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The FOXO signaling pathway has been reported to have an important role in human cancer. Expression of miR-629 was markedly upregulated in pancreatic cancer and negatively correlated with FOXO3. Therefore, exploring the regulatory mechanism of miR-629 and FOXO3 signaling may provide valuable clinical targets for pancreatic cancer therapy. In the current study, we found that overexpressing and inhibiting miR-629, respectively, enhanced and reduced the cell proliferation and metastasis of pancreatic cancer cells in vitro and in vivo compared with parental cells or cells transfected with a control vector. Furthermore, we found that miR-629 negatively regulated FOXO3 protein expression and decreased the activity of a luciferase reporter construct containing the FOXO3 3'-untranslated region. These results show that miR-629 regulates FOXO3 at the posttranscriptional level, resulting in enhanced cell proliferation and invasion of pancreatic carcinoma. Furthermore, we found that overexpressing miR-629 enhanced, while inhibiting miR-629 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. A functional polymorphism at miR-629-binding site in the 3'-UTR of FOXO3 gene confers a decreased risk of progression in pancreatic carcinoma. Furthermore, these findings suggest that miR-629 has a vital role in promoting the development of pancreatic cancer and may represent a novel prognostic biomarker and therapeutic target.

The aim of the study was to investigate IL-33 expression in gastric cancer (GC) and its association with the clinical characteristics and the prognosis. IL-33 protein in tumor and corresponding adjacent tissues were detected by immunohistochemistry in 179 GC patients and clinical features plus prognostic value were analyzed via Pearson's chi-square test and Kaplan-Meier test in Cox proportional hazards model, respectively. IL-33 protein levels were significantly lower in tumor tissues than adjacent tissues (29.05% vs. 78.77%, χ 2  = 89.05, P < 0.001). The positive rate of IL-33 in the ulcerative type group was the lowest among all groups (P < 0.05). IL-33 levels were correlated with age (P = 0.025) and invasion depth (P = 0.030) while not significantly associated with the overall survival of GC patients. IL-33 expression is associated with age and invasive depth of GC patients but not an independent risk factor of prognosis.

Aims and Background: This study was designed to compare the efficacy and safety of paclitaxel/oxaliplatin/fluorouracil (TOF) regimen and S-1/oxaliplatin (SOX) regimen for metastatic gastric cancer (GC) patients., Methods: Sixty patients were divided into TOF group and SOX groups randomly. Patients in the TOF group received paclitaxel (135 mg/m2 iv) on day 1, oxaliplatin (100 mg/m2 iv) on day 1, fluorouracil (500 mg/m2 continuous iv) on day 1-5. The patients in the SOX group received oxaliplatin (130 mg/m2 iv) on day 1 and S-1 (40 mg~60mg orally twice/day based on body surface area) on days 1-14. All the treatments were repeated every 21d for 4-6 cycles., Results: The ORR and DCR of TOF group was 43.3% and 60.0%, respectively while that of SOX group was 36.7% and 56.7%. There were no statistical differences between the ORRs (χ2 = 0.278) and the DCRs (χ2 = 0.069) of the 2 groups. The majority of adverse events of two groups were hematological and digestive ones. Most of them were grade I and II. The adverse event rate of TOF group was higher than SOX group. The PFS times of TOF and SOX groups were 6.5 and 5.8 months, respectively. There was no statistical difference between the PFSs of the 2 groups (P = 0.451)., Conclusions: The efficacies of TOF and SOX regimens are similar but the safety of SOX regimen better than TOF regimen.

The aim of this study was to evaluate the correlations between p53, COX2, EGFR, nm23 expression and the progression free survival (PFS) of post-operative patients with colorectal carcinoma. Immunohistochemistry was used to detect the expression of p53, COX2, EGFR and nm23 in 459 specimens from colorectal carcinoma patients. Kaplan-Meier estimates, Cox proportional hazard regression analyses and hierarchical analyses were performed on the collected data. Kaplan-Meier estimates analysis suggested that EGFR expression was as a negative predictor, the median PFS of patients with EGFR high expression was 21.73 months, and the median PFS of patients with low EGFR expression was 57.83 months (χ2=20.880, P<0.001); nm23 expression was positive predictive factor for the prognosis of patients with colorectal carcinoma, the median PFS of patients with high nm23 expression was 37.77 months, and the median PFS was 21.47 months in the patients with low nm23 expression (χ2=7.364, P=0.007). Cox regression analysis revealed that comparing with the patients with low expression of EGFR, the patients with high EGFR expression were at higher risk of tumor progression (HR=1.667, P=0.004); Comparing with the patients with high nm23 expression, the patients with nm23 low expression had a higher risk of tumor progression (HR=0.412, P<0.001); and the risk of tumor progression was higher in the patients with high EGFR expression and low nm23 expression (HR=0.245, P<0.001). Hierarchical analysis showed that EGFR expression mainly correlates with the PFS of TNM stage I-II colorectal cancer patients, the median PFS was 33.53 months in the TNM stage I-II colorectal cancer patients with high EGFR expression patients; The median PFS of the TNM stage I-II colorectal cancer patients with low EGFR expression was 70.43 months (χ2=9.530, P=0.002); The median PFS was 19.2 months in the TNM stage III-IV colorectal cancer patients with high expression EGFR, the PFS of the TNM stage III-IV colorectal cancer patients with low EGFR expression was 37.87 months (χ2=7.97, P=0.005). nm23 expression mainly correlates with the PFS of TNM stage III-IV colorecatal cancer patients. The median PFS was 47.27 months in TNM stage I-II colorectal cancer patients with nm23 high expression, the median PFS was 48.85 months in TNM stage I-II colorectal cancer patients with low nm23 expression (χ2=0.101, P=0.750); The median PFS was 28.8 months in TNM stage III-IV colorectal cancer patients with nm23 high expression, the median PFS was 14.7 months in TNM stage III-IV colorectal cancer patients with low nm23 expression (χ2=13.213, P<0.001). EGFR is mainly a predictive factor for the prognosis of post-operative patients with TNM stage I-II colorectal cancer, and nm23 is important for predicting the prognosis of patients with stage III-IV, and EGFR and nm23 could be as predictor of combination.

