Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment.

Leptomeningeal metastasis (LM) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. LM will occur once tumor cells spread to the cerebrospinal fluid (CSF) space. Patients may suffer blindness, paralysis, and mental disorders that seriously affect their quality of life. There is a clear unmet need to improve the efficacy of diagnosis and treatment of LM. To better solve this problem, it is helpful to clarify the potential mechanisms of LM. Clinical manifestations, magnetic resonance imaging, and CSF biopsy are the key components in the diagnosis of NSCLC with LM. CSF cytology is insufficient and should be combined with liquid biology. The application of radiotherapy, intrathecal treatment, targeted therapy and immunotherapy provides more options for LM patients. Each treatment has a particular level of efficacy and can be used alone or in combination for individual patients. New technologies in radiotherapy, drug repositioning in intrathecal treatment, and the higher CSF permeability in TKIs have brought new breakthroughs in the treatment of LM. This review focused on clarifying the potential mechanisms, discussing the major clinical challenges, and summarizing recent advances in the diagnosis and treatment of LM from NSCLC. Future research is essential to improve the efficiency of diagnosis, to optimize therapy and to enhance patient prognosis.

Prostate-derived IL-1ß upregulates expression of NMDA receptor in the paraventricular nucleus and shortens ejaculation latency in rats with experimental autoimmune prostatitis.

Experimental autoimmune prostatitis (EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus (PVN). However, the mechanism has not yet been elucidated. Herein, we screened out the target prostate-derived inflammation cytokines (PDICs) by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid (CSF) between EAP rats and their controls. After identifying the target PDIC, qualified males in initial copulatory behavior testing (CBT) were subjected to implanting tubes onto bilateral PVN. Next, they were randomly divided into four subgroups (EAP-1, EAP-2, Control-1, and Control-2). After 1-week recovery, EAP-1 rats were microinjected with the target PDIC inhibitor, Control-1 rats were microinjected with the target PDIC, while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF (aCSF). Results showed that only interleukin-1ß(IL-1ß) had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls (P < 0.001) and significantly higher protein concentrations in both the serum (P = 0.001) and CSF (P < 0.001) of the EAP groups compared to the Control groups. Therefore, IL-1ß was identified as the target PDIC which crosses the blood-brain barrier, thereby influencing the central nervous system. Moreover, the EAP-1 subgroup displayed a gradually prolonged ejaculation latency (EL) in the last three CBTs (all P < 0.01) and a significantly lower expression of NMDA NR1 subunit in the PVN (P = 0.043) compared to the respective control groups after a 10-day central administration of IL-1ß inhibitors. However, the Control-1 subgroup showed a gradually shortened EL (P < 0.01) and a significantly higher NR1 expression (P = 0.004) after homochronous IL-1ß administration. Therefore, we identified IL-1ß as the primary PDIC which shortens EL in EAP rats. However, further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1ß upregulates NMDA expression.

Robotic-assisted partial nephrectomy with sequential clamping of segmental renal arteries for multiple ipsilateral renal tumors: initial outcomes.

BACKGROUND: To assess the technical feasibility and outcomes of robotic-assisted partial nephrectomy (RPN) with sequential segmental renal artery (SRA) clamping for multiple ipsilateral renal tumors (MIRTs). METHODS: From April 2016 to February 2018, consecutive eleven cases successfully underwent RPN with sequential SRA clamping under the guidance of dual-source computed tomography (DSCT). RESULTS: Ten cases had two lesions and two cases had three at the ipsilateral kidneys. The mean size and the mean R.E.N.A.L score for the dominant lesion of single case were 3.3 cm and 5.7, respectively. Twenty-two lesions (84.6%) had one target SRA and four (15.4%) had two target SRAs. Satisfactory ischemic areas were achieved by sequentially clamping two (81.8%) or three (18.2%) target SRAs with mean clamping time of 18.8 (15.0-27.0) min for single lesion, and the mean of total clamping time for single case was 37.5 (32.0-52.0) min. Only the complications of grade 1-2 were found and no positive surgical margin was discovered. The mean follow-up time was 5.4 months and no local recurrence or metastasis was found. The mean postoperative eGFR was 71.2 ml/minute/1.73m2 that was only an insignificant reduction (9.3%) compared with the preoperative baseline. CONCLUSION: This novel nephron-sparing technique, RPN with sequential SRA clamping, represents a good alternative for selected patients with MIRTs. With the guidance of DSCT and skilled robotic experience, this technique is feasible and can maximize renal function preservation. Large-scale multicenter clinical studies are still needed to further prove these initial outcomes.

