胸腔积液中肺腺癌细胞发生胶原化的形态观察与研究

目的胶原蛋白是细胞外基质的主要成分之一,我们在临床数千例恶性胸水转移的非小细胞肺癌细胞胞浆中常见到围绕细胞核或局灶状葱皮排列的纤维样结构,由此我们假设肺腺癌细胞在侵袭转移形成胸腔积液过程中发生与细胞外基质相同的结构变化,即肿瘤细胞胶原化形成"盔甲"式保护膜起到对肿瘤细胞结构及功能的支撑,达到抵御化疗药物、毒素的穿透和放射线的轰击,提高了自我保护能力,适应新的肿瘤细胞增生微环境。方法 TCT方法选取224例肺腺癌细胞学标本,其中胸腔积液标本144例,肺泡灌洗液40例,痰液标本40例,24例为良性胸腔积液作为对照。常规制成细胞包埋块,切片、HE染色及CK7、TTF-1、vimintin的免疫细胞化学染色。透射电镜观察肿瘤细胞内部结构。Masson特殊染色,胶原蛋白Ⅰ、Ⅱ、Ⅲ亚型染色,Western-blot蛋白检测。观察肺腺癌细胞是否存在胶原蛋白亚型及肺腺癌不同标本的表达情况。结果Masson细胞化学染色显示胶原纤维在恶性胸腔积液、支气管肺泡灌洗液及痰肺腺癌标本中的表达率分别为59.7%(86/144)、0%(0/40)、0%(0/40),在良性标本中不表达均为阴性(0/24)。免疫细胞化学结果显示:COL1A1、COL2A1和COL3A1在肺腺癌细胞中的阳性表达率分别为22.6%(38/168),5.4%(9/168),22.6%(38/168),阳性表达主要定位于胞浆,而在增生的上皮细胞中不表达,统计学分析结果显示COL1A1、COL3A1的表达率要显著高于COL2A1的表达率(P=0.024),并且我们发现COL1A1与COL3A1的表达成正相关性(r=0.886,P=0.000)。透射电镜可观察到在肿瘤细胞胞浆中可见多量纤维状物质。结论本研究从形态学上观察到在转移的肺腺癌细胞胞浆内有一些围绕胞核呈葱皮样改变的纤维样结构,结果表明肺腺癌细胞可以产生胶原蛋白,以纤维性胶原Ⅰ,Ⅲ为主,并在转移的肺腺癌细胞中高表达可能与晚期肺癌细胞的抗药性增强有关。

Transfection of the Human Sodium/Iodide Symporter(NIS) Gene with Liposomes and the Expression of the NIS Protein in Human Lung A549 Cancer Cells

OBJECTIVE To examine the possibility of human sodium iodide symporter （hNIS） protein expression in lung cancer cells. METHODS Human lung A549 cancer cells were thawed and cultured in vitro. The cells were divided into an experimental group transfected with a recombinant pcDNA3-hNIS plasmid and a control group transfected only with a pcDNA3 plasmid. The recombinant plasmid vector encoding the hNIS gene （pcDNA3-hNIS） was amplified, purified and identified. The hNIS gene was followed by DNA sequencing. A Western blot and an immunohistochemical assay were applied to detect the hNIS protein expression in the transfected human lung A549 cancer cells. RESULTS Restriction enzyme digestion and DNA sequencing results showed the size and direction of the inserted gene in the recombinant pcD- NA3-hNIS plasmid was correct. The Western blot method and immunohistochemical analysis showed a positive NIS protein expression in the experimental group. The NIS protein was detected mainly in the cell membranes showing a positive rate up to 70.6% with no expression of the NIS protein in the control group. There was a significant difference between two groups （P=0.000）. CONCLUSION The hNIS gene was transfected effectively into human lung A549 cancer cells mediated by Lipofectamine 2000, and was expressed with its protein in vitro.

