ß-Glucan Combined With PD-1/PD-L1 Checkpoint Blockade for Immunotherapy in Patients With Advanced Cancer.

Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) checkpoint blocking antibodies have been shown to be a powerful immune checkpoint blockade (ICB) therapy for patients with cancer. However, patients quickly develop resistance to immunotherapy. ß-glucan, an immune adjuvant, has been found to stimulate innate and adaptive immune responses. In this study, we assessed the use of whole glucan particle (WGP) ß-glucan in combination with PD-1/PD-L1-blocking antibodies to slow down the resistance to immunotherapy. Results from a tumor mouse model demonstrated that administration of WGP ß-glucan plus PD-1/PD-L1-blocking antibodies led to increased recruitment of immune-associated cells, improved regulation of the balance between T-cell activation and immune tolerance, and delayed tumor progression. This combination therapy was also found to improve progression-free survival in patients with advanced cancer who had previously discontinued anti-PD-1/PD-L1 because of disease progression. These findings suggest that ß-glucan could be used as an immune adjuvant to reverse anti-PD-1/PD-L1 resistance by regulating the immune system.

Efficacy and Safety of Low-Dose Nab-Paclitaxel Plus Tislelizumab in Elderly Patients With Previously Treated Metastatic Non-Small Cell Lung Cancer.

The combination of immunotherapy and chemotherapy has a synergic effect in non-small cell lung cancer (NSCLC). However, the elderly are often excluded from clinical trails due to their poor health status and more comorbidities. We sought to assess the efficacy and safety of low-dose nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus tislelizumab (an anti-PD-1 antibody) in elderly patients with advanced NSCLC. In this phase 2 clinical trail, eligible patients were those aged ≥65 years with metastatic NSCLC who had disease progression after treatment with ≥1 line of chemotherapy or targeted therapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) variations were eligible if they demonstrated disease progression after treatment with ≥1 corresponding inhibitor. Primary endpoints were progression-free survival and safety/tolerability. Secondary endpoints included objective response rate and overall survival. Among 29 patients enrolled from May 2019 through August 2020, 21 (72.4%) had adenocarcinoma, 17 (58.6%) had a performance status of 2, 8 (27.6%) had asymptomatic brain metastases, and 13 (44.8%) had EGFR/ALK variations. As of the data cutoff point on April 1, 2021, median progression-free survival and overall survival were 9.5 months and 16.5 months, respectively. Ten patients achieved a partial response (objective response rate of 34.5%). Seventeen (58.6%) patients had ≥1 treatment-related adverse event, with grade 3 events seen in 3 patients (10.3%). The most common adverse events were fatigue (20.7%), fever (17.2%), abnormal liver function (17.2%), and rash (17.2%). These results suggest that low-dose nab-paclitaxel plus tislelizumab is well tolerated and effective in elderly patients with advanced NSCLC, including those with EGFR/ALK variations.

Ascites and Serial Plasma Circulating Tumor DNA for Predicting the Effectiveness of Hyperthermic Intraperitoneal Chemotherapy in Patients With Peritoneal Carcinomatosis.

PURPOSE: We investigated the value of ascites and serial plasma circulating tumor DNA (ctDNA) for predicting response to hyperthermic intraperitoneal chemotherapy (HIPEC), monitoring tumor burden, and predicting prognosis in patients with peritoneal carcinomatosis (PC). EXPERIMENTAL DESIGN: In this observational study, 19 patients with PC were enrolled. Serial plasma ctDNA was analyzed using next-generation sequencing. The molecular tumor burden index (mTBI) was used to detect ctDNA, and concurrent changes in the dominant clone variant allele frequency (VAF) and common tumor markers were used as controls. The correlation between ascites and plasma ctDNA comutated genes was expressed by VAF. The overall response rate (complete response + partial response) after HIPEC was determined. Ascites progression-free survival (PFS) and overall survival (OS) were determined, and potential correlations between these outcomes and change in mTBI (△mTBI), change in sum-VAF (△sum-VAF), dominant close VAF, and tumor markers were assessed. RESULTS: The overall response rate at 1 month after HIPEC was 100%. The △mTBI (r = 0.673; P = 0.023) and △sum-VAF (r = 0.945; P <0.001) were significantly positively correlated with ascites PFS; these correlations were stronger than those of the dominant clone VAF (r = 0.588; P = 0.057) and tumor markers in the same period (r =0.091; P = 0.790). Patients with a low baseline mTBI (<0.67) demonstrated significantly longer ascites PFS (P = 0.003; HR = 0.157; 95% CI: 0.046-0.540) and OS (P = 0.017; HR = 0.296; 95% CI: 0.109-0.804) than those with a high baseline mTBI (≥0.67). Consistent mutations were detected in plasma and ascites (r = 0.794; P = 0.001). CONCLUSION: A real-time serial plasma ctDNA assay accurately reflected tumor burden. The △mTBI and △sum-VAF can be used as predictors of HIPEC efficacy in patients with PC. A high baseline mTBI may be a negative risk factor for prognosis.