Fluvastatin-mediated down-regulation of SATB1 affects aggressive phenotypes of human non-small-cell lung cancer cell line H292.

AIMS: Fluvastatin reduces tumor proliferation and increased apoptotic activity in various cancers. Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer that reprogrammes the gene transcription profiles of tumors to promote growth and metastasis. The antitumor effect and molecular mechanisms of fluvastatin on lung cancer is poorly understood. This study aimed to investigate the antitumor effect of fluvastatin on lung cancer and its possible mechanics. MAIN METHODS: Cell viability assay was used to examine the inhibition of fluvastatin on proliferation of H292 cells. In order to investigate the antitumor mechanics, SATB1 knock-down H292 cells was constructed by lentiviral transfection. RT-PCR and Western blot were performed to examine the effects of fluvastatin on expression of SATB1 and Wnt/ß-catenin signaling components. KEY FINDINGS: Fluvastatin significantly inhibited proliferation and invasion of H292 cells in a time- and dose-dependent manner and promoted the apoptosis (p < 0.05). The expression of SATB1 was down-regulated by fluvastatin in a dose-dependent manner. The proliferation and invasion of SATB1-shRNA cells was significantly suppressed, and the apoptosis was significantly enhanced (p < 0.05). We also show that the common target genes were regulated by SATB1 and Wnt/ß-catenin pathway simultaneously. There may be a functional link between SATB1 and Wnt/ß-catenin pathway. SIGNIFICANCE: We presented a possible mechanism of statins that fluvastatin significantly suppressed the in vitro tumor progression of H292 cells possibly by down-regulation of SATB1 via Wnt/ß-catenin pathway, which provided new therapeutic possibilities for more cancers driven by hyperexpression of SATB1 and Wnt/ß-catenin pathway.

Robotic renal cyst decortication with calyceal diverticulectomy in a toddler - technical practicalities: a case report.

BACKGROUND: Incidence of simultaneous renal cyst with calyceal diverticula in contralateral kidney is rare in children. A minimally invasive procedure in different sittings is often recommended. CASE PRESENTATION: A Chinese 15-month-old boy presented to the Urology department of a tertiary care center with right flank pain. He was subjected to magnetic resonance urography and was diagnosed as having right renal cyst and contralateral calyceal diverticula. He underwent robotic cyst decortication and calyceal diverticulectomy using da Vinci robot. His postoperative period was uneventful. He was discharged on fifth postoperative day. Histopathology was consistent with simple renal cyst. CONCLUSIONS: Robotic combined cyst decortication and contralateral diverticulectomy is feasible in selected small children. However, it demands adequate technical skill and experience.

Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy.

PURPOSE: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. METHODS AND MATERIALS: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose. RESULTS: Compared with CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not immunocompromised, mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8+ T cells. Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented with greater efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field. CONCLUSIONS: Targeting MDSC recruitment and enhancing antitumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT was more potent for cancer treatment.

An Up-to-date Meta-analysis of Coffee Consumption and Risk of Prostate Cancer.

PURPOSE: Results of the association between coffee consumption (CC) and the risk of prostate cancer (PC) are still controversy. Based on published relevant studies, we conducted an up-to-date meta-analysis to investigatethis issue. MATERIALS AND METHODS: The protocol used in this article is in accordance with the PRISMA checklist. Eligible studies were screened and retrieved by using PUBMED and EMBASE as well as manual review of references up to July 2016. We calculated the pooled relative risk (RR) with 95% confidence interval (CI) with random effect models. The dose-response relationship was assessed by generalized least-squares trend estimation analysis. RESULTS: Totally, we included twenty-eight studies (14 case-control and 14 cohort studies) on CC with 42399 PC patients for the final meta-analysis. No significant association of PC was found for high versus non/lowestCC, with RR = 1.07 (95% CI: 0.96-1.18). In subgroup meta-analysis by study design, there were no significant positive associations between CC and PC in case-control studies (RR = 1.19, 95% CI: 1.05-1.35) or in the cohort studies (RR = 0.97, 95% CI: 0.84-1.12). Additionally, RR with different quality of studies were respectively 1.15 (95% CI: 0.99-1.34) and 1.28 (95% CI: 1.03-1.58) for high and low quality in the case-control studies; while were respectively 1.02 (95% CI: 0.88-1.20) and 0.81 (95% CI: 0.57-1.14) in the cohort studies. When analyzed by geographic area, we found no association between CC and PC, with RR = 1.06 (95% CI: 0.86-1.30) for 10 studies from Europe, 1.06 (95% CI: 0.94-1.20) for 13 studies conducted in America; 1.12 (95% CI: 0.70-1.79) for 4 studiesfrom Asia. However, in subgroup analysis by subtype of the disease, there was a significant negative (beneficial) association in the localized PC (RR = 0.90, 95% CI: 0.84-0.97), but not for the advanced PC (RR = 0.90, 95%CI: 0.70-1.16). Additionally, RR = 0.99 (95% CI: 0.98-0.99) for an increment of one cup per day of coffee intake shows significant association with the localized PC. CONCLUSION: Our results indicate that CC has no harmful effect on PC. On the contrary, it has an effect on reducing the localized PC risk. Further prospective cohort studies of high quality are required to clarify this relationship.