The Promoter Hypermethylation of DAPK Gene and pl6 Gene in Sera from Chinese Non-small Cell Lung Cancer Patients

Objective： To evaluate the clinical significance of the aberrant methylation of DAPK gene and p16 gene in sera from 65 NSCLC patients from Nanjing General Hospital of Nanjing Command, China. Methods： A methylation-specific PCR （MSP） was performed for the detection of promoter hypermethylation of DAPK gene and p16 gene in blood DNA from 65 cases of NSCLC, and to analyze the relation of the aberrant methylation of DAPK gene and p16 gene and the clinicopathological data. Results： 30.8% （20/65） of the sera from 65 cases of NSCLC showed hypermethylation for DAPK promoter and 43.1% （28/65） the same for p16 promoter, whereas no methylated DAPK gene promoter and p16 gene promoter were found in sera from the patients with lung benign diseases and normal controls. Methylated DAPK gene promoter and p16 gene promoter in sera were not closely correlated with the pathological classification, stage, metastasis and differentiation in NSCLC. Conclusion： Detection of the aberrant methylation of DAPK gene and p16 gene in blood DNA from NSCLC patients might offer an effective means for the earlier auxiliary diagnosis of the malignancy.

Expression of Hypoxia Inducible Factor lα and Its Significance in Non-small Cell Lung Cancer

Objective： To explore the expression level and its clinical significance of hypoxia inducible factor 1α （HIF-1α ） in non-small lung cancer. Methods： The expression of HIF-1α was detected in 68 human non-small lung cancer samples by immunohistochemistry. Results： （1） Thirty-nine （57.35%） out of the 68 human non-small lung cancer samples was positive for HIF-1α ; （2） The positive rate of HIF-1α in adenocarcinoma and squamous carcinoma was 54.76% （23/42） and 61.54% （16/26） respectively. No significant difference was found between adenocarcinoma and squamous carcinoma of non-small lung cancer in the expression of HIF-1α （P〉0.05）. The positive rate of HIF-1α in middle-high differentiation was 74.28% （26/35）, significantly higher than in low differentiation （39.39%, 13/33） （P〈0.05）; （3） The positive expression of HIF-1α was not correlated to the sexes, ages, tumor stage and lymph node status. Conclusion： The expression of HIF-1α is higher in non-small lung cancer and is correlated to differentiation.

High Serum CEA and CYFRA21-1 Levels after a Two-Cycle Adjuvant Chemotherapy for NSCLC:Possible Poor Prognostic Factors

Objective The aim of this study was to test whether carcinoembryonic antigen （CEA） and cytokeratin 19 fragments （CYFRA21-1） can be used as a prognostic factor for non-small-cell lung cancer （NSCLC） after two cycles of adjuvant chemotherapy in NSCLC patients. Methods A total of 169 patients underwent at least two cycles of adjuvant chemotherapy. The serum levels of CEA and CYFRA21-1 were recorded after the second cycle of chemotherapy, and the patient follow-up was conducted. Overall survival （OS） and disease- free survival （DFS） were used as the primary endpoint and the secondary endpoint, respectively. Results The high levels of CEA and CYFRA21-1 after two cycles of adjuvant chemotherapy were poor prognostic factors for OS, with risk ratios （RR） of 2.003 and 1.702, respectively. A high CEA level was a poor prognostic factor （RR 1.152） for DFS. The median survival time （MST） of the high CEA level group was 26 months, whereas that of the normal group was 61 months （P〈0.0001）. The median DFS time of the high CEA group and the normal group was 34 and 53 months, respectively （P〈0.0001）. The MST of the high CYFRA21-1 group and the normal group was 43 and 56 months, respectively （P〈0.0001）. Conclusions The high serum levels of CEA or CYFRA21-1 after two cycles of adjuvant chemotherapy are poor prognostic factors for NSCLC patients.