Hypofractionated Low-Dose Radiotherapy Combined with Immune Checkpoint Inhibition in Metastatic Solid Tumors.

BACKGROUND: The combination of radiotherapy and immunotherapy can bring benefits to patients, especially advanced patients. However, conventional radiotherapy brings about great adverse reactions. How about the hypofractionated low-dose radiotherapy? MATERIALS AND METHODS: In this retrospective cohort study, we included 32 patients with metastatic solid tumors treated with hypofractionated radiotherapy combined with an immune checkpoint inhibitor. Patients underwent radiotherapy of 4Gy/Fx on day 1, 3, and 5, and received single-drug immunotherapy of PD-1 inhibitor on day 2. We evaluated the following outcomes: objective response rate (ORR), disease control rate (DCR), change of nonirradiated and irradiated lesions, quality of life, and symptom improvement. RESULTS: Among the 32 patients, the ORR was 9.4% (3/32) and the DCR was 56.25% (18/32). Hypofractionated radiotherapy combined with immunotherapy showed a remarkable efficacy of local control on metastatic tumor patients. Local masses irradiated in two patients (6.25%) were complete remission, partial response rate was 37.5% (12 patients), and 56.25% was stability (18 patients). Out of those 18 patients, 15 patients had the local masses shrank more or less. The ORR of local control reached 43.75%, and its DCR was 100%. In addition, the intratumor necrosis rate was 44.4% in the SD patients. Median progression-free survival was 3.8 months (95%Cl: 2.2-5.4). By treating the local mass, the symptoms of most patients were alleviated, and the quality of life was improved. CONCLUSION: Our retrospective analysis revealed that hypofractionated radiotherapy combined with immunotherapy was effective in local control, it also relieved clinical symptoms and improved quality of life. The adverse effect rate was low. However, the incidence of abscopal effects was low either. This mode was suitable for the palliative treatment and expected to improve survival for patients with metastatic tumors.

Upregulation of the Coatomer Protein Complex Subunit beta 2 (COPB2) Gene Targets microRNA-335-3p in NCI-H1975 Lung Adenocarcinoma Cells to Promote Cell Proliferation and Migration.

BACKGROUND The coatomer protein complex subunit beta 2 (COPB2) gene is upregulated and promotes cell proliferation in some cancer cells. This study aimed to investigate the role of microRNA (miRNA) targeting by COPB2 gene expression in human lung adenocarcinoma cell lines, including NCI-H1975 cells. MATERIAL AND METHODS COPB2 expression in normal human bronchial epithelial cells and lung adenocarcinoma cells was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. NCI-H1975 human lung adenocarcinoma cells were transfected with short-interfering COPB2 (siCOPB2). Cell apoptosis and cell proliferation were evaluated by flow cytometry and Cell Counting Kit-8 (CCK-8) assays, respectively. The transwell assay evaluated cell migration. Targeting of miR-335-3p by COPB2 was predicted using TargetScan 7.2 and verified using a dual-luciferase reporter assay in NCI-H1975 cells. MiR-335-3p mimics were transfected into NCI-H1975 cells. The further functional analysis included detection of protein expression for cyclin D1, tissue inhibitor matrix metalloproteinase-1 (TIMP-1), matrix metallopeptidase 9 (MMP9), Bcl-2, and Bax, to verify the role of miR-335-3p targeting by COPB2 in lung adenocarcinoma cells. RESULTS COPB2 was upregulated in lung adenocarcinoma cells and was a direct target of miR-335-3p mimics. COPB2 knockdown promoted cell apoptosis, inhibited cell migration and proliferation in NCI-H1975 cells. The effects of COPB2 knockdown on NCI-H1975 cells were increased by miR-335-3p mimics, which also further reduced the expression levels of cyclin D1, MMP9, and Bcl-2 and further increased TIMP-1 and Bax by siCOPB2. CONCLUSIONS This study showed that COPB2 was the functional target of miR-335-3p in NCI-H1975 human adenocarcinoma cells.