MicroRNA Expression Profile on Solid Subtype of Invasive Lung Adenocarcinoma Reveals a Panel of Four miRNAs to Be Associated with Poor Prognosis in Chinese Patients.

According to the reclassification of lung adenocarcinoma (LAC) proposed in 2011, solid predominant lung adenocarcinoma (SPA) has been associated with poor outcomes for LAC patients. However, the prognostic value of the presence of solid subtype remains unclear. Besides, there is little data about the roles of microRNA (miRNA) in solid subtype of LAC. In this study, 243 LAC patients were classified into solid subtype positive and negative groups (S+ LAC, n=134 and S- LAC, n=109) according to whether the solid subtype was more than 5% of the tumor component or not. We analyzed the relationship between solid subtype and patients' outcome by univariate and multivariate analyses. Solid subtype was proved to be significantly associated with the 5-year overall survival and played as an independent prognostic factor for stage I-III invasive LAC patients. Then miRNA microarray was used to identify differentially expressed miRNAs in solid subtype, resulting in 31 differential miRNAs. Quantitative reverse transcription-PCR (QRT-PCR) was used to validate 4 key miRNAs (miR-133b, miR-155-5p, miR-124-3p, miR-145-5p). Further, CCK-8 and transwell assays were performed to validate the impact of one dysregulated miRNA (miR-133b) on LAC cell function. Interestingly, while miR-133b could significantly inhibit the proliferation of A549 and SPC-A1, it showed no effect on the migration or invasion of LAC cell lines. These results suggest that solid subtype can exert independent prognostic impact on LAC patients, and 4 important dysregulated miRNAs in solid subtype of LAC may be involved in the malignancy of S+LAC, thus may further have clinical perspective for S+ LAC in the future.

[Simultaneous Detection of External and Internal Quality Parameters of Huping Jujube Fruits using Hyperspectral Imaging Technology].

Nondestructive detection of external and internal quality parameters of jujube is crucial for improving jujube's shelf life and industry production. Hyperspectral imaging is an emerging technique that integrates conventional imaging and spectroscopy to acquire both spatial and spectral information from a sample. It takes the advantages of the conventional RGB, near-infrared spectroscopy, and multi-spectral imaging. In this work, hyperspectral imaging technology covered the range of 450~1000 nm has been evaluated for nondestructive determination of "natural defects" (shrink, crack, insect damage and peck injury) and soluble solids content (SSC) in Huping jujube fruit. 400 RGB images were acquired through four different defect (50 for each stage) and normal (200) classes of the Huping jujube samples. After acquiring hyperspectral images of Huping jujube fruits, the spectral data were extracted from region of interests (ROIs). Using Kennard-Stone algorithm, all kinds of samples were randomly divided into training set (280) and test set (120) according to the proportion of 3:1. Seven principal components (PCs) were selected based on principal component analysis (PCA), and seven textural feature variables (contrast, correlation, energy, homogeneity, variance, mean and entropy) were extracted by gray level co-occurrence matrix (GLCM). The least squares support vector machine (LS-SVM) models were built based on the PCs spectral, textural, combined PCs and textural features, respectively. The satisfactory results show the correct discrimination rate of 92.5% for the prediction samples, as well as correlation coefficient (Rp) of 0.944 for the prediction set to calculate SSC content based on PCs and textural features. The study demonstrated that hyperspectral image technique can be a reliable tool to simultaneous detection of external ("natural defects") and internal (SSC) quality parameters of Huping jujube fruits, which provided a theoretical reference for nondestructive detection of jujube fruit.