HES5 is a transcription factor activated downstream of the Notch pathway and regulates cell differentiation in multiple tissues. Disruption of its normal expression has been associated with developmental diseases and cancer. But its role in non-small cell lung cancer (NSCLC) remains elusive. Western blot analysis and immunohistochemistry assays demonstrated that HES5 expression was frequently increased in NSCLC tumor tissues and cell lines. Moreover, immunohistochemistry analysis revealed that upregulation of HES5 expression was positively correlated with a more invasive tumor phenotype and poor prognosis. Immunoprecipitation assay indicated that HES5 directly interacted with STAT3. In addition, depletion of HES5 resulted in inhibited phosphorylation of STAT3 and decreased expression of the downstream genes. In vitro studies, using serum starvation-refeeding experiment and HES5-siRNA transfection assay demonstrated that HES5 expression promoted proliferation of NSCLC cells, while HES5 knockdown caused growth arrest of cell cycle at G0/G1 phase, decreased rate of colony formation and alleviated cellular apoptosis. Taken together, out data have delineated that HES5 might contribute to the proliferation of NSCLC by STAT3 signaling.

Background: Mecapegfilgrastim (code name HHPG-19K) is a biosimilar to pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF). The efficacy and safety of mecapegfilgrastim, using a regimen of once-per-cycle injection of 100-μg/kg or a fixed 6-mg dose, were evaluated for the prophylactic therapy for neutropenia in patients with advanced non-small-cell lung cancer (NSCLC) who were treated with myelosuppressive chemotherapy., Materials and Methods: Patients were randomized (1:1:1) blindly to 3 treatment arms to receive a single injection of mecapegfilgrastim 100 μg/kg, a 6-mg fixed dose of mecapegfilgrastim, or saline (control) in cycle 1. In cycles 2 to 4 following unblinding at the end of cycle 1, patients in the control arm received daily injections of short-acting rhG-CSF at a dose of 5 μg/kg, whereas patients in the 2 mecapegfilgrastim arms continued the same treatment as in cycle 1. All patients received 4 chemotherapy cycles of docetaxel combined with cisplatin or carboplatin every 21 days. The primary endpoint was the incidence of grade ≥ 3 neutropenia in cycle 1., Results: A single dose of 100 μg/kg or a fixed 6-mg dose of mecapegfilgrastim per cycle effectively reduced chemotherapy-induced neutropenia and was comparable to daily rhG-CSF with regard to all efficacy endpoints, including incidence of grade ≥ 3 neutropenia, incidence of febrile neutropenia, duration of grade ≥ 3 neutropenia, and time to neutrophil recovery. No difference in efficacy parameters was observed between the 2-dose regimens of mecapegfilgrastim across all cycles. Mecapegfilgrastim was well-tolerated and was as safe as daily rhG-CSF., Conclusion: Once-per-cycle injection of mecapegfilgrastim is as effective and safe as daily rhG-CSF for prophylaxis of chemotherapy-induced neutropenia in patients with NSCLC. Mecapegfilgrastim (fixed 6-mg dose) is recommended in clinical practice for its convenient dose management., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Androgen deprivation therapy is the mainstay of treatment of advanced prostate cancer (PCa). However, a significant portion of patients experience disease relapse and tumors ultimately evolve into castration resistant prostate cancer (CRPC), for which there is no cure in the clinic. The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in CRPC. It is unclear whether EZH2 can be a therapeutic target in CRPC. Here, we demonstrated that chemo- and radiotherapy agents such as camptothecin (CPT) and γ irradiation decrease EZH2 expression in various PCa cell lines. We provided evidence that functional p53 and RB proteins are required for CPT- and irradiation-induced downregulation of EZH2 in CRPC cells. We demonstrated that EZH2-specific small molecule inhibitors mitigate CRPC cell growth. We further showed that the EZH2 inhibitor GSK126 inhibits both Polycomb-dependent and -independent functions of EZH2 in PCa cells. Importantly, we found that inhibition of EZH2 by genetic and pharmacological means sensitizes CRPC cells to CPT-induced apoptotic death and growth inhibition in culture and in mice. Our data suggest that concomitant administration of small molecule inhibitors of EZH2 may significantly increase the anti-tumor efficacy of conventional chemo- and radiotherapies in CRPC.

B7-H3, a member from B7-family co-stimulatory ligands, plays an important role in adaptive immune responses. In addition, recent studies also demonstrated that B7-H3 could be highly expressed in various types of human cancers, and its expression level was significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. As of now, the exact role of B7-H3 expression in human esophageal cancer still remains elusive. In the present study, we characterized the B7-H3 expression in the human esophageal cancer cell line Eca-109 and TE-1, and in 174 cases of human esophageal cancer tissues, and to analyze its clinical implications and its correlation to T cell infiltration. By using the RNA interference method to down-regulate the B7-H3 expression in human esophageal cancer cell line Eca-109, we further studied the contribution of high B7-H3 expression to the biological features of this malignancy. Our results showed that B7-H3 was highly expressed in the cell line Eca-109 and TE-1, the high expression level of B7-H3 in esophageal cancer tissues was significantly associated with tumor invasion and patient's poor survival. Moreover, the higher B7-H3 expression was significantly and inversely correlated to the CD3(+)T cells infiltration in tumor nest of esophageal cancer tissues. We successfully constructed the recombinant lentivirus of siRNA targeting B7-H3, and the cellular studies showed that the down regulation of B7-H3 expression could suppress the proliferation, colony formation, migration and invasion in Eca-109 cells, which was consistent with the finding from the clinical sample cohort study. Collectively, the high B7-H3 expression was involved in the cancer progression of human esophageal cancer, and might contributed to the negative regulation of T-cell mediated antitumor response in tumor microenvironment, and the proliferation and mobility of esophageal cancer cells. The detailed mechanism and the potential value of clinical use targeting B7-H3 against human esophageal cancer merit further investigation.