Silencing stomatin-like protein 2 attenuates tumor progression and inflammatory response through repressing CD14 in liver cancer.

PURPOSE: Toll-like receptor 4 (TLR4) is involved in the inflammation in liver cancer. High-expressed stomatin-like protein 2 (SLP-2) is commonly reported in many cancer types. This study aims to investigate the functions of SLP-2 in TLR4-mediated inflammatory responses and tumor progression of liver cancer. PATIENTS AND METHODS: Plasmid transfection technique was applied to silence and overexpress genes. Changes in cell viability and apoptosis were determined by performing cell counting kit-8 assay and flow cytometry. The levels of pro-inflammatory cytokines were determined by ELISA. We further measured the several types of the malignant transformation of SK-Hep1 cells to assess the effects of SLP-2 silencing on the cell migration and invasion, proliferation and angiogenesis of liver cancer in vitro. Western blot and RT-qPCR were performed for expression analysis. RESULTS: Lipopolysaccharide (LPS) promoted the cell proliferation of SK-Hep1 and production of tumor necrosis factor-α (TNF-α) and IL-6. SLP-2 silencing could inhibit the protein and mRNA levels of CD14 and Cdc42 and subsequently inhibited the levels of TNF-α and IL-6. Overexpressed CD14 not only remarkably reversed the proapoptotic ability of SLP-2 silencing and promoted the expression of Cdc42 and production of TNF-α and IL-6, but also notably reversed the inhibitory effects on the malignant abilities of SK-Hep1 cells by SLP-2 silencing. CONCLUSION: SLP-2 silencing could significantly attenuate the inflammatory responses and tumor progression of liver cancer via inhibiting LPS/TLR4 signal transduction through the repression of CD14.

Thermoresponsive Bentonite for Water-Based Drilling Fluids.

As an important industrial material, bentonite has been widely applied in water-based drilling fluids to create mud cakes to protect boreholes. However, the common mud cake is porous, and it is difficult to reduce the filtration of a drilling fluid at high temperature. Therefore, this paper endowed bentonite with a thermo response via the insertion of N-isopropylacrylamide (NIPAM) monomers. The interaction between NIPAM monomers and bentonite was investigated via Fourier infrared spectroscopy (FTIR), isothermal adsorption, and X-ray diffraction (XRD) at various temperatures. The results demonstrate that chemical adsorption is involved in the adsorption process of NIPAM monomers on bentonite, and the adsorption of NIPAM monomers accords with the D-R model. With increasing temperature, more adsorption water was squeezed out of the composite when the temperature of the composite exceeded 70 °C. Based on the composite of NIPAM and bentonite, a mud cake was prepared using low-viscosity polyanionic cellulose (Lv-PAC) and initiator potassium peroxydisulfate (KPS). The change in the plugging of the mud cake was investigated via environmental scanning electron microscopy (ESEM), contact angle testing, filtration experiments, and linear expansion of the shale at various temperatures. In the plugging of the mud cake, a self-recovery behavior was observed with increasing temperature, and resistance was observed at 110 °C. The rheology of the drilling fluid was stable in the alterative temperature zone (70-110 °C). Based on the high resistance of the basic drilling fluid, a high-density drilling fluid (ρ = 2.0 g/cm3) was prepared with weighting materials with the objective of drilling high-temperature formations. By using a high-density drilling fluid, the hydration expansion of shale was reduced by half at 110 °C in comparison with common bentonite drilling fluid. In addition, the rheology of the high-density drilling fluid tended to be stable, and a self-recovery behavior was observed.