SNAILs promote G1 phase in selected cancer cells.

Cells can acquire a stem-like cell phenotype through epithelial-mesenchymal transition (EMT). However, it is not known which of the stem-like cancer cells are generated by these phenotype transitions. We studied the EMT-inducing roles of SNAILs (the key inducers for the onset of EMT) in selected cancer cells (lung cancer cell line with relatively stable genome), in order to provide more implications for the investigation of EMT-related phenotype transitions in cancer. However, SNAILs fail to induce completed EMT. In addition, we proved that Snail accelerates the early G1 phase whereas Slug accelerates the late G1 phase. Blocking G1 phase is one of the basic conditions for the onset of EMT-related phenotype transitions (e.g., metastasis, acquiring stemness). The discovery of this unexpected phenomenon (promoting G1 phase) typically reveals the heterogeneity of cancer cells. The onset of EMT-related phenotype transitions in cancer needs not only the induction and activation of SNAILs, but also some particular heredity alterations (genetic or epigenetic alterations, which cause heterogeneity). The new connection between heredity alteration (heterogeneity) and phenotype transition suggests a novel treatment strategy, the heredity alteration-directed specific target therapy. Further investigations need to be conducted to study the relevant heredity alterations.

DNA repair gene polymorphisms and clinical outcome of patients with primary small cell carcinoma of the esophagus.

Polymorphisms in DNA repair genes impact on the synthesis of DNA repair proteins that are crucial to the repair of DNA damages induced by chemotherapy and radiotherapy. We retrospectively examined whether there was an association between the selected six single nucleotide polymorphisms (SNPs) of five DNA repair genes (PARP1-Val762Ala, XRCC1-Arg194Trp, XRCC1-Arg399Gln, XPC-Lys939Gln, BRCA1-Lys1183Arg, and BRCA2-Asn372His) and the clinical outcome of patients with primary small cell carcinoma of esophagus (SCCE), and it showed that the median progression-free survival (PFS) and the overall survival (OS) were 11.8 versus 9.7 months (P = 0.041) and 17.4 versus 14.8 months (P = 0.032) for patients carrying the variant allele (T/C + C/C) and the wild-type allele (T/T) of PARP1-Val762Ala polymorphism, respectively. However, no statistical significance was observed in the other five polymorphic loci (P > 0.05). When these six SNPs were combined, however, patients with at least three variant genotypes had significantly longer PFS and OS compared with those carrying less than three variant genotypes (P = 0.009 and P = 0.007, respectively). The presence of at least three polymorphic variants in certain DNA repair genes may impact on patient survival and could be a potential genomic predictor of clinical response to DNA-damaging treatment in SCCE patients.

CARP is a potential tumor suppressor in gastric carcinoma and a single-nucleotide polymorphism in CARP gene might increase the risk of gastric carcinoma.

BACKGROUND: The caspase-associated recruitment domain-containing protein (CARP) is expressed in almost all tissues. Recently, the tumor-suppressive function of CARP was discovered and attracted increasing attention. This study aimed to investigate the role of CARP in the carcinogenesis of human gastric carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Compared with normal gastric tissue, the downregulation of CARP expression was observed in gastric carcinoma tissue by cDNA array and tissue microarray assay. In vitro, the gastric carcinoma cell line (BGC-823) was stably transfected with pcDNA3.1B-CARP or plus CARP siRNA, and we used MTT, flow cytometry, cell migration on type I collagen, cell-matrix adhesion assay and western blot analysis to investigate the potential anti-tumor effects of CARP. The data showed that overexpressing CARP suppressed the malignancy of gastric carcinoma BGC-823 cell line, including significant increases in apoptosis, as well as obvious decreases in cell proliferation, migration, adhesion ability, and tumor growth. The tumor-suppressive effects of CARP were almost restored by siRNA-directed CARP silence. In addition, overexpression of CARP induced G1 arrest, decreased the expressions of cyclin E and CDK2, and increased the expressions of p27, p53 and p21. In vivo, the tumor-suppressive effect of CARP was also verified. A single-nucleotide polymorphism (SNP) genotype of CARP (rs2297882) was located in the Kozak sequence of the CARP gene. The reporter gene assay showed that rs2297882 TT caused an obvious downregulation of activity of CARP gene promoter in BGC-823 cells. Furthermore, the association between rs2297882 and human gastric carcinoma susceptibility was analyzed in 352 cases and 889 controls. It displayed that the TT genotype of rs2297882 in the CARP gene was associated with an increased risk of gastric carcinoma. CONCLUSIONS/SIGNIFICANCE: CARP is a potential tumor suppressor of gastric carcinoma and the rs2297882 C>T phenotype of CARP may serve as a predictor of gastric carcinoma.

