The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.
Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspirin ; administration & dosage ; therapeutic use ; Bevacizumab ; therapeutic use ; Biological Products ; therapeutic use ; Brain Neoplasms ; drug therapy ; genetics ; Cetuximab ; therapeutic use ; Clinical Decision-Making ; methods ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; prevention & control ; therapy ; Contraindications ; Humans ; Mutation ; physiology ; Neoadjuvant Therapy ; standards ; Neoplasm Metastasis ; drug therapy ; Neoplastic Syndromes, Hereditary ; drug therapy ; genetics ; Practice Guidelines as Topic ; Prognosis ; Secondary Prevention ; methods ; standards

OBJECTIVETo investigate the role of epidermal growth factor receptor (EGFR) expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) effect against A549 lung cancer cell line.

METHODSA549 cell line and NKTm cells were used as the target cell and the effector cell, respectively. pEGFR-EGFP plasmids were transfected into A549 cells by nucleofector method. EGFR expression levels were measured by immunohistochemistry. The ADCC activity induced by cetuximab was assessed by cell counting kit-8 assay.

RESULTSA549 cells transfected with pEGFR-EGFP plasmids expressed higher level of EGFR protein on membrane and were more sensitive to ADCC activity mediated by cetuximab (P<0.05). The inhibition rate of A549 cells showed no significant difference between transfection group and wild-type group when treated with cetuximab alone (P> 0.05).

CONCLUSIONEGFR expression level influences the sensitivity of A549 lung cancer cell line to ADCC activity mediated by cetuximab but not to cetuximab alone.

Adenocarcinoma ; pathology ; Antibodies, Monoclonal, Humanized ; pharmacology ; Antineoplastic Agents ; pharmacology ; Cetuximab ; Humans ; Immunohistochemistry ; Lung Neoplasms ; pathology ; Receptor, Epidermal Growth Factor ; metabolism ; Tumor Cells, Cultured

OBJECTIVE: To determine an approach enriching cancer stem cells from laryngeal cancer cell line. To investigate whether laryngeal cancer stem cells in chemoradiotherapy have the characteristic of resistance. METHOD: CD133+ cells and CD133- cells was detected and isolated from Hep-2 cell line by fluorescence activated cell sorting technology. The cytotoxicities of cisplatin and radiation were investigated by cell counting kit-8(CCK-8) assay. The apoptosis and cell cycle was analyzed with flow cytometry. RESULT: CD133+ cells accounted for a fraction of (2.43 +/- 0.77)% in Hep-2 cell line. CD133+ cells have a more obvious characteristics of cancer stem cells. Different cisplatin and radiation concentrations of for two cell have inhibition, in a certain concentration range and the dosage dependence. Cisplatin and radiation had synergistic inhibitory effects with CD133- cells on the growth of two cell. Moreover, cell cycle arrest at G0/G1 phase and more apoptosis was induced by synergistic combination. Different concentrations of cetuximab for Hep-2 cells have inhibition, in a certain concentration range and time and the dosage dependence. The half maxial inhibitory concentration (IC50) of cetuximab to Hep-2 cells on 24 h was 1 036.84 microg/L. Cisplatin and radiation had synergistic inhibitory effects with cetuximab on the growth of Hep-2 cell line. Moreover, cell cycle arrest at G0/G1 phase and more apoptosis was induced by synergistic combination. CONCLUSION Compared with CD133- cells, CD133+ cells subpopulation exhibited extraordinary cancer stem.
AC133 Antigen ; Antibodies, Monoclonal, Humanized ; pharmacology ; Antigens, CD ; analysis ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Cell Cycle ; Cell Line, Tumor ; Cetuximab ; Chemoradiotherapy ; Cisplatin ; pharmacology ; Drug Resistance, Neoplasm ; Flow Cytometry ; Glycoproteins ; analysis ; Humans ; Laryngeal Neoplasms ; therapy ; Neoplastic Stem Cells ; drug effects ; radiation effects ; Peptides ; analysis ; Radiation Tolerance

OBJECTIVE: This research aims to investaigate the effect of cetuximab and dendritic cells (DCs) to kill the head and neck squamous cell (HNSCC), in order to provide a new way for the patients of HNSCC. METHOD: DCs were induced from peripheral blood monocytes by rhIL-4, rhGM-CSF and TNF-alpha in vitro, 7days later, detecting the surface marks of DCs for example CD83, CD86, and then using MTT and flow cytometry detecting the effect T lymphocytes induced by DCs combining cetuximab to kill HNSCC; EGFR and pEGFR in each group were anlysised by Western blot. RESULT: It is successful to induce DCs in vitro. Mature DCs (mDCs) expressed the suface mark such as CD83, CD86 higher compared with immature DCs (imDCs). Compared with other groups, cetuximab combined with DCs significantly enhanced the cytotoxicty and apoptosis to HNSCC (P < 0.05). pEGFR were gradually reduced as the concenetration of cetuximab increasing (P < 0.05). However, comparing with the group of cetuximab, the group of cetuximab combined with DC has no significant difference at the same concentration of cetuximab. In each group EGFR also has no significant diference (P > 0.05). CONCLUSION Cetuximab and DCs have synergistic effects, which can significantly enhance the killing effect of HNSCC.
Antibodies, Monoclonal, Humanized ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Squamous Cell ; pathology ; Cetuximab ; Dendritic Cells ; immunology ; Head and Neck Neoplasms ; pathology ; Humans ; Squamous Cell Carcinoma of Head and Neck ; Tumor Cells, Cultured

OBJECTIVETo evaluate the influence and safety of denosumab on bone mineral density (BMD) of lumbar spine in women with low bone mass.