Silence of Stomatin-Like Protein 2 Represses Migration and Invasion Ability of Human Liver Cancer Cells via Inhibiting the Nuclear Factor Kappa B (NF-κB) Pathway.

BACKGROUND Liver cancer is the third leading cause of tumor-related deaths worldwide. Stomatin-like protein 2 (STOML2) is obviously upregulated in various tumors. In this study, we explored the potential roles and mechanisms of si-STOML2 in the migration and invasion of human hepatoma LM3 cells. MATERIAL AND METHODS The expression levels of STOML2 in tissues and cells were separately analyzed with quantitative real-time PCR (qRT-PCR) and Western blotting. The viability, migration, and invasion of cells were assessed by cell counting kit-8 (CCK-8), wound healing, and transwell analysis, respectively. The mRNA and protein levels of various factors were separately measured using qRT-PCR and Western blotting. Correlation analysis between the expression of STOML2 and the clinicopathological features of liver cancer patients was evaluated using the chi-square test. RESULTS Surprisingly, our results showed that STOML2 was upregulated in liver cancer tissue and cells, and this upregulation was linked to tumor size, histologic grade, and metastasis, but was not associated with sex, age, or TNM stage. The knockdown of STOML2 significantly repressed the viability, migration, and invasion of LM3 cells. We also observed that silencing STOML2 markedly downregulated the expression levels of matrix metalloproteinase-2 (MMP-2), MMP-9, metastatic tumor antigen 1 (MTA1), and nuclear factor kappa B (NF-κB), and upregulated levels of E-cadherin, tissue inhibitor of metalloproteinases 2 (TIMP2), and the inhibitor of kappa B (IκB). CONCLUSIONS STOML2 has a vital role in the progression of liver cancer. STOML2 silencing in LM3 cells obviously repressed the abilities of migration and invasion via suppressing the NF-κB pathway.

COPB2 promotes cell proliferation and tumorigenesis through up-regulating YAP1 expression in lung adenocarcinoma cells.

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer and responsible for more than 500,000 deaths per year worldwide. In this study, we aimed to explore the effects of COPB2 in the progression of lung adenocarcinoma and its underlying mechanism. The mRNA and protein levels of COPB2 in tumor tissues and cell lines were determined by qRT-PCR and western blotting analysis. siRNAs and over-expressed vector targeting COPB2 were used to down-regulate and up-regulate COPB2 expression in lung adenocarcinoma cell lines H1975. Cell apoptosis rate, proliferation and tumorigenesis of H1975 cells were determined by flow cytometry analysis, MTT assay and in vivo xenotransplantation assay, respectively. Western blotting and immunofluorescence assays were performed to evaluate the effects of COPB on the expression and subcellular location of YAP. Results showed COPB2 was significantly up-regulated in lung adenocarcinoma tissues and cell lines, which showed a close correlation with advanced clinical symptoms, such as tumor differentiation, TNM stage and the occurrence of lymph node metastasis and distance metastasis. Besides, the overall survival time of patients with high expression of COPB2 was shorter than that of patients with low COPB2 expression. After knockdown of COPB2, cell apoptosis rate was increased, whereas cell proliferation was decreased. Compared with that in the normal lung cell line H1688 cells, YAP1 expression was obviously increased in H1975, and over-expression of COPB2 translocated YAP1 from cytoplasm to nuclear, whereas knockdown of COPB2 showed the opposite effect. Overexpression of COPB2 enhanced cell proliferation, tumorigenesis and inhibited cell apoptosis. However, these effects were abolished when down-regulated YAP1 expression on the base of COPB2 over-expression. In conclusion, the increased expression of COPB2 was significantly correlated with the progression of lung adenocarcinoma. Up-regulation of COPB2 inhibited cell apoptosis and promoted cell growth and tumorigenesis through up-regulating YAP1 expression in lung adenocarcinoma.