Pulmonary artery invasion, high-dose radiation, and overall survival in patients with non-small cell lung cancer.

PURPOSE: To investigate whether high-dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with medically inoperable/unresectable NSCLC treated with definitive radiation therapy in prospective studies were eligible for this study. Pulmonary artery involvement was defined on the basis of pretreatment chest CT and positron emission tomography/CT fusion. Pulmonary artery was contoured according to the Radiation Therapy Oncology Group protocol 1106 atlas, and dose-volume histograms were generated. RESULTS: A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiation therapy. Radiation dose ranged from 60 to 85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤2, 3, 4, and 5 had 1-year OS and median survival of 67% and 25.4 months (95% confidence interval [CI] 15.7-35.1), 62% and 22.2 months (95% CI 5.8-38.6), 90% and 35.8 months (95% CI 28.4-43.2), and 50% and 7.0 months, respectively (P=.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of radiation therapy. Maximum and mean doses to PA were not significantly associated with OS. The V45, V50, V55, and V60 of PA were correlated significantly with a worse OS (P<.05). Patients with V45 >70% or V60 >37% had significantly worse OS (13.3 vs 37.9 months, P<.001, and 13.8 vs 37.9 months, P=.04, respectively). CONCLUSIONS: Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.

[The bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma].

OBJECTIVE: To investigate the bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma. METHODS: Female 8-week-old C57 mice bearing 4-6 mm diameter Lewis lung carcinoma tumors in the hind legs were divided into 3 groups, control group (0 Gy), high single-dose group (12 Gy/one fraction/day) and routine radiation group (22 Gy/11 fraction/15 d). The mean biological effective dose (BED) of both radiation groups was 26.4 Gy. Changes in hypoxia, DNA damage and cell cycle of the tumor cells at 1, 3, 8, 15 and 21 d after first irradiation was assessed by immunofluorescence and flow-cytometry and the tumor growth curve was also made. RESULTS: Compared to the fractionated treatment, the tumor growth was delayed after single dose irradiation. The percent of hypoxic cells after single dose radiation was lower than fractioned irradiation at 3, 8, 15 d after first radiation. The foci of gamma-H2AX showed that the single dose caused heavier DNA damages than fractioned irradiation at 1, 3 d after first radiation. The decline of G0/G1 percentage and increase of G2/M percentage of cells was found in both radiation schedules, but the G2/M percentage after single dose radiation was higher. CONCLUSION: In the C57 mice bearing Lewis lung carcinoma, the high single-dose regimen inhibits the tumor growth more than fractioned irradiation. We hypothesized that conversion of high single-dose to BED using the LQ formalism under estimated the in vivo effect of hypofractionated radiation.

[Outcomes of treatment of 32 cases of advanced or relapsed post-surgery pulmonary sarcomatoid carcinoma].

OBJECTIVE: To determine the efficacy of the third generation chemotherapy agents on relapsed post-surgery and advanced pulmonary sarcomatoid carcinoma (PSC). METHODS: We reviewed the medical records of 32 PSC patients. Their treatment modalities and survival rate, as well as risk factors associated with the survival rate including gender, age, location and size of tumor, relapse, initial diagnosis of stage, pathologic subtypes and smoking history were analysed. RESULTS: All of the 32 PSC patients received chemotherapy with gemcitabine combined with cisplatin (GP) or paclitaxel combined with cisplatin (TP). They had a median of 14 months overall survive (OS) and 5 months progress-free survive (PFS). The remission rate was 21.9%. An initial stage IV diagnosis and a larger than 6 cm tumor in diameter were independent factors associated with poor prognosis. CONCLUSION: The efficacy of TP and GP chemotherapy on patients with relapsed post-surgery and advanced PSC is comparable with that reported by other researchers. An initial stage IV diagnosis and a larger than 6 cm tumor in diameter are predictors of poor prognosis.