Application of video-assisted thoracic surgery in the standard operation for thoracic tumors

Objective： To evaluate the short-term outcomes of video-assisted thoracic surgery （VATS） for thoracic tumors. Methods： The data of 1,790 consecutive patients were retrospectively reviewed. These patients underwent VATS pulmonary resections, VATS esophagectomies, and VATS resections of mediastinal tumors or biopsies at the Cancer Institute ＆ Hospital, Chinese Academy of Medical Sciences between January 2009 and January 2012. Results： There were 33 patients converted to open thoracotomy （OT, 1.84%）. The overall morbidity and mortality rate was 2.79% （50/1790） and 0.28% （5/1790）, respectively. The overall hospitalization and chest tube duration were shorter in the VATS lobectomy group （n=949） than in the open thoracotomy （OT） lobectomy group （n=753）. There were no significant differences in morbidity rate, mortality rate and operation time between the two groups. In the esophageal cancer patients, no significant difference was found in the number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS esophagectomy group （n=8 1） and open esophagectomy group （n=81）. However, the operation time was longer in the VATS esophagectomy group. In the thymoma patients, there was no significant difference in the chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS thymectomy group （n=41） and open thymectomy group （n=41）. However, the operation time was longer in the VATS group. The median tumor size in the VATS thymectomy group was comparable with that in the OT group. Conclusions： In early-stage （Ⅰ/Ⅱ） non-small cell lung cancer patients who underwent lobectomies, VATS is comparable with the OT approach with similar short-term outcomes. In patients with resectable esophageal cancer, VATS esophagectomy is comparable with OT esophagectomy with similar morbidity and mortality. VATS thymectomy for Masaoka stage I and II thymoma is feasible and safe, and tumor size is not contraindicated. Longer follow-ups are needed to determine the oncologic equivalency of VATS lobectomy, esophagectomy, and thymectomy for thymoma vs. OT.

Programmed cell death ligand-1(PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer?

Blockade of immune checkpoints has recently emerged as a novel therapeutic strategy in various tumors. In particular,monoclonal antibodies targeting programmed cell death 1(PD-1) or its ligand(PD-L1) have been most studied in lung cancer,and PD-1 inhibitors are now established agents in the management of non-small cell lung cancer(NSCLC). The reports on highprofile clinical trials have shown the association of PD-L1 expression by immunohistochemistry(IHC) with higher overall response rates to the PD-1/PD-L1 axis blockade suggesting that PD-L1 expression may serve as a predictive marker. Unfortunately,however, each PD-1 or PD-L1 inhibitor is coupled with a specific PD-L1 antibody, IHC protocol and scoring system for the biomarker assessment, making the head-to-head comparison of the studies difficult. Similarly, multiple clinical series that correlated PD-L1 expression with clinicopathologic and/or molecular variables and/or survival have reported conflicting results.The discrepancy could be explained by the differences in ethnicity and/or histologic types included in the studies, but it appears to be attributed in part to the differences in PD-L1 IHC methods. Thus, orchestrated efforts to standardize the PD-L1 IHC are warranted to establish the IHC as a predictive and/or prognostic biomarker in NSCLC.

Effects of Tai Chi Chuan training on cellular immunity in post-surgical non-small cell lung cancer survivors:A randomized pilot trial

Background： Although emerging evidence points to benefits from Tai Chi Chuan （TCC） in improving immune system function, its effects on cellular immune responses remain under-studied. The objective of this study was to evaluate the effects of TCC training on cellular immunity in non-small cell lung cancer patients. Methods： A 2-group randomized trial design in which post-surgical, non-small cell lung cancer survivors were randomly assigned to a TCC training group （n = 16） or a control group （n = 16）. The participants in the TCC group completed a 16-week intervention. The main immune response outcome measures assayed included the ratio of T-helper cells/T-suppressor cells （CD4＋：CD8＋ ratio） and complement regulatory proteins status （CRPs; CD55 and CD59）. Using repeated measures ANOVA, the data were analyzed for the participants who completed the study （n = 27）. Results： At 16 weeks, the TCC participants showed a significantly lower increment in the expression of CD55 （p 〈 0.05） as compared to the control group. No significant between-group differences were found in the CD4＋：CD8＋ ratio or CD59 expression. There were also no significant correlations among the changes in CRPs or T lymphocyte subpopulations, either. Conclusion： A 16-week TCC intervention caused no alterations in CD4＋：CD8＋ ratio, but significantly attenuated CD55 expression among post- surgical non-small cell lung cancer survivors.

