Jiang JT, Shen YP, Wu CP, Zhu YB, Wei WX, Chen LJ, Zheng X, Sun J, Lu BF, Zhang XG. Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J Gastroenterol 2010; 16(48): 6155-6162 [PMID: 21182234 DOI: 10.3748/wjg.v16.i48.6155]
Corresponding Author of This Article
Xue-Guang Zhang, MD, PhD, Key Laboratory of Stem Cell of Jiangsu Province, Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Suzhou 215123, Jiangsu Province, China. xueguangzh@yahoo.com.cn
Article-Type of This Article
Brief Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jing-Ting Jiang, Chang-Ping Wu, Lu-Jun Chen, Xiao Zheng, Department of Tumor Biological Treatment, Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
Jing-Ting Jiang, Yi-Bei Zhu, Jing Sun, Xue-Guang Zhang, Key Laboratory of Stem Cell of Jiangsu Province, Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Suzhou 215123, Jiangsu Province, China
Yue-Ping Shen, Wen-Xiang Wei, Department of Medicine, Soochow University, Suzhou 215123, Jiangsu Province, China
Bin-Feng Lu, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
ORCID number: $[AuthorORCIDs]
Author contributions: Jiang JT and Shen YP contributed equally to this work, designed the study and drafted the manuscript; Wu CP and Zhu YB participated in the experimental design; Wei WX and Chen LJ provided the clinical samples; Zheng X and Sun J analyzed the data and formatted the figures; Zhu YB performed all the experiments; Lu BF and Zhang XG drafted the manuscript and designed the study; all authors read and approved the final manuscript.
Supported by The National Natural Science Foundation of China, No. 30872176, 30950022 and 30972703; grants of Jiangsu Province and Soochow University Medical Development Foundation, No. EE126765
Correspondence to: Xue-Guang Zhang, MD, PhD, Key Laboratory of Stem Cell of Jiangsu Province, Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Suzhou 215123, Jiangsu Province, China. xueguangzh@yahoo.com.cn
Telephone: +86-512-65125022 Fax: +86-512-65104908
Received: October 12, 2010 Revised: November 16, 2010 Accepted: November 23, 2010 Published online: December 28, 2010
Abstract
AIM: To analyze the correlation between cytokine-induced killer (CIK) cells adoptive immunotherapy and cancer-related death in gastric cancer patients.
METHODS: One hundred and fifty-six gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University were enrolled in this study. Their clinical data including demographic characteristics, operation time, tumor size, pathological type and staging, tumor metastasis, outcome of chemotherapy or CIK cells adoptive immunotherapy, survival time or time of death were collected with a standard structured questionnaire. Kaplan-Meier method was used to estimate the median survival time, and the 2- and 5- year survival rates. Hazard risk (HR) and 95% confidence interval (95% CI) of CIK cells adoptive immunotherapy for gastric cancer were calculated using the two-stage time-dependent covariates Cox model.
RESULTS: The survival time of gastric cancer patients was longer after CIK cells adoptive immunotherapy than after chemotherapy (χ2 = 10.907, P = 0.001). The median survival time of gastric cancer patients was also longer after CIK cells adoptive immunotherapy than after chemotherapy (49 mo vs 27 mo, P < 0.05). The 2- and 5-year survival rates of gastric cancer patients were significantly higher after CIK cells adoptive immunotherapy than after chemotherapy (73.5% vs 52.6%, 40.4% vs 23.9%, P < 0.05). A significant difference was observed in the survival curve for patients who received CIK cells adoptive immunotherapy (0, 1-10, 11-25, and over 25 frequencies) (χ2 = 14.534, P = 0.002). The frequencies of CIK cells adoptive immunotherapy were significantly related with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients, tumor stage and relapse (HR = 0.54, 95% CI: 0.36-0.80) when the first stage Cox model was used to define the subjects who remained alive beyond 36 mo as survivors. However, no correlation was observed between the frequencies of death in CIK cells adoptive immunotherapy and the risk of gastric cancer patients (HR = 1.09, 95% CI: 0.63-0.89) when the second stage Cox model was used to define the subjects who survived for more than 36 mo as survivors.