As a negative regulatory molecule, T-cell immunoglobulin-and mucin domain-3 (Tim-3) plays a crucial role in the tumor immunological tolerance. In the present study, we aimed to determine the Tim-3 expression in gastric cancer tissue and its relationship with clinicopathological parameters and prognosis. The Tim-3 expression was assessed in 52 gastric cancer specimens and 15 gastritis tissues by flow cytometry, and gastritis tissues served as the control. As a result, we found that the Tim-3 expressions on CD4(+)T cells and CD8(+)T cells in gastric cancer tissue was significantly higher than those in gastritis tissue (P=0.022, P=0.047, respectively). The median expression level of Tim-3 on CD4(+)T cells were significantly correlated with clinicopathological parameters, such as tumor size, lymph node metastasis, the depth of tumor invasion and TNM staging (P=0.042, P=0.026, P=0.001, P=0.003, respectively), while it was not correlated with sex, age and histological subtype (all P>0.05). In CD8(+)T cells, the Tim-3 expression was relevant to tumor invasion and TNM staging (P=0.035, P=0.017, respectively), while it was irrelevant to other clinicopathological parameters (all P>0.05). Additionally, Kaplan-Meier survival curves showed that the median overall survival time of patients with lower Tim-3 expression was greater than that of patients with higher Tim-3 expression in CD4(+)T cells and CD8(+)T cells (χ(2)=18.036, P<0.001 and χ(2)=18.036, P<0.001, respectively). Moreover, the multivariate analysis revealed that the Tim-3 expression and TNM stage were independent prognostic factors for gastric cancer patients (P=0.029, P=0.043 and P=0.003, respectively). These results suggest that Tim-3 played an important role in the development and progression of gastric cancer, and it could be used as an independent prognostic factor for gastric cancer patients.

B7-H6, a newly identified B7 family member molecule, binds to its receptor on NK cells, NKp30, and then triggers the anti-tumor NK cell cytotoxicity and leads to the cytokine secretion. As of now, numerous studies have demonstrated that the higher B7-H6 expression could be found in certain human cancers and have important clinical significance. In our present study, we carried out the tissue microarray and the immunohistochemistry assay to investigate the clinical significance of B7-H6 expression in human ovarian cancer. Our results showed that the positive B7-H6 staining was predominantly observed on the membrane and in the cytoplasm of the ovarian cancer cells. In order to further investigate the correlation between clinical parameters and the B7-H6 protein levels in the ovarian tissues, we categorized all the 110 patients into two major subgroups according to the intensity of B7-H6 immunohistochemical staining, i.e., the lower B7-H6 expression group, 34 cases (0 ≤ H-score < 100), and the higher B7-H6 expression group, 76 cases (H-score ≥ 100), and we found that B7-H6 expression in the ovarian cancer tissues is significantly correlated with distant metastasis status (P = 0.028) and FIGO stage (P = 0.031), whereas it is not correlated with patient's age, tumor size, tumor location, pathological stage or nodal metastasis. The survival analysis demonstrated that the overall survival rate of the subgroup with lower B7-H6 expression is significantly better than that of the subgroup with higher B7-H6 expression (P = 0.0456, Hazard Ratio: 1.707, 95% CI, 1.010-2.885). Thus, our present data revealed that higher B7-H6 expression in ovarian cancer tissues was positively correlated with tumor metastasis and cancer progression, and supports the notion that B7-H6 expression is involved in the progression of human ovarian cancer, the detailed mechanism merits further investigation.

Lenalidomide has been shown to produce durable responses in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). In order to gain better understanding of the efficacy of lenalidomide and compared the difference in clinical outcome between two subtypes of DLBCL. Seven eligible trials involving 375 adult patients were included in this meta-analysis. The patients in non-germinal center B-cell (non-GCB) subtype had higher overall response (OR) rate compared with GCB patients (P=0.21). In subgroup analysis, as first-line and second-line treatment for DLBCL patient, GCB DLBCL did not show significantly better outcome compared with non-GCB subtype patients (P=0.96; P=0.27). More importantly, after lenalidomide treatment, the patients with non-GCB DLBCL did not show significantly worse progression-free survival (PFS) and overall survival (OS) compared with GCB subtype. Lenalidomide as treatments for DLBCL patients, non-GCB DLBCL patients did not show significantly worse prognosis compared with GCB DLBCL.

Hydrogen sulfide (H2S) has been reported to be interwined in multiple systems, specifically in the cardiovascular system. However, the mechanisms underlying remain controversial. In the present study, we assessed the cardio-protective effects of H2S in the rat hemorrhagic shock model. Hemorrhagic shock was induced in adult male Sprague-Dawley rats by drawing blood from the femoral artery to maintain the mean arterial pressure at 35-40 mmHg for 1.5 h. The rats were assigned to four groups and the H2S donor, NaHS (28 μmol/kg, i.p.), was injected before the resuscitation in certain groups. After resuscitation the animals were observed and then killed to harvest the hearts. The morphological investigation and ultrastructural analyses were done and apoptotic cells were detected. The levels of relevant proteins were examined using Western blotting and immunohistochemical analyses. Resuscitated hemorrhagic shock induced heart injury and significantly increased the levels of serum myocardial enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Furthermore, it caused marked increase of apoptotic cells in heart tissue. Moreover, the expression of death receptor Fas and Fas-ligand, as well as the expression of apoptosis-relevant proteins active-caspase 3 and active-caspase 8 were markedly increased. Administration of NaHS significantly ameliorated hemorrhagic shock caused hemodynamic deterioration, decreased myocardial enzymes elevation, protected myocardial ultrastructure, and inhibited the expression of apoptosis-relevant proteins. It suggested that H2S might exert its cardio-protective roles via both the extrinsic Fas/FasL/caspase-8/caspase-3 pathway and the intrinsic mitochondria-involved pathways.

Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in western countries, however, infrequent in Eastern countries. We report on a rare case of synchronous breast carcinoma and chronic lymphocytic leukemia in a Chinese female patient. A 47-year-old female patient who presented with right breast lump for three month was admitted to our hospital. An ultrasound scan showed two mass in right breast and axillary swollen lymph node. Then, this patient was given right mastectomy and axillary lymph node dissection. Histology report showed invasive ductal carcinoma of the breast (grade I) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Bone marrow was infiltrated by CLL cell. To the best of our knowledge, this is the first report of a Chinese patient suffering from breast carcinoma and chronic lymphocytic leukemia.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that contribute to tumorigenesis and metastasis due to their ability to degrade the extracellular matrix (ECM) and basement membrane. In despite of many reports in other solid tumors, the role of membrane type-2 MMP (MT2-MMP) in gastric cancer (GC) remains to be elucidated. The aim of this study was to investigate MT2-MMP expression in human GC tissue microarray (TMA) samples using immunohistochemistry (IHC). We found that MT2-MMP expression in tumor tissues was significantly higher compared to peritumoral tissues (P < 0.01). However, there were no statistically significant differences between MT2-MMP expression and clinicopathological parameters. In addition, univariate and multivariate Cox regression analysis showed GC patients with high MT2-MMP expression have poor overall survival (OS) compared to patients with low MT2-MMP expression (P = 0.013, P = 0.040, respectively). In conclusion, MT2-MMP is involved in GC invasion and metastasis and may serve as an independent prognostic factor for GC patients.

In recent years, the number of patients exhibiting multiple primary malignant neoplasms has been increasing. The current study reports the rare case of a 61-year-old Chinese female with eight histopathologically confirmed primary malignant neoplasms; to the best of our knowledge, such a high number of malignant neoplasms in one patient has not previously been described in the English literature. The tumors originated from the colon (five separate tumors over 32 years), the endometrium, the breast and the small intestine. It is important to diagnose multiple primary malignant neoplasms as such patients generally exhibit a more favorable prognosis compared with metastatic carcinoma patients. In addition, prolonged follow-up after surgery should be considered.

Purpose: Hepatic arterial infusion (HAI) has been proved to be an effective strategy to increase the chances of resection for colorectal cancer patients with liver metastasis (CRCLM). Herein, we aimed to evaluate the benefits and risks of initial treatment with HAI floxuridine (FUDR) and systemic XELOX in un-resectable synchronous CRCLM., Materials and Methods: HAI catheter systems were implanted radiologically in 54 patients with un-resectable synchronous CRCLM. Upfront HAI FUDR and systemic XELOX were delivered without primary cancer resection. Patients underwent deferred surgery when the metastatic diseases were converted to resectability, or any serious colorectal cancer-related complications occurred., Results: Thirty-eight patients (70.4%) were converted to resectability and underwent staged or synchronous resection of the primary tumor and metastatic disease, with an estimated 3-year survival rate of 76% compared with 15% in un-resected patients. Uni-variate analysis showed that hepatic involvement, number of lesion, and the location of primary cancer did not affect resectability rate. Only 3 patients (5.6%) required palliative surgery to treat complications related to primary cancer., Conclusions: Initial HAI FUDR and systemic XELOX are effective to help patients with CRCLM to obtain a high resection rate for asymptomatic colorectal cancer and un-resectable liver metastases, and associated with a low rate of complications related to the intact primary cancer.

Lysine specific demethylase 1 (LSD1), the first characterized histone demethylase, roles importantly in epigenetic regulation of carcinogenesis and cancer progression. In the present study, we examined LSD1 expression in 103 cases of esophageal cancer tissues, and further investigated its relationship to patient's clinical parameters and post-operative prognosis. We found that the positive LSD1 immunochemical staining was predominantly observed on the nuclei and cytoplasm of esophageal cancer cells, while negative or very weak in adjacent normal tissues. The intensity of LSD1 immunostaining was significantly correlated to the tumor size (P = 0.013), nodal metastasis (P = 0.002), distant metastasis (P = 0.025), and TNM stage (P = 0.010), whereas it was not correlated to patient's gender, age and tumor invasion depth. The overall survival rate of patients with low LSD1 expression was better than those with high LSD1 expression (P = 0.014). We also showed that the tumor size (P = 0.003) as well as the TNM stage (P = 0.007) was a useful prognostic predictor for esophageal cancer. However, when the gender, age, tumor size, TNM stage and LSD1 expression level were involved in the multivariate proportional hazards regression analysis in a Cox's model, we showed that the tumor size (P = 0.013) and the TNM stage (P = 0.032) could be used as independent risk factors to predict patient's postoperative prognosis, but LSD1 expression level as well as other factors could not independently predict patient's outcome. Thus, our results indicated that LSD1 was involved in cancer progression and metastasis in human esophageal cancer, and could be a potential prognostic predictor for this malignancy.

Unlabelled: Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P=0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%)., Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS., (© 2014 by the American Association for the Study of Liver Diseases.)

The epithelial-mesenchymal transition (EMT) is an essential step in invasion and metastasis of human cancers. Identification of EMT status would help us to properly understand the mechanism of cancer metastasis and progression. In the present study, tissue microarray and immunohistochemical staining of two important markers, E-cadherin and Vimentin, were used to characterize the EMT status in human esophageal cancer. We selected the appropriate cut-off values of expression levels of E-cadherin and Vimentin, and found 63 out of 105 cases of esophageal cancers underwent EMT. And we also found that in the subgroup with (T₃ + T₄), the ratio of patients undergoing EMT was significantly higher than that in the subgroup with (T₁ + T₂) (P = 0.0097), and in the subgroup with metastasis, the ratio of patients undergoing EMT was significantly higher than that in the subgroup with no metastasis (P = 0.0253). The log-rank survival analysis showed that the overall survival rate of the patients undergoing EMT was significantly poorer than that of the patients with wide type status (P = 0.0278, HR = 2.470, 95% CI: 1.971~2.970). In the COX model analysis, we also found that the EMT status of the esophageal cancer patients could be used as an independent risk factor for the prediction of prognosis of this malignancy (P = 0.026, HR = 2.306, 95% CI: 1.103~4.824). Thus, our present study successfully established a method by using tissue microarray and the markers, E-cadherin and Vimentin, to conveniently and properly identify the EMT status in human esophageal cancer, and revealed that the EMT status significantly associated with invasion, metastasis and prognosis in this malignancy.