Expression of Collagen Ⅳ, Fibronectin, Laminin in Non-small Cell Lung Cancer and Its Correlation with Chemosensitivities and Apoptosis~*

Objective： To study the expression of extracellular matrix （ECM） proteins including Collagen Ⅳ （Co Ⅳ）, Fibronectin, Laminin in human non-small cell lung cancer （NSCLC） specimens and the relationship between ECM and cell adhesion, proliferation, apoptosis and drug sensitivity in NSCLC cell line. And to investigate the role of phosphatidylinositol 3-kinase （PI3-K） in signal transduction of Co Ⅳ in NSCLC. Methods： The expression of ECM proteins was detected by using immunohistochemical staining （Envision＇s）. Adherent cells were stained with 1% methylene blue. Cell proliferation and cytotoxic effects were monitored by MTT assay. Cell apoptosis was analyzed by FITC-Annexin V/PI double staining variables flow cytometry （FCM）. Results： The expression rate of Co Ⅳ （93%） was the highest compared to others in NSCLC stroma. After treated with Co Ⅳ, the adhesion of H1299 cells was increased and the cytotoxicity of cis-platinum （DDP） against H1299 cells was decreased compared to the control （P〈0.05）. After treated with Co Ⅳ both survival and proliferation rates were higher and apoptosis rate was lower than without Co Ⅳ （P〈0.05）. PI3-K inhibitor LY294002 decreased both survival and proliferation rates （82.7%±2.0% and 75.2%±6.8%, respectively）, even on Co Ⅳ-coated surface （92.2%±2.8% and 84.6%±9.2%, respectively）. And it also helped DDP increase apoptosis. Conclusion： ECM remodeling existed in NSCLC. Co Ⅳ protected NSCLC cells from DDP-induced apoptosis and weakened the cytotoxicity of DDP. PI3-K pathway might be the crucial mechanism of apoptosis impairment and drug resistance.

Advances in immunotherapy for treatment of lung cancer

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

Assays for predicting and monitoring responses to lung cancer immunotherapy

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 （PD-1） and its ligand （PD-L1）, have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer （NSCLC）. Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry （IHC） with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-I/PD-L1 pathway.

Relationship Between Programmed Death-ligand 1 and Clinicopathological Characteristics in Non-small Cell Lung Cancer Patients

Objective To evaluate the correlation between programmed death-ligand 1 （PD-L1） expression in primary lung cancer cells, tumor associated macrophages （TAM） and patients＇ clinicopathological characteristics. Methods From 2008 to 2010, 208 non-small cell lung cancer patients who underwent surgery or CT-guided biopsy were recruited from Huadong Hospital, Fudan University. Immunohistochemistry staining was performed to evaluate the PD-L1 expression in both primary lung cancer cells and CD68 positive TAM.

Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

Objective： A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase （PI3K） and mitogen-activated protein kinase （MAPK） pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） treatment of non-small cell lung cancer （NSCLC） patients. Methods： Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios （ORs） for objective response rate （ORR） and hazard ratios （HRs） for progression-free survival （PFS） and overall survival （OS） were calculated. Results： Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval （CI）, 0.13-0.35], shorter PFS （HR =1.56; 95% CI, 1.27-1.92）, and shorter OS （HR =1.59; 95% CI, 1.33-1.91） in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS （HR =1.83; 95% CI, 1.05-3.20）, showed poor ORR （OK =0.70; 95% CI, 0.22-2.18）, and shorter PFS （HR = 1.79; 95% CI, 0.91-3.53） in NSCLC patients treated with EGFR-TKIs. Conclusion： K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR- TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.