METHODSThe clinical literatures concerning denosumab for the treatment of osteopenia or osteoporosis in women were searched from Medline, Embase, Cochrane Central Register of Controlled Trials, Wanfang database, China National Knowledge Infrastructure database, Chinese Biomedical Database. Randomized controlled trials (RCT) were selected by the inclusive and exclusive criteria. The jadad scale was used in the quality assessment of included studies. Meta-analysis of valid data picked from included studies was performed by RevMan 5.0.24 software.

RESULTS5 RCT were included in this meta-analysis. The results of meta-analysis using the fixed effects model showed that, the increase level of lumbar BMD after 12 month was 5.45% (95% CI, 5.05%~5.84%) higher in denosumab group than in placebo control group (P<0.00001). The serious adverse event, serious infection event and pack pain occurred during the followed-up were analysed using fixed effects model. The results showed no significant difference between two groups.

CONCLUSIONCompared with placebo control group, denosumab can significant increase the BMD of lumbar spine, and the safety of two groups is similar.

Antibodies, Monoclonal, Humanized ; adverse effects ; pharmacology ; Bone Density ; drug effects ; Bone Density Conservation Agents ; adverse effects ; pharmacology ; Denosumab ; Female ; Humans ; Lumbar Vertebrae ; Randomized Controlled Trials as Topic

This study was purposed to investigate the efficacy and feasibility of recombinant humanized anti-CD25 monoclonal antibody for treating steroid-resistant acute graft-versus-host disease (aGVHD ) following allo-hematopoietic stem cell transplantation (allo-HSCT) . Twenty-one cases with II-IV grade steroid-resistant aGVHD after allo-HSCT were treated by intravenous injection of recombinant humanized anti-CD25 monoclonal antibody at a dose of 1 mg/(kg·d) on days 1, 4, 8. Injection was repeated after 1 week for the patients who did not achieve CR. The results indicated that 13 cases (61.9%) got complete response (CR), 4 cases out of them have been still in disease-free survival, 8 cases have been in survival with mild cGVHD, 1 cases died from AML relapse, 6 cases (28.57%) got partial response (PR), 3 cases out of them have been in survival with mild cGVHD, 3 case died from pulmonary infection, 2 cases without response died from GVHD. Overall response rate was 90.5% and long term survival rate was 71.48%. There were no infusion-associated side-effects after treatment with recombinant humanized anti-CD25 monoclonal antibody.It is concluded that recombinant humanized anti-CD25 monoclonal antibody is effective and feasible for treatment of steroid-refractory grade II-IV aGVHD after allo-HSCT.
Adolescent ; Adult ; Antibodies, Monoclonal, Humanized ; immunology ; therapeutic use ; Child ; Child, Preschool ; Drug Resistance, Neoplasm ; Female ; Graft vs Host Disease ; drug therapy ; Hematopoietic Stem Cell Transplantation ; methods ; Hormones ; pharmacology ; Humans ; Interleukin-2 Receptor alpha Subunit ; immunology ; Male ; Middle Aged ; Transplantation, Homologous ; Young Adult

PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1alpha. Recent reports suggested that HIF-1alpha also mediated the induction of class III beta-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1alpha and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro. MATERIALS AND METHODS: The protein expression levels of HIF-1alpha and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel. RESULTS: Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1alpha and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1alpha and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1alpha and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. CONCLUSION: We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.
Angiogenesis Inhibitors/pharmacology ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; *Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockdown Techniques ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Paclitaxel/*pharmacology ; Pregnancy Proteins/pharmacology ; Stomach Neoplasms/drug therapy/genetics ; Tubulin/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors/*physiology ; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors/*physiology