B7-H1, an important member of the B7-CD28 super family, has been reported to play an important role in regulation of T-cell mediated anti-tumor response, and also has effect in the biological characteristics of the tumor cells themselves. The bulk of data indicate that cancer immunotherapy targeting the molecule B7-H1 recently has sparked growing interest. We have previously reported that higher expression of B7-H1 in human gastric cancer significantly associated with tumor size, invasion, nodal metastasis, survival and the density of infiltrating Foxp3(+) Tregs. In the present study, we used tissue microarray to further study B7-H1 expression in human esophageal cancer tissues and its clinical significance. We found that positive membranous B7-H1 expression could be found in some human esophageal cancer cell lines, and both membranous/cytoplasm and nuclear staining of B7-H1 could be found in esophageal cancer tissues. We demonstrated that the membranous/cytoplasm B7-H1 expression in human esophageal cancer tissues was significantly correlated with tumor invasion depth (P = 0.0261), whereas it was not correlated with patient's gender, age, tumor size, nodal metastasis, distant metastasis and TNM stage. The survival analysis showed that the overall survival of the patients with positive B7-H1 membrane/cytoplasm expression was significantly poorer than that of the patients with negative B7-H1 membrane/cytoplasm expression (Hazard ratio = 2.157, 95% CI: 1.017-4.577, P = 0.0452). Moreover, we also found that the nuclear B7-H1 expression in human esophageal cancer tissues was significantly correlated with tumor invasion depth (P = 0.0331), whereas it was not correlated with other parameters. The log-rank survival analysis showed that there was no statistically significant difference in prognosis between the patients with positive nuclear B7-H1 staining and the patients with negative nuclear B7-H1 staining (P = 0.6755). Thus, our data showed that B7-H1 can serve as a prognostic predictor for human esophageal cancer, and also could be an important therapeutic target for the immune therapy against this malignancy.

Matrix metalloproteinases (MMPs) are a family of important proteolytic enzymes that play an important role in the remodeling of the tumor microenvironment and associate with tumorigenesis and metastasis. We previously reported that membrane type-2 MMP (MT2-MMP) is highly expressed in human esophageal cancer tissues, and its expression level is positively correlated to tumor size and intratumoral angiogenesis. In order to reveal whether MT2-MMP expression is operative in human lung cancer and its underlying physio-pathological role, in the present study, we examined both mRNA and protein expression levels of MT2-MMP in non-small cell lung caner (NSCLC) tissues and in adjacent normal tissues by using real-time RT-PCR and immunohistochemistry respectively, which showed that both MT2-MMP mRNA (P=0.0359) and protein (P<0.0001) expression levels were significantly increased in cancer tissues in contrast to adjacent normal tissues. Moreover, we also found that the MT2-MMP protein level in cancer tissues positively correlated to lymph node metastasis (P=0.0483), tumor stage (P=0.0483), intra-tumoral microvessel density (MVD) (P=0.0445). We have not found statistically significant correlation between MT2-MMP expression and patients' prognoses, but we found that the patients with both higher MT2-MMP protein expression and higher intra-tumoral microvessel density showed better prognoses than that of the patients with either higher MT2-MMP protein expression or higher intra-tumoral microvessel density (P=0.0311). Thus, our data suggest that MT2-MMP expression positively involves in NSCLC, and might play an important role in promoting the tumor progression and intra-tumoral angiogenesis in NSCLC.

Lack of effective biomarkers is one of the challenges in current chemotherapy to predict drug response and sensitivity. This study was carried out to investigate the relationships between the expressions of class III β-tubulin, microtubule-associated protein tau (MAPT), survivin, and the sensitivity of primary gastric cancer (GC) to paclitaxel treatment. Reverse transcription PCR and Western blot were used to evaluate the mRNA and protein expressions of class III β-tubulin, MAPT, and survivin in fifty-four GC tissues. Viable tumor cells from gastric carcinomas were tested for their sensitivity to paclitaxel using adenosine triphosphate-based tumor chemosensitivity assay in vitro. Out of 54 samples, 30 samples were sensitive to paclitaxel, while the other 24 samples were resistant. The overall efficacy of paclitaxel was 55.56% (30/54). The mRNA expressions of class III β-tubulin and survivin were significantly correlated with the histological grade (P = 0.029, 0.009, respectively). The sensitivity of GC patients to paclitaxel treatment was inversely correlated with the mRNA and protein expressions of class III β-tubulin (P < 0.01), MAPT (P < 0.05), and survivin (P < 0.05). A significant positive correlation was found between class III β-tubulin and MAPT expression at mRNA and protein levels (mRNA: P = 0.037; protein: P = 0.001). Our results indicate that the expression levels of class III β-tubulin, MAPT, and survivin are good biomarkers for predicting the sensitivity of GC to paclitaxel treatment.

Objective: A prospective, multicenter and non-interventional prospective study was conducted to evaluate the clinical features of rituximab combined with chemotherapy (R-Chemo) as first-line treatment on newly diagnosed Chinese patients with diffuse large B-cell lymphoma (DLBCL)., Methods: This was a single arm, prospective, observational multicenter and phase IV clinical trial for 279 patients, who were newly diagnosed as CD20-positive DLBCL from 24 medical centers in China 2011 and 2012, no special exclusion criteria were used. All patients received rituximab based R-Chemo regimes, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone) and other regimes as the first-line treatment. The treatment strategies were determined by physicians and patients without detailed description for treatment course, dose, interval time and examination. Clinical response and safety of all patients were investigated in 120 days after completion of last dose of rituximab., Results: Of 279 patients, 258 with stage I-IV who received at least 1 cycle of rituximab treatment and completed at least one time of tumor assessment were enrolled into intention-to-treat analysis, including 148 male and 110 female. The median age of all patients was 57.2(12.8-88.4) years. ECOG performance statuses of 0 or 1 were observed in 91.1% of patients, international prognostic index levels in the low-risk and low-middle-risk groups in 76.4% of patients, the tumor diameters smaller than 7.5 cm in 69.0% of patients. All patients received 6 median cycles of R-Chemo treatment every 24.4 days. R-CHOP treatment was shown to improve the clinical response with overall response rates of 94.2%. Common adverse events included anemia, marrow failure, leukopenia, thrombocytopenia, digestive diseases, infection and liver toxicity. All adverse events are manageable., Conclusion: Non-interventional clinical trial of R-Chemo remains the standard first-line treatment for newly diagnosed patients with DLBCL in real clinical practice, which is consistent with international treatment recommendations for DLBCL patients. R-Chemo can provide the clinical evidence and benefit as the first-line standard treatment for Chinese patients with DLBCL.