Prognostic role of hypoxic inducible factor expression in non-small cell lung cancer: a meta-analysis.

INTRODUCTION: Reported prognostic roles of hypoxic inducible factor (HIF) expression in non-small cell lung cancer (NSCLC) have varied. This meta-analysis aimed to examine the relationship between HIF expression and clinical outcome in NSCLC patients. METHODS: PubMed were used to identify relevant literature with the last report up to December 20th, 2012. After careful review, survival data were collected from eligible studies. We completed the meta-analysis using Stata statistical software (Version 11) and combined hazard ratio (HR) for overall survival (OS). Subgroup specificity, heterogeneity and publication bias were also assessed. All of the results were verified by two persons to ensure accuracy. RESULTS: Eight studies were finally stepped into this meta-analysis in which seven had available data for HIF-1α and three for HIF-2α. Combined HRs suggested that higher expression of HIF1α had a negative impact on NSCLC patient survival (HR=1.50; 95%CI =1.07-2.10; p=0.019). The expression of HIF-2α was also relative to a poorer survival (HR=2.02; 95%CI =1.47-2.77; p=0.000). No bias existed in either of the two groups. CONCLUSION: This study suggests that elevations of HIF-1α and HIF- 2α expression are both associated with poor outcome for patients with NSCLC. The data support further and high quality investigation of HIF expression for predicting poor outcome in patients with NSCLC.

Ablative hypofractionated radiotherapy normalizes tumor vasculature in lewis lung carcinoma mice model.

Ablative hypofractionated radiotherapy (HFRT) significantly improves the overall survival of inoperable non-small cell lung cancer (NSCLC) patients compared with conventional radiation therapy. However, the radiobiological mechanisms of ablative HFRT remain largely unknown. The purpose of this study was to investigate the dynamic changes of tumor vessels and perfusion during and after ablative hypofractionated radiotherapy. Lewis lung carcinoma-bearing mice were treated with sham (control) and ablative hypofractionated radiotherapy of 12 Gy in 1 fraction (12 Gy/1F) and 36 Gy in 3 fractions (36 Gy/3F). Tumor microvessel density (MVD), morphology and function were examined at different times after irradiation. The results showed that, compared to the controls the MVD and hypoxia in ablative HFRT groups decreased, which were accompanied by an increase in the number of pericytes and their coverage of vessels. Functional tests revealed that tumor hypoxia and perfusion were improved, especially in the 36 Gy/3F group. Our results revealed that ablative hypofractionated radiotherapy not only repressed MVD and hypoxia, but also increased the vascular perfusion and the number of pericyte-covered vessels, suggesting that ablative HFRT normalized the tumor vasculature.

Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: experimental and clinical evidence.

PURPOSE: This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT). METHODS: Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood-vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated. RESULTS: Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium. CONCLUSION: This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation.

[The protection effects of resveratrol on irradiated human pneumonic cell lines and its mechanism].

OBJECTIVE: This study was to explore whether resveratrol could protect human bronchial epithelial cells (HBE) and human fetal lung fibroblasts (MRC5) from radiation injury and to investigate its potential HBE and MRC5 were divided into four groups: Group 1 (Vehicle), control group, only mechanism. METHODS: treated with vehicle; Group 2 (resveratrol, Res), the resveratrol group, treated with 5 micromol/L resveratrol; Group 3 (RT+Vehicle), the X-ray irradiation group, only subjected to irradiation of 20 Gy X-ray; Group 4 (RT+Res), the combination therapy group, 2 hours before X-ray treatment (20 Gy, 8. 33 Gy/min for 144 s), 5 micromol/L resveratrol was added to the cells. Several experimental methods were used to observe cellular morphology, ultrastructure, viability, DNA damage, apoptosis, and to determine the change of oxidative stress indexes such as reactive oxygen species (ROS), malondialdehyde (MDA), total glutathione (GSH) and superoxide dismutase (SOD). RESULTS: X-ray could induce HBE and MRC5 cell injury. Resveratrol could significantly ease the morphological and ultrastructure injury, relieve the decrease of cellular viability and the damage of DNA, and reduce cellular apoptosis. Besides, oxidative stress indexes including ROS, MDA, GSH, SOD were improved by resveratrol after irradiation. CONCLUSION: Resveratrol protect HBE and MRC5 from radiation injury, which is related to the alleviation of oxidative stress injury.