OBJECTIVE: To determine the sensitivity of cetuximab induced apoptosis in laryngeal squamous carcinoma cells Hep-2, and to evaluate the synergistic killing effects and regulation mechanism of cetuximab alone or cetuximab in combination with chemotherapeutic agents (cisplatin) or radiation means on Hep-2 cells. METHOD: To investigate the cytotoxicities of cetuximab, cisplatin and radiation, cell counting kit-8 (CCK-8) assay was used for the detection of cell growth inhibition ratio, and fluorescence activated cell sorter FACS for the apoptotic rate and cell cycle distribution. RESULT: Cetuximab had inhibitive effect on Hep-2 cells within a certain range of concentration in a time- and dose-dependence manner. The inhibition concentration 50% (IC50) of cetuximab on Hep-2 cells for 24 h was 1 036.84 microg/ml. For application of cisplatin and radiation, the apoptotic rate of Hep-2 cell was higher by combining with cetuximab than their single or combined administration. Moreover, the cell cycle arrested at G0/G1 phase. CONCLUSION Laryngeal cancer Hep-2 cells was sensitive to the cetuximab induced apoptosis. Cetuximab combined with cisplatin and/or radiation can increase the antiproliferative effects on Hep-2 cells. These findings suggest the synergistic combination of cetuximab and cytotoxic agents was sequence depended.
Antibodies, Monoclonal, Humanized ; pharmacology ; Apoptosis ; drug effects ; radiation effects ; Cell Line, Tumor ; Cetuximab ; Cisplatin ; pharmacology ; Combined Modality Therapy ; Humans

OBJECTIVETo evaluate the effects of Bevacizumab on the tumor growth, proliferation and apoptosis of gastric cancer xenograft, and the impacts on the VEGF and Sp1 expression.

METHODSGastric cancer xenografts in nude mice were established using SGC-7901 gastric cancer cell line. The nude mice were randomly divided into two groups, Bevacizumab treatment group and PBS group. The tumor sizes were measured for tumor growth curve. The proliferation and angiogenesis were evaluated by immunohistochemistry (IHC) staining of Ki67 and CD34. TUNEL assay was used for apoptosis evaluation. The expression of VEGF and Sp1 in tumor cells were detected by IHC and Western blot.

RESULTSCompared to the PBS group, the tumor growth decreased significantly (P<0.05), the proliferation of tumor cells and angiogenesis decreased, and apoptosis index increased significantly [(5.3 ± 1.8)% vs. (16.7 ± 6.7)%, P<0.01] in Bevacizumab group. The results of IHC and Western blot demonstrated that the expression of VEGF and the microvessel density (MVD) was decreased (4.0 ± 1.0 vs. 16.3 ± 1.5, P<0.001) in Bevacizumab treatment group. No obvious changes of Sp1 expression were observed in Bevacizumab treatment group.

CONCLUSIONSBevacizumab can inhibit the growth of gastric cancer xenografts in nude mice, decrease the VEGF expression and MVD. However, the compensatory up-regulation of transcription factor Sp1 is not affected by Bevacizumab.

Animals ; Antibodies, Monoclonal, Humanized ; pharmacology ; Apoptosis ; Bevacizumab ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Mice ; Mice, Nude ; Sp1 Transcription Factor ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Vascular Endothelial Growth Factor A ; metabolism ; Xenograft Model Antitumor Assays

The aim of this study was to investigate the effects of Avastin on aquaporin4 (AQP4) expression in human retinal Müller cells in vitro under hypoxia, so as to explore the mechanism of Avastin treating retinal edema. The human Müller cells were cultured using the enzymatic digestion method. Müller cells were identified under the transmission electron microscopy and by using immunofluorescence staining. By using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), the expression of AQP4 mRNA and VEGF mRNA in Müller cells cultured with 500 μmol/L CoCl(2) for 0, 3, 6, 12 and 24 h, and with 0, 100, 300, 500 and 700 μmol/L CoCl(2) for 24 h was detected. The expression of AQP4 mRNA in Müller cells cultured with 50 ng/mL exogenous vascular endothelial growth factor (VEGF) for 0, 0.5, 1, 2 and 4 h, and with 0, 25, 50 and 75 ng/mL VEGF for 24 h was detected. Amplified cDNA products of AQP4 mRNA in Müller cells cultured with 500 μmol/L CoCl(2) and 200 μg/mL Avastin for 24 h were detected. The results showed that more than 95% cells displayed positive immunofluorescence reaction. Characteristic 8-10 nm intracellular filaments could be seen in the cytoplasm under the transmission electron microscopy. In the CoCl(2) experimental groups, the expression of AQP4 mRNA and VEGF mRNA in Müller cells was increased as compared with the control group. Alteration of AQP4 mRNA and VEGF mRNA levels showed a significantly positive correlation (r (2)=0.822, P<0.05). The expression of AQP4 mRNA in Müller cells was increased by VEGF. The expression of AQP4 mRNA was significantly decreased by Avastin as compared with the control group. It is suggested that Avastin can decrease the expression of AQP4 mRNA in human Müller cells under chemical hypoxic conditions partially via VEGF path, which may be one of the mechanisms of Avastin treating retinal edema.
Antibodies, Monoclonal, Humanized ; pharmacology ; Aquaporin 4 ; genetics ; metabolism ; Bevacizumab ; Cells, Cultured ; Ependymoglial Cells ; metabolism ; Gene Expression ; drug effects ; genetics ; Humans ; Hypoxia ; genetics ; metabolism