Lemur tyrosine kinase-3 (LMTK3) belongs to the family of serine-threonine-tyrosine kinases and the aberrant expression of LMTK3 was observed in several human malignancies. However, the association of LMTK3 with clinical outcomes in colorectal cancer patients is unclear. Thus, this present study was to evaluate the association of LMTK3 expression level with clinicopathologic factors and prognosis of patients with colorectal cancer (CRC). The expression level of LMTK3 in 69 archival paraffin-embedded colorectal tumor tissue specimens was examined by immunohistochemistry (IHC). As a result, we found that the LMTK3 expression level was significantly elevated in CRC tissues as compared with Crohn's disease or colorectal polyp tissues (P<0.0001, P<0.0001, respectively). Positive LMTK3 signals in the colorectal cancer cells were observed in about 89.9% (62 of 69) CRC tissue specimens. Additionally, LMTK3 expression was significantly correlated with lymph node metastasis and tumor-node-metastasis (TNM) classification (P=0.003, and P=0.008, respectively), but not with sex, age, tumor location, histological differentiation, tumor size, or depth of tumor invasion (all P>0.05). Kaplan-Meier survival curves showed that the overall survival rate was significantly higher in the patients with low expression of LMTK3 when compared with those patients with high LMTK3 (P=0.010). Moreover, multivariate analysis revealed that LMTK3 expression was an independent prognostic factor for CRC patients (P=0.047). These results suggest that LMTK3 protein could serve as a prognostic marker for CRC patients.

Unlabelled: Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4(+) T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c(+) MHCII(hi) CD80(lo) CD86(lo) regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c(+) B220(-) DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner., Conclusion: MSCs induce regulatory DCs from CD11c(+) B220(-) DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy., (Copyright © 2013 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases.)

MicroRNAs (miRNAs or miRs) are small, non-coding, single-stranded RNA molecules that regulate gene expression at the post-transcriptional level to repress protein expression of target genes. Among these, miR-181b has been found to be a critical regulatory miRNA linking inflammation and cancer. The functional significance of miR-181b in various tumors and translational research suggests that it exhibits great potential as a predictive and prognostic biomarker. Extensive efforts are underway to identify mRNA targets and the affected regulatory networks, which may be the key to providing a better understanding of miR-181b-mediated signaling pathways.

Lemur tyrosine kinase-3 (LMTK3) is a member of the families of serine-threonine-tyrosine kinases, which has been suggested to be a possible target and marker of breast cancer. However, its definitive physiopathological function in colorectal cancer (CRC) is poorly understood at present. The aim of this study was to determine the expression levels of preoperative-soluble LMTK3 (sLMTK3) in patients' blood with CRC and to subsequently evaluate whether or not its level in serum can be used to predict cancer progression and prognosis. The expression levels of sLMTK3 were measured by sandwich enzyme-linked immunosorbent assay in blood specimens from 60 patients with CRC and 53 healthy volunteers. As a result, we found that the mean concentration of sKMTK3 in CRC patients was significantly higher than that in healthy volunteers (P = 0.012). The expression levels of sLMTK3 were significantly correlated with histological subtype, depth of tumor invasion, and tumor-node-metastasis (TNM) classification (P = 0.038, 0.021, and 0.049, respectively), but not with sex, age, tumor location, tumor size, or lymph node metastasis. Additionally, Kaplan-Meier survival curves showed that patients with high levels of sLMTK3 had a poorer overall survival rate when compared with those of patients with low levels of sLMTK3 (P = 0.041). Moreover, multivariate analysis demonstrated that sLMTK3 expression and TNM stage were independent prognostic factors for CRC patients (P = 0.047 and 0.008, respectively). These results suggest that serum LMTK3 could be a valuable biomarker for predicting the progression and prognosis of patients with CRC.

Introduction: The Wilms' tumor gene (WT1) has been identified as an oncogene in many malignant diseases, and aberrant WT1 expression has been linked to development, progression, and prognosis of non-small-cell lung cancer (NSCLC). We sought to investigate the underlying mechanism of WT1 and metastasis in NSCLC., Methods: Real-time polymerase chain reaction was applied to detect WT1 and CDH1 mRNA in 159 NSCLC samples and corresponding adjacent tissues. Stable clones with overexpression and knockdown of WT1 were generated with plasmid and shRNA via lentivirus technology in H1568 and H1650 NSCLC cell lines. Wound-healing assay, transwell assays, and polymerase chain reaction array were carried out for invasion evaluation. Dual luciferase reporter assay was performed to validate the effect of WT1 on CDH1., Results: The level of the WT1 mRNA was negatively correlated with that of E-cadherin (CDH1) and associated with pathological stage, metastasis, and survival rate of 159 NSCLC patients. A series of genes were regulated by WT1, and WT1 could suppress CDH1 transcription via direct binding to its promoter and may enhance the invasive ability of H1568 and H1650 NSCLC cell lines., Conclusions: WT1 expression was correlated with clinical stage, metastasis, and survival rate in 159 NSCLC patients. Via direct binding to the promoter, WT1 could suppress CDH1 and promote NSCLC invasion.

Rationale and Objectives: To assess whether r(2)* values can be used to determine the nuclear grade of clear cell renal cell carcinomas (CRCC)., Materials and Methods: A total of 26 patients with pathologically proven CRCCs underwent blood oxygen level-dependent magnetic resonance imaging. r(2)* values were determined for the solid components of CRCC lesions. Histological nuclear grade was determined for each lesion. All patients were divided into low- and high-grade groups. r(2)* values were compared between different grades and between low- and high- grade groups. Receiver operating characteristic curve was drawn to establish the cutoff point for r(2)* values. The correlation between r(2)* values and pathological groups was assessed., Results: Low-grade group (grades I + II) contained 17 cases and high-grade group (grades III + IV) contained nine cases. The intraclass correlation coefficient for r(2)* values was 0.89. Significant difference was seen between different grades (P < .005). r(2)* values of the high-grade group were higher than the low-grade group (P < .005). A sensitivity of 78% and a specificity of 100% were achieved with a cutoff of 31.87 seconds(-1). r(2)* values directly correlated with pathological groups (P < .005)., Conclusion: r(2)* values of CRCCs could be employed as a noninvasive biomarker to help classify the nuclear grade of CRCC., (Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.)