CONCLUSION: The survival time of the gastric cancer patients treated with chemotherapy combined with CIK cells adoptive immunotherapy is significantly longer than that of the patients treated with chemotherapy alone and increasing the frequency of CIK cells adoptive immunotherapy seems to benefit patients more.
Citation: Jiang JT, Shen YP, Wu CP, Zhu YB, Wei WX, Chen LJ, Zheng X, Sun J, Lu BF, Zhang XG. Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J Gastroenterol 2010; 16(48): 6155-6162
Gastric cancer is one of the most common causes of cancer-related death in China[1]. Its incidence in Jiangsu Province of China is particularly high, and its mortality rate is much higher than the national average[2]. The early clinical detection rate of gastric cancer is less than 15%, and about 85% cases of gastric cancer are at the advanced stage when their gastric cancer is diagnosed[3]. Surgery is the standard treatment procedure for localized and resectable gastric cancer[4]. However, surgery alone does not improve the 5-year survival rate of local advanced gastric cancer patients[3]. Although standardized surgical resection and adjuvant therapeutic modalities are available for gastric cancer, the survival rate of advanced gastric cancer patients remains very low after operation[5]. About 60% of gastric cancer patients usually experience local recurrence and metastasis to other organs[6]. It has been demonstrated that local recurrence and distant metastasis constitute a major problem in the failure of cancer therapies[7]. Therefore, considerable efforts are needed to improve the current therapeutic modalities and to explore new therapies. In recent years, immune therapy has become the fourth important treatment modality for malignant tumors following surgery, radiotherapy and chemotherapy[8-10].
A number of adoptive immunotherapy with killer cells have been reported, including lymphokine-activated killer cells[11], tumor infiltrating lymphocytes[12], or anti-CD3 monoclonal antibody-induced killer cells[13]. However, their therapeutic efficacy is limited due to their low anti-tumor activities[14]. At present, cytokine-induced killer (CIK) cells are a new type of anti-tumor effector cells, which can proliferate rapidly in vitro, with a stronger anti-tumor activity and a broader target tumor spectrum than the reported anti-tumor effector cells[10,15]. Moreover, CIK cells can regulate and enhance immune function[16]. Studies have reported the level of tumor markers, change in cellular immune functions, exploration of molecule targets and a short-term efficacy in gastric cancer patients after chemotherapy plus CIK cells immunotherapy despite some side effects[17-19]. However, the relation between the frequencies of CIK cells immunotherapy and its clinical efficacy has not been examined. In the present study, data obtained from 156 gastric cancer patients in fitting multivariate Cox model showed that more frequencies of CIK cells immunotherapy could improve the survival rate of gastric cancer patients.
MATERIALS AND METHODS
Patients
One hundred and fifty-six primary gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University (Jiangsu Province, China) were enrolled in this study. Those who did not meet the inclusion criteria, or had other tumors were excluded.
A standard questionnaire was designed to collect the data from the patients, including demographic characteristics, operation time, tumor size and location, pathological type and staging, tumor metastasis, outcome of chemotherapy or CIK cells immunotherapy. Meanwhile, time of relapse and death of the patients was recorded. Patients received 6 cycles of chemotherapy before CIK cells immunotherapy. Some patients underwent CIK cells immunotherapy due to cancer recurrence during chemotherapy. Recurrence of gastric cancer was defined when local, peritoneal or distant metastasis was detected at any site during chemotherapy[20]. The study was conducted according to the principles of the Declaration of Helsinki. All patients gave their informed consent prior to inclusion in the study. The study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University.