Synthesis and characterization of comb-shaped copolymer as a filtration reducer and comparison with counterparts.

A comb-shaped copolymer of 2-acrylamide-2-methyl propane sulfonic acid (AMPS), allyl polyoxyethylene ether (APEG), N-vinyl-2-pyrrolidone (NVP) and sodium styrene sulfonate (SSS) was synthesized by free-radical polymerization. The structure of the comb-shaped copolymer was characterized by Fourier transform infrared (FTIR) spectroscopy, and its molecular weight was determined by gel permeation chromatography (GPC). FTIR measurements and environmental scanning electron microscopy (ESEM) analysis were used to characterize the working mechanism of different filtrate loss reducers. Thermogravimetry and differential scanning calorimetry (TG-DSC) results showed that thermal degradation of the copolymer was significant only after 295.24 °C. The comb-shaped copolymer helped reduce filtration, while maintaining the rheological properties of the drilling fluid at high temperature and high salinity conditions as long PEG chains sterically stabilized colloids by protruding into the suspension. The filtration control of the comb-shaped copolymer was comparable to that of the sulfonated phenolic resin (SMP) mixture and outperformed AM/AMPS/NVP/SSS (NS-1) and polymeric product PAC in terms of high-temperature resistance and rheological advantages. The morphology of the comb-shaped copolymer was found with a compact 3-D film structure due to the intramolecular and intermolecular association by hydrogen bonding in the side chains. Small curly debris at high temperature and salinity remained capable of filtration control. The NS-1 had a lower temperature resistance, as large areas of flaky films thermally degraded into a small chain structure at 180 °C. Only separated filiform and coarse lines were found in PAC with a linear structure that makes the drilling fluid more viscous. Compact and structured films were formed with the SMP mixture at high temperature and salinity.

Single pemetrexed is noninferior to platinum-based pemetrexed doublet as first-line treatment on elderly Chinese patients with advanced nonsquamous nonsmall cell lung cancer.

BACKGROUND: To evaluate the clinical efficacy and toxicity of single pemetrexed treatment compared with platinum-based pemetrexed doublet pemetrexed-based as first-line treatment for advanced nonsquamous nonsmall cell lung cancer (NS-NSCLC) in elderly Chinese patients. METHODS: The study retrospectively reviewed 175 elderly Chinese patients with NS-NSCLC from June 2010 to September 2013: 90 patients received single pemetrexed treatment, 45 received pemetrexed plus oxaliplatin, and 40 received pemetrexed plus carboplatin. Clinical efficacy was assessed using disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: DCR, OS, and PFS did not significantly differ between single pemetrexed treatment (OS: 14.9 months; DCR: 62.2%; PFS: 3.3 months), pemetrexed plus oxaliplatin (OS: 16.5 months; DCR: 71.1%; PFS: 4.5 months), and pemetrexed plus carboplatin (OS: 15.5 months; DCR: 70.0%; PFS: 4.6 months) groups. Pemetrexed treatment caused significantly lower incidences of adverse events, such as hepatotoxicity and peripheral nerve injury. Performance status (PS), TNM stage, and Thymidylate synthase (TS) expression were predictive factors of DCR. Pemetrexed chemotherapy cycles, PS, and TNM stage were independent prognostic factors. CONCLUSIONS: Single pemetrexed was noninferior to platinum-based pemetrexed doublet for clinical efficacy and safety in elderly Chinese patients with advanced NS-NSCLC. Chemotherapy cycles, performance status, and TNM stage were independent prognostic factors.

The role of thymidylate synthase in non-small cell lung cancer treated with pemetrexed continuation maintenance therapy.

