed recurrent disease. Patients undergoing surgery combined with adjuvant radiotherapy had significantly higher 5-year overall survival (67.5% vs. 33.3%, P=0.043) and progress-free survival (60.0%vs. 18.7%, P=0.008) than those receiving other treatment approaches. No-Skin-involved ENB was associated with markedly better 5-year overall survival (45.5%vs.0 %, P=0.038) and progress-free survival (31.3% vs. 0 %, P=0.001) compared with skin-involved tumor. CONCLUSIONS: ENB is a rarely malignant tumor with high probability of locoregional recurrence and poor survival. Surgical resection followed by radiotherapy has been shown to achieve optimal local control and overall survival.

Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair.

The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair. NU7441 profoundly radiosensitized wild-type MEF cells and SUNE-1 cells, but not DNA-PKcs-/- MEF cells. NU7441 significantly suppressed radiation-induced DSB repair post-irradiation through unrepaired and lethal DNA damage, the cell cycle arrest. The effect was associated with the activation of cell cycle checkpoints. The present study revealed a mechanism by which inhibition of DNA-PK sensitizes cells to irradiation suggesting that radiotherapy in combination with DNA-PK inhibitor is a promising paradigm for the management of NPC which merits further investigation.

Analysis of Clinical characteristics to predict pathologic complete response for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

To explore clinical characteristics which could be applied to predict pathologic complete response (pCR) for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (neo-CRT) and total mesorectal excision (TME). 297 patients with locally advanced rectal cancer (cT3-4 or cN+) who were treated with neo-CRT followed by TME were retrospectively reviewed. Clinical characteristics including age, gender, tumor distance from anus, serum CEA, hemoglobin levels before treatment and clinical TN stage were used to investigate the association with pCR after neo-CRT. Seventy-nine (26.6%) patients achieved pCR after neo-CRT. pCR were achieved in 42 (34.4%) patients in cT1-3 stage and 37 (21.1%) in cT4 stage. pCR rate was 36.4% and 16.4% for patients with pre-treatment serum CEA ≤5.33ng/ml and >5.33ng/ml, respectively. Uni- and multi-variate analyses revealed that pre-treatment serum CEA level ≤5.33ng/ml and clinical T stage, (i.e., cT1-3 versus cT4) were highly correlated with pCR (p < 0.05). Clinical T stage and pre-treatment serum CEA level were strongly associated with pCR for patients with locally advanced rectal cancer treated with neo-CRT followed by TME which could be applied as clinical predictors for pCR.

Evaluation of 7th Edition of AJCC Staging System for Nasopharyngeal Carcinoma.

Purpose: To evaluate and improve the 7th edition International Union against Cancer/American Joint Committee on Cancer staging system for nasopharyngeal carcinoma. Methods: A retrospective review of the data from 905 patients with biopsy-proven non-disseminated nasopharyngeal carcinoma was performed. All the patients were examined by magnetic resonance imaging (MRI) and received radiotherapy. Results: Satisfied distributions among the stages were observed in the 7th edition staging systems. LRFS only differed in classifications betweenT1 and T3, T1 and T4 (P=0.022 and P=0.016, respectively). Significant differences were observed between patients without and with masticator space involvement for OS, DMFS and PFS (p<0.05). No statistically significant differences in LRFS were observed among different groups with anatomical masticator space involvement. The DMFS between N2 and N3b, N3a and N3b were lack of significance (P=0.060 and P=0.59). The T category and N category were independent prognostic factors for the major endpoints in the Cox multivariate regression analysis (P<0.01). Conclusion: This study confirmed the prognostic value of the 7th edition UICC/AJCC staging system, the revisions of the 7th edition staging system are acceptable. However, our study also revealed limitations in the current staging system and suggested some potential modifications in future revision.

Predictive Value of Primary Tumor Site for Loco-regional Recurrence in Early Breast Cancer Patients with One to Three Positive Axillary Lymphadenophy.

Introduction: It remains controversial on high risks for early breast cancer patients with one to three axillary nodes after mastectomy who is predisposition to locoregional recurrence. The present study is to investigate the relationship between primary tumor site and loco-regional recurrence (LRR) and explore the predictive value of clinicopathological characteristics in LRR for early breast cancer patients with one to three positive axillary lymph nodes after mastectomy. Methods: We reviewed the clinical data of 656 consecutively diagnosed patients with pT1-2N1M0 breast cancer who were treated in Sun Yat-sen University Cancer Center with radical operation without postoperative radiotherapy between March 1998 and December 2010. The primary tumor sites included outer quadrant in 455 patients (69.36%), inner quadrant in 156 patients (23.78%)and central quadrant in 45 patients (6.86%). LRR and LRR-free survival (LRFS) in combination with clinical and pathological features were analyzed to screen out patients with higher risk of LRR. Results: The median follow-up time was 64.9 months. The 5-, 10-year LRR for the cohort was 8.6% and 12.9%, respectively; the 5-, 10-year LRFS was 86.2% and 76.4%, respectively. Multivariate analyses showed that age of ≤35 years, inner quadrant tumor and non-luminal subtype were independent risk factors for LRR and LRFS. Patients with primary tumor in inner quadrant showed higher LRR and poorer LRFS when risk factors are ≥2 than those with tumors in other sites. Conclusions: Inner quadrant tumor was an independent predictor for LRR and LRFS in patients with early breast cancer and one to three positive axillary lymph nodes, which would be more accurate in combination with other prognostic indexes including patients' age, pathological T stage, Ki67 status, molecular subtypes.

Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Inhibition of DNA-PKcs prolonged IR-induced G2/M phase arrest because of sequential activation of cell cycle checkpoints. DSBs were introduced, and cell cycle checkpoints were recruited after exposure to IR in nasopharyngeal carcinoma SUNE-1 cells. NU7441 radiosensitized MEF cells and SUNE-1 cells by interfering with DSB repair. Together, these results reveal a mechanism in which coupling of DSB repair with the cell cycle radiosensitizes NHEJ repair-deficient cells, justifying further development of DNA-PK inhibitors in cancer therapy.