Background: Locoregional recurrence is the typical pattern of recurrence in gastric cancer, and cannot be removed by surgery in most of the patients. We aimed to evaluate the feasibility and efficacy of computed tomography (CT)-guided brachytherapy for patients with locoregional recurrent gastric cancer., Materials and Methods: We reviewed the case histories of 28 patients with locoregional recurrent gastric cancer that were selected for CT- guided brachytherapy by a multidisciplinary team. The clinical data of the patients including patient characteristics, treatment parameters, short-term effects, and survival data were collected and analyzed., Results: 15-75 125I seeds were implanted into each patient to produce a minimal peripheral dose (MPD) 100-160 Gy. Median day 0 dosimetry was significant for the following: V100 (the volume treated with the prescription dose) 95.8% (90.2-120.5%) and D90 (prescription dose received by at least 90% of the volume) 105.2% (98.0-124.6%) of prescription dose. No serious complications occurred during the study. Two months after brachytherapy, complete response, partial response and progressive disease were observed in 50.0%, 28.6% and 21.4% of patients, respectively. The median survival time was 22.0 ± 5.2 months, and the 1, 2,and 3-year survival rate was 89 ± 6%, 52 ± 10% and 11 ± 7%, respectively. A univariate analysis showed that the tumor size was a significant predictor of overall survival (P = 0.034). Patients with tumors <3 cm had relatively higher complete response rate (66.7%), compared to those with tumors >3 cm (30.8%). The PTV (planning target volume) smaller than 45 cm3 was significantly correlated with achieving complete tumor eradication in the treated region (P = 0.020)., Conclusions: For selected patients with limited locoregional recurrent gastric cancer, CT-guided brachytherapy using 125I seeds implantation can provide a high local control rate, with minimal trauma.

Inhibitory costimulatory molecule CD274 expresses in various cancers and contributes to cancer immune evasion by inhibiting T cell activation and proliferation, yet the regulatory mechanisms for CD274 overexpression in cancers are poorly understood. In this study, we discovered a novel mechanism of CD274 expression regulated by miR-570. A guanine-to-cytosine mutation at the 3'-UTR of CD274 mRNA led to CD274 overexpression by disrupting the miR-570 binding. The mutations were widely observed in cancers by sequencing of 276 gastrointestinal cancers (esophageal, gastric, colorectal, hepatocellular, and pancreatic cancers). This mutation was significantly associated with CD274 overexpression in gastric cancer (P = 1.44×10(-10)) and with the pathological features including differentiation grade, depth of tumor invasion, lymph node metastasis, and tumor-node-metastases (TNM) stage. These findings suggest a novel regulatory mechanism for CD274 overexpression in gastric cancer mediated by miR-570 and a somatic mutation in CD274 3'-UTR, and provide a new insight to gastric carcinogenesis., (© 2011 Wiley-Liss, Inc.)

Background: Androgens control homeostasis of the normal prostate and growth of prostate cancer (PCa) through the androgen receptor (AR) by regulating gene networks involving in cell proliferation, differentiation, and survival. We demonstrated previously that expression of Skp2, a key protein regulating cell entry into the S phase, is inhibited by androgens in an AR-dependent manner (Oncogene, 2004; 23(12): 2161-2176). However, the underlying mechanism of this regulation is unknown., Methods: Using the LNCaP PCa cell line as a working model, the effect of androgens on the expression of Skp2 was examined by Western and Northern blot analyses. Cell cycle was measured by fluorescence-activated cell sorting (FACS). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied., Results: At physiological levels androgens markedly repressed Skp2 expression but slightly induced Skp2 expression at subphysiological levels. Androgens modestly decreased the stability of the Skp2 protein. Androgenic repression of Skp2 expression was completely abolished by E1A-mediated inactivation of pocket proteins including RB, p130, and p107. Moreover, ectopic expression of p107 inhibited Skp2 expression, and silencing of p107 partially blocked androgenic repression of Skp2., Conclusions: Our data indicate that androgens repress Skp2 expression via p107-dependent and -independent pathways in PCa cells. These regulatory mechanisms may be targeted for the development of new therapeutics of androgen-refractory PCa., (Copyright © 2011 Wiley Periodicals, Inc.)

Tumorigenesis can induce adaptive T-cell-mediated immune responses against malignant cells. Such cellular immune responses are actively suppressed by cancer cells via mechanisms of immune tolerance. We studied T-cell responses against tumor growth by examining tumor-infiltrating lymphocytes (TILs) in upper gastrointestinal (GI) cancers. The number of T-bet(+) TILs correlates with better survival of esophageal cancer patients. Using well-defined mouse models, we have further shown that T-bet and Eomes are both required for the adaptive anti-tumor immunity by regulating T-cell trafficking into the tumor tissue and their effector functions inside the tumor microenvironment. In order to gain further insight into the tumor immune microenvironment in the upper GI cancer, we have also studied expression levels of co-inhibitory molecules such as B7-H1/PD-L1 and B7-H4 in tissue specimens of esophageal and gastric cancers. These inhibitory B7 molecules were expressed at high but variable levels by cancer cells. The overexpression of these molecules correlates with poor clinicopathological parameters and shorter patient survival time. The number of CD3(+) and CD8(+) TILs correlates inversely with expression levels of B7-H4 in samples from esophageal cancer, supporting a role of active immune suppression by inhibitory B7 molecules in the tumor microenvironment. In addition, TILs show functional exhaustion and express high levels of PD-1 and Tim-3. We propose that metabolic competition mediated by phosphatidylinositol 3-kinases (PI3Ks) characterizes the immune suppression within cancer tissues. Future tumor vaccine design should combine blockade of B7 inhibitory molecules and enhancement of T-bet and Eomes levels within the tumor microenvironment.