Pemetrexed continuation maintenance therapy has been proven to be beneficial for patients with advanced non-squamous non-small cell lung cancer (NSCLC). However, the eligibility criteria for maintenance treatment are too simple. This study sought to evaluate thymidylate synthase (TS) as a predicting biomarker for pemetrexed continuation maintenance treatment in NSCLC. Specimens were collected from 87 patients treated with pemetrexed continuation maintenance therapy before and after four-cycle induction chemotherapy. Real-time quantitative PCR was used to detect TS expression in tissues. The TS expression level was correlated with characteristic clinical data, radiographic response, progression-free time (PFS) and overall survival (OS). Low total TS expression (<8.47) was associated with improved PFS (median: 4.7 months vs. 3.5 months, p = 0.034) and improved OS (time from random assignment: 16.4 months vs. 11.7 months, p = 0.026; time from induction: 19.7 months vs. 14.8 months, p = 0.022). Our results indicate that in NSCLC patients treated with pemetrexed continuation maintenance therapy, low TS expression is associated with improved PFS and OS.

RASSF1A gene methylation is associated with nasopharyngeal carcinoma risk in Chinese.

In order to explore the association between RASSF1A methylation and nasopharyngeal carcinoma (NPC) risk of Chinese, we carried out a meta-analysis with searches of PubMed, Web of Science, ProQest and Medline databases. Ultimately, 14 articles were identified and analysised using R Software (R version 3.1.2) including meta packages. Overall, we found a significant relationship between RASSF1A methylation and NPC risk (OR 30.7; 95 % CI, 16.71~56.23; z=11.0591; p<0.0001) in a fixed effects model and (OR 32.1; 95% CI, 14.27~72.01; z=8.3984; p<0.0001) in a random effects model pooled. In tissue and NP brushings groups , similar results were found. Hence, our study identified a strong association between RASSF1A methylation and NPC and highlighted a promising potential for RASSF1A methylation in NPC risk prediction of Chinese.

CD137 ligand-mediated reverse signaling inhibits proliferation and induces apoptosis in non-small cell lung cancer.

CD137 ligand (CD137L), a member of the tumor necrosis factor superfamily, is expressed on antigen-presenting cells and also on various tumor cells. Crosslinking of CD137L transmits signals that evoke different cellular responses in a variety of tumor cells. This study was designed to investigate signaling pathways activated by CD137L and its physiologic role in the progression of NSCLC. We investigated the expression of CD137L in tissues from 102 cases of human non-small cell lung cancer (NSCLC) using immunohistochemistry and analyzed the correlation with clinicopathological features using Fisher's exact test and overall survival using Kaplan-Meier curves and the log-rank test. The effect of CD137L reverse signaling induced by recombinant human CD137-Fc protein on NSCLC cell lines was assessed using proliferation and apoptosis assays, flow cytometry and Western blotting. Positive CD137L expression was observed in 53/102 (52.0%) of the NSCLC samples and correlated with early TNM stage (P = 0.046), well-differentiated tumors (P = 0.009) and better overall survival (P = 0.004). Moreover, induction of CD137L reverse signaling using CD137-Fc inhibited proliferation and induced apoptosis and cell cycle arrest in H1650 cells, which express high levels of CD137L; CD137L reverse signaling had no significant effects in PC9 cells, which express low levels of CD137L. In addition, CD137L reverse signaling-induced apoptosis occurred via activation of the intrinsic pathway and depended on phosphorylation of JNK. This study demonstrates a hitherto unrecognized role for CD137L reverse signaling in the development of NSCLC and indicates that CD137L has potential as a novel therapeutic target in NSCLC.

High SHIP2 expression indicates poor survival in colorectal cancer.

SH2-containing inositol 5'-phosphatase 2 (SHIP2), which generally regulates insulin signaling, cytoskeleton remodeling, and receptor endocytosis, has been suggested to play a significant role in tumor development and progression. However, the associations between SHIP2 expression and the clinical features to evaluate its clinicopathologic significance in colorectal cancer (CRC) have not been determined yet. In the present study, one-step quantitative real-time polymerase chain reaction (qPCR) test and immunohistochemistry (IHC) analysis with CRC tissue microarrays (TMA) were employed to evaluate the mRNA and protein expression of SHIP2 in CRC. The results showed that SHIP2 expression in the mRNA and protein levels was significantly higher in CRC tissues than that in corresponding noncancerous tissues (both P < 0.05). The expression of SHIP2 protein in CRC was related to lymph node metastasis (P = 0.036), distant metastasis (P = 0.001), and overall survival (P = 0.009). Kaplan-Meier method and Cox multifactor analysis suggested that high SHIP2 protein level (P = 0.040) and positive distant metastasis (P = 0.048) were critically associated with the unfavorable survival of CRC patients. The findings suggested that SHIP2 may be identified as a useful prognostic marker in CRC and targeting CRC may provide novel strategy for CRC treatment.

Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma.

The tissue inhibitor of metalloproteinase-1 (TIMP-1) is an endogenous inhibitor of matrix metalloproteinases and potential biomarker of various types of human cancers. However, the association between TIMP-1 expression and the clinical features of laryngeal squamous cell carcinoma (LSCC) is barely investigated. In this study, one-step quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining with tissue microarrays were employed to evaluate the relationship between TIMP-1 expression and the clinicopathological characteristics of LSCC. Results showed that the TIMP-1 mRNA and protein expression levels were significantly higher in LSCC than in the corresponding non-cancerous tissues (p<0.05). TIMP-1 protein expression in LSCC was associated with tumor differentiation (p=0.012) and overall survival (p=0.043). Kaplan-Meier method and Cox multi-factor analysis suggested that high TIMP-1 expression (p=0.008) and positive lymph node metastasis (p=0.029) were significantly associated with the poor survival of patients with LSCC. These data indicated that TIMP-1 may be identified as a prognostic marker of LSCC.

Significance of thymidylate synthase expression for resistance to pemetrexed in pulmonary adenocarcinoma.

Pemetrexed (PEM), a multi-targeted antifolate, has promising clinical activity in non-squamous non-small cell lung cancer. However, the majority of patients eventually acquire resistance to PEM. To evaluate the resistant mechanisms, the A549 lung adenocarcinoma cell line was exposed to stepwise increasing PEM concentrations of 1.6, 6.4 and 16 µM to establish three PEM-resistant lung cancer cell lines, A549/PEM-1.6, -6.4 and -16. Growth inhibition was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), reduced folate carrier (RFC) and folypoly-γ-glutamate synthetase (FPGS) were analyzed by quantitative real-time reverse transcription polymerase chain reaction. The three A549 cell lines showed more resistance to PEM (3.7-, 17.3- and 38.0-fold, respectively) compared with that of the parental cell line, which also showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine and 5-Fluorouracil (5-FU). TS gene expression was significantly increased in three PEM-resistant cells, relative to that of the parental cells, in a PEM dose-dependent manner. Knockdown of TS expression with siRNA enhanced the cytotoxicity of PEM in A549/PEM-16 cells. By contrast, the levels of RFC and FPGS gene expression in A549/PEM-1.6 and -6.4 cells were significantly decreased, whereas the levels of the two genes were restored in A549/PEM-16 cells. In summary, PEM-resistant A549 cells remained sensitive to docetaxel, vinorelbine and 5-FU. TS expression appeared to be associated with resistance to PEM, which may be a predictive marker for PEM sensitivity in lung adenocarcinoma.

Elevated expression of SHIP2 correlates with poor prognosis in non-small cell lung cancer.

SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a vital regulator of phosphoinositide pools in metabolic pathways and is considered to downregulate phosphatidylinositol 3'-kinase signaling, which underlies the development of several kinds of human cancers. However, SHIP2 expression in non-small cell lung cancer (NSCLC) and its relationship with the clinical characteristics of NSCLC remain poorly understood. In this study, one-step quantitative reverse transcription-polymerase chain reaction and immunohistochemistry analysis with tissue microarray was used to evaluate SHIP2 expression in NSCLC and to investigate the relationship of this expression to NSCLC prognosis. Results showed that the expression of SHIP2 messenger RNA and protein was significantly higher in NSCLC than in corresponding non-cancerous tissues (both p < 0.05). SHIP2 protein expression in NSCLC was related to lymph node metastasis (p = 0.042), TNM stage (p = 0.036), and 5-year survival rate (p = 0.046). The Kaplan-Meier method and log-rank test suggested that high SHIP2 expression, tobacco consumption, and advanced tumor stage were significantly associated with low survival of NSCLC patients. The results of this research suggested that SHIP2 expression was correlated with malignant phenotypes of NSCLC and may thus serve as a poor prognostic factor and valuable oncogene for NSCLC.