CT image fusion in the evaluation of radiation treatment planning for non-small cell lung cancer

Objective: We studied the application of CT image fusion in the evaluation of radiation treatment planning for non-small cell lung cancer (NSCLC). Methods: Eleven patients with NSCLC, who were treated with three-dimensional con-formal radiation therapy, were studied. Each patient underwent twice sequential planning CT scan, i.e., at pre-treatment, and at mid-treatment for field reduction planning. Three treatment plans were established in each patient: treatment plan A was based on the pre-treatment planning CT scans for the first course of treatment, plan B on the mid-treatment planning CT scans for the second course of treatment, and treatment plan F on the fused images for the whole treatment. The irradiation doses received by organs at risk in the whole treatment with treatment A and B plans were estimated by the plus of the parameters in treatment plan A and B, assuming that the parameters involve the different tissues (i.e. V20=AV20+BV20), or the same tissues within an organ (i.e. Dmax=ADmax+BDmax). The assessment parameters in the treatment plan F were calculated on the basis of the DVH of the whole treatment. Then the above assessment results were compared. Results: There were marked differ-ences between the assessment results derived from the plus of assessment parameters in treatment plan A and B, and the ones derived from treatment plan F. Conclusion: When a treatment plan is altered during the course of radiation treatment, image fusion technique should be performed in the establishment of a new one. The estimation of the assessment parameters for the whole treatment with treatment plan A and B by simple plus, is inaccurate.

Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints

Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Clinical observation of Shenmai injection in the treatment for adverse reactions of chemotherapy on advanced non-small cell lung cancer

Objective: To observe the efficacy of Shenmai injection in the treatment for adverse reactions of chemotherapy on advanced non-small cell lung cancer (NSCLC). Methods: 45 NSCLC patients with stages IIIb-IV were randomly divided into two groups: the treatment group (treated by chemotherapy combined with Shenmai injection) and the control group (treated by chemotherapy only). The efficacy of the two groups was evaluated after 3 cycles of treatment. Results: There was no significant difference between the two groups in the recent curative effects (P > 0.05), while there were significant differences between them in Karnofsky score and weight (P < 0.05). The treatment group was better than the control group in preventing leucopenia and decreased hemoglobin, and significant differences were found between them (P < 0.05). The incidence of thrombocytopenia, nausea and vomiting, hepatic and renal dysfunction in the treatment group was lower than that in the control group, but no significant differences were found between them (P > 0.05). Conclusion: Shenmai injection would not influence the efficacy of chemotherapy on advanced NSCLC patients, while it could improve the quality of life, increase the body weight of patients, alleviate adverse reactions of chemotherapy as myelosuppression so as to improve the tolerance of organism to chemotherapy.

Shenqi Fuzheng injection combined with GP chemotherapy in the treatment of advanced non-small cell lung cancer： a meta-analysis

Objective： To evaluate the clinical efficacy of Shenqi Fuzheng injection combined with gemcitabine plus cisplatin（GP） in the treatment of advanced non-small cell lung cancer （NSCLC）. Methods： we performed a systematicsearch in the electronic databases such as Cochrane Library, Pubmed, Embase, Chinese Journal Full-text Database,Chinese Biomedical Literature Database, Chinese Science and Technology Periodical Full-text Database andWanfang Database up to 30 January 2017. Randomized controlled trials （RCT） of Shenqi Fuzheng Injectioncombined with GP chemotherapy in the treatment of advanced NSCLC were searched, and all the RCTs wereconducted on methodological quality assessment. Data extraction and data analysis were according to standards ofCochrane systematic review. Results： Eight trials were included including a total of 701 patients. Meta-analysisresults： Shenqi Fuzheng injection combined with GP chemotherapy could significantly improve the functionalstatus of patients with NSCLC （OR = 3.44, 95% CI [2.26, 5.25], P 〈 0.0001） and clinical treatment efficacy （OR =（OR = 0.31, 95%CI [0.20, 0.47], P 〈 0.0001. The rate of leukopenia （OR = .31, 95%CI [0.20,0.47], P 〈 0.0001）,thrombocytopenia （OR = 0.58, 95%CI [0.37, 0.91], P = 0.020）, hemoglobin decline （（OR = 0.31, 95%CI [0.16,0.59], P = 0.0004） and incidence of gastrointestinal reactions （OR = 0.58,P 〈 0.05） could be reduced. Conclusion：Shenqi Fuzheng injection combined with GP chemotherapy in the treatment of advanced NSCLC obtainedsignificantly clinical efficacy. The quality of the literature incorporated is low, the conclusion requires high-qualityresearch to further prove.