Diagnosis of primary hepatocellular carcinoma (HCC) at early stages has obviously been improved since determination of serum levels of free alpha-fetoprotein (AFP) was implemented. AFP has been considered as the standard tumor marker of primary HCC, although certain patients have very low serum free AFP levels. In the present study, clinical application of measuring serum AFP-IgM immune complexes compared to the serum free AFP was evaluated for diagnosis of small HCC. One hundred and three healthy controls, 74 patients with primary HCC, 27 patients with liver cirrhosis and 63 patients with chronic hepatitis were included in the present study. Serum levels of AFP-IgM immune complexes and free AFP were determined by ELISA and electrochemiluminescence, respectively. The best cut-off values of AFP-IgM immune complexes and free AFP for the diagnosis of primary HCC were 300 AU/ml and 10 μg/l, respectively, according to the area under the curve (AUC). At these cut-off values, the sensitivities of AFP-IgM and AFP for HCC were 64.9% and 79.7%, respectively, with specificities of 75.6% and 80.3%, respectively. Combining positivity for both tumor markers, the specificity and accuracy of diagnosis of HCC were 89.1% and 79.0%, respectively. Moreover, when the diameter of the tumor was ≤ 3 cm (being considered as small HCC), the sensitivity and specificity were 100.0% and 75.3%, respectively. There was no significant correlation between AFP-IgM level, patient sex or age (p>0.05). The ROC area was significantly different between AFP-IgM and AFP (Z = 2.19, p = 0.0286). In addition, the serum AFP-IgM levels were significantly higher in the patients with tumor diameter ≤ 3 cm (1090.4 ± 571.8 AU/ml) than in the patients with tumor diameter >3 cm (604.9 ± 749.9 AU/ml). It is concluded that determining serum levels of both AFP-IgM immune complex and AFP may have potential benefit for the diagnosis of small HCC.

To establish the prognostic value of B7-H4 expression by tumor cells in gastric cancer patients, we evaluated the association of B7-H4 expression with clinicopathologic factors and overall survival of gastric cancer patients. A retrospective cohort study including 156 gastric cancer patients was performed in the present report. Immunohistochemical assay was used to evaluate the expression of B7-H4 in the surgical specimens of gastric cancer tissues. Multi-univariate COX model was then used to evaluate the association of B7-H4 expression with the patients' survival and clinicopathological parameters. B7-H4 expression in the gastric cancer cells was observed in about 44.9% gastric cancer specimens. Univariate analysis demonstrated that there was no correlation between B7-H4 expression and sex, age, histological type, pathological grade or tumor size. In contrast, B7-H4 expression correlated positively with cancer invasiveness and lymph node metastasis. In addition, the median overall survival time of patients with lower B7-H4 expression was 13 months longer than that of patients with higher expression (chi(2) = 12.38, P < 0.0001), and the median disease-free survival time of patients with lower B7-H4 expression was significantly longer than that of patients with higher expression (33 vs. 16 months, chi(2) = 14.977, P < 0.0001). After adjustment for other confounding factors, the COX model analysis indicated that the death risk was significantly higher in patients with higher B7-H4 expression than those with lower expression (RR = 1.85, 95% CI = 1.15-2.96). The present study demonstrated that higher B7-H4 expression in cancer cells was associated with poor prognosis of gastric cancer patients. This is consistent with the idea that B7-H4 promotes cancer progression, likely via inhibition of anti-tumor immune responses.

The present study evaluated the clinical efficacy of chemotherapy in combination with cytokine-induced killer (CIK) biotherapy compared to the chemotherapy alone. Fifty-nine advanced non-small cell lung cancer (NSCLC) patients were randomly divided into two groups, group A (chemotherapy alone, including docetaxel 75 mg/m2, day 1; cisplatin, 25 mg/m2, days 1-4, tri-weekly) and group B (chemotherapy plus CIK cell transfusion). Autologous CIK cells were induced from the patients'peripheral mononuclear cells in vitro and separated by cytometry and then transfused back the patients. The host cellular immune function, clinical curative effects and quality of life (QOL) were examined and were compared between the two groups. The host immune function was enhanced and QOL was improved in the patients treated by chemotherapy plus CIK biotherapy compared to the patients treated by chemotherapy alone. The overall response rate (ORR) was 43.3% and 44.8% in groups A and B, respectively. The disease control rate (DCR) was higher in group B than in group A (89.7% vs. 65.5%, p = 0.030). The time to progression was 4.67 months (95% CI 3.98-6.02 months) in group A and 6.65 months (95% CI 4.70-7.30 months) in group B and the median survival time was 11.0 months (95% CI 7.88-14.1 months) in group A and 15.0 months (95% CI 11.04-18.96 months) in group B. Compared to patients in group A, the patients in group B had significantly longer progression-free survival (p = 0.042) and overall survival (p = 0.029). No severe side-effects occurred in the CIK cell transfusion patients. It was concluded that chemotherapy plus CIK cells has potential benefits compared to chemotherapy alone in patients suffering from advanced NSCLC and autologous CIK cell transfusion has no obvious side-effects.

The effects of autologous cytokine-induced killer (CIK) (CD3+CD56+) cells together with chemotherapy were investigated in patients who suffered from advanced gastric cancers (stage IV). Fifty-seven patients were divided into two groups: chemotherapy plus CIK biotherapy and chemotherapy alone. CIK cells were induced from autologous peripheral blood mononuclear cells in vitro and separated by flow cytometry and then transfused into the patients. The T-lymphocyte subgroups (CD3+, CD4+ or CD8+), CIK cells and NK cells (CD3-CD56+) were separated and determined by flow cytometry and the serum levels of MG7-Ag, CA72-4, CA19-9 and CEA were determined by ELISA or ECLIA. It was demonstrated that the cytotoxic activity of CIK cells reached a maximum between days 14 to 21 (68.7+/-10.9% and 65.3+/-10.4%, respectively). The amounts of CIK cells were gradually increased from day 0 to day 21 and slightly decreased in the further incubations. Thereafter, the CIK cells on days 14 to 21 (with the highest population of CIK cells) transfused back to the patients. The serum levels of the tumor markers were significantly decreased, the host immune function was increased and the short-term curative effect as well as the quality of life (QOL) were improved in the patients treated by chemotherapy plus CIK cells compared to the patients treated by chemotherapy alone. Moreover, the 2-year life-span was prolonged in the group treated by chemotherapy plus CIK cells compared to the group treated with chemotherapy alone. It is concluded that chemotherapy plus CIK cells has obvious benefits for patients who suffer from advanced gastric cancers.