Evaluation of oral chemotherapy with capecitabine and cyclophosphamide plus thalidomide and prednisone in prostate cancer patients.

PURPOSE: The aim of this study was to evaluate clinical outcomes of second-line chemotherapy with capecitabine and cyclophosphamide (CTX) plus thalidomide and prednisone in refractory advanced castrate-resistant prostate cancer (CRPC) patients. METHODS: We retrospectively reviewed patients with advanced CRPC who had previously progressed to first-line docetaxel-based chemotherapy. Patients were given second-line chemotherapy with capecitabine and CTX plus thalidomide and prednisone throughout the course. Patients were evaluated for response and toxicity, and treatment was continued until the disease progression or excessive toxicity was noted. RESULTS: From April 2007 to February 2010, a total of 28 patients (median age, 72.8 ± 2.9 years) received second-line chemotherapy. The median cycle and duration of metronomic chemotherapy were six (range: 1-12) cycles and 6.3 (range 1.5-20.5) months, respectively. Prostatic-specific antigen was decreased by more than 50% in 10 (35.7%) of the 28 patients. All patients had bone metastases, and 8 patients (28.6%) had measurable soft tissue lesions. Among the 8 patients, 1 patient achieved partial response, and 3 patients had stabilized disease. With a median follow-up time of 29.5 (95% CI, 26.4-33.4) months, median composite progression-free survival and overall survival were 4.7 (95% CI, 3.4-5.7) months and 19.5 (95% CI, 18.9-25.5) months, respectively. No grade 3-4 toxicity was observed, and none of the patients experienced grade 3-4 hematological and nonhematological toxicities. CONCLUSIONS: These data suggested that oral combination second-line chemotherapy with capecitabine and CTX plus thalidomide and prednisone offers promising activity with an excellent safety profile for patients with advanced CRPC.

[Risk factors and prognosis of lung cancer combined with pulmonary embolism].

BACKGROUND AND OBJECTIVE: Malignant tumors often combined with venous thrombosis and pulmonary embolism, especially in lung cancer. It has been proven that, the mechanisms and risk factors for lung cancer patients contracting pulmonary embolism are unclear. The aim of this study is to summarize the clinical data on 54 patients with lung cancer and concomitant pulmonary embolism, and to analyze the risk factors and prognosis of lung cancer with pulmonary thromboembolism (PTE). METHODS: From April 1999 to January 2010, the clinical presentation of lung cancer patients with PTE from the Jiangsu Cancer Hospital and the Jiangsu Gerontic Institute were evaluated in the present retrospective study. Univariate analysis was conducted to determine the possible associated variables. Conditional logistic regression analysis was applied to explore risk factors of pulmonary embolism. Patient survival was also compared with matched controls via a Log-rank test. RESULTS: A total of 54 lung cancer patients with PTE, matched with 162 lung cancer patients as controls, were included. In the univariate analysis, a P<0.20 was considered as possible risk factor, which was included into the logistic regression model. The logistic regression model showed that the OR combined with pulmonary embolism was 2.64 in patients receiving chemotherapy, 2.25 in patients with stage III-IV disease, 2.39 in patients combined with chronic obstructive pulmonary disease (COPD), 2.12 in patients with adenocarcinoma, 2.10 in patients with serum hemoglobin>140 g/L, and 1.76 in patients with central venous catheters. A significant difference was observed among the groups that received chemotherapy, adenocarcinoma, stage III-IV disease and high henoglobin (P<0.05). The survival time in patients with pulmonary embolism was remarkably lower than that in patients without pulmonary embolism (P=0.02). CONCLUSIONS: Chemotherapy, late stage disease and high serum hemoglobin are important risk factors for lung cancer patients with concomitant pulmonary embolism. The survival time of these patients is significantly lower than that in patients without pulmonary embolism.