Phase Ⅲ Clinical Trials of the Cell Differentiation Agent-2 （CDA-2）： Therapeutic Efficacy on Breast Cancer, Non-Small Cell Lung Cancer and Primary Hepatoma

OBJECTIVE The objective of this study was to explore the effect of CDA-2, a selective inhibitor of abnormal methylation enzymes in cancer cells, on the therapeutic efficacy of cytotoxic chemotherapy. METHODS Advanced cancer patients, all of whom had previously undergone chemotherapy, were randomly divided into 2 groups, one receiving chemotherapy only as the control group, and the other receiving CDA-2 in addition to chemotherapy as the combination group. The therapeutic efficacies and the toxic maniestations of the 2 groups were compared based on the WHO criteria. RESULTS Of 454 cancer patients enrolled in phase Ⅲ clinical trials of CDA-2, 80, 188, and 186 were breast cancer, NSCLC, and primary hepatoma patients, respectively. Among them 378 patients completed treatments according to the protocols. The results showed that the overall effective rate of the combination group was 2.6 fold that of the control group, 4.8 fold in the case of breast cancer, 2.3 fold in the case of primary hepatoma, and 2.2 fold in the case of NSCLC. Surprisingly, the combination therapy appeared to work better for stage Ⅳ than stage Ⅲ patients. CDA-2 did not contribute additional toxicity. On the contrary, it reduced toxic manifestations of chemotherapy, particularly regarding white blood cells, nausea and vomiting. CONCLUSION Modulation of abnormal methylation enzymes by CDA-2 is definitely helpful to supplement chemotherapy. It significantly increased the therapeutic efficacy and reduced the toxic manifestation of cytotoxic chemotherapy on breast cancer and NSCLC.

Clinical observation of gemcitabine and concomitant three-dimensional conformal radiotherapy in the treatment of locally advanced non-small cell lung cancer

Objective： To evaluate the clinical effect of gemcitabine and concurrent three-dimensional conformal radiation therapy （3D-CRT） for locally advanced non-small cell lung cancer （NSCLC）. Methods： From April 2002 to June 2005, 38 patients with inoperable stage Ⅲ NSCLC were treated with gemcitabine and 3D-CRT simultaneously. Chemotherapy consisted of intravenously gemcitabine 350 mg/m^2 on days 1, 8, 15, 22, 29, 36.3D-CRT was delivered up to a total dose of 60-64 Gy with a 2.0 Gy dose fraction per day, 5 days per week. Results： The overall response rates of primary tumor and mediastinum metastatic node were 86.8% （33/38） and 90.6% （29/32） respectively, and 91.7% （22/24） and 78.6% （11/14） for squamous cell carcinoma and adenocarcinoma respectively. The acute side effects of patients were mostly myelosuppression, nausea, vomiting, radiation-induced esophagitis and pneumonitis （RTOG 1/11）, however, all of them were cured. Conclusion： Concurrent application of gemcitabine and 3D-CRT can improve the overall response rate for locally advanced NSCLC without aggravating the side effects.