Eighty-one patients (62 males, 19 females) at the age of 59.9 ± 10.5 years with a median age of 60.5 years who underwent chemotherapy alone served as chemotherapy group (group I), and those (60 males at the age of 62.4 ± 10.8 years with a median age 60.5 years, 15 females at the age of 51.0 ± 10.7 years with a median age of 50 years) who received chemotherapy plus CIK cells immunotherapy served as treatment group (group II) (Table 1).
Table 1 Distribution of demographic and clinical characteristics in two groups.
Peripheral blood mononuclear cells (PBMC) were collected with a COBE spectra blood cell separator (Gambro BCT, Inc., Lakewood, USA). Viability of PBMC was assessed by trypan blue exclusion. PBMC (2.0 × 106 /mL) were plated onto 6-well dishes (Nunc, Denmark) and cultured with medium I containing RPMI 1640 in the presence of 1.0 × 106 U/L human interferon-γ (IFN-γ, Shanghai Fosun Pharma Co., China), 5.0 × 105 U/L recombinant human interleukin-2 (IL-2, Shangdong Quangang Pharmaceutical Co., China), 10% inactivated human serum, 25 mmol/L HEPES, 2 mmol/L L-glutamine, 100 U/mL penicillin and 100 μg/mL streptomycin. The cells were incubated in a humidified atmosphere containing 5% CO2 at 37°C. Monoclonal antibody (MAb) against CD3 (100 μg/L, Antibody Diagnostic Inc., USA) and IL-1α (1.0 × 105 U/L, Promega) were added after 24 h culture. Supernatant was aspirated and the cells were cultured in Medium II in the absence of INF-γ after another 48 h culture. The cells were transferred to Kolle flasks (Nunc, Denmark) and cultured in the same medium after 1 wk. The medium was changed every 3 d. The cytotoxic activity was assayed as previously described[17,21]. Patients in group I were treated with oxaliplatin (120 mg/m2 D1, 5-Fu 400 mg/m2 CIV 24 h D1-5, CF 200 mg/m2 D1-5) as previously described[22] with the doses adjusted according to the toxicity. Patients in group II received CIK cells immunotherapy as previously described[17] after 6 cycles of chemotherapy, with 1.0 × 109 CIK cells transfused into the patients within 1 h.
Statistical analysis
All data were loaded into the Epidata3.0 database with double-check, and analyzed with the SAS software package (version 9.13; SAS Institute, Cary, NC, USA). The data were expressed as mean ± SD. χ2-test or cmh2 χ2-test was used to compare the difference in balance between the concerned clinical indexes and to find the confounding factors between the two groups. Survival data were analyzed using Kaplan-Meier method and log-rank test to estimate the median survival time, 2- and 5-year survival rates, and to determine if the survival curves for the two groups were different.
When the frequency of CIK cells immunotherapy and the survival time were introduced into the Cox model, the interaction item was significantly associated with the death of gastric cancer patients (wald-χ2 = 4.946, P = 0.0261). A two-stage time-dependent Cox model was established to precisely estimate the hazard risk (HR) and 95% confidence interval (95% CI) of the association between the frequency of CIK cells immunotherapy and the death of gastric cancer patients. Because the median survival time of gastric cancer patients was about 36 mo, 36 mo was used as the optimum cutoff point.
The first stage Cox model involved 154 patients with a survival time of over 36 mo who were defined as survivors. Otherwise, the survival status was the same as the original definition.
The second stage Cox model only involved 56 patients with a survival time longer than 36 mo, and their survival status was defined as the original definition.
Pearson correlation test was performed between Schoenfeld residual of the frequencies of CIK cells immunotherapy and the survival time of gastric cancer patients to determine whether the frequency of CIK cells immunotherapy is a time-dependent variable in the two Cox models[23].
RESULTS
Distribution of demographic and clinical characteristics in two groups
No statistical difference was found in sex and age of the patients, tumor site, histological type, invasion depth, lymph node metastasis, pathological grade, tumor size and stage between the two groups. However, the number of patients was significantly greater in group II with recurrent disease than in group I (46.7% vs 28.4%, χ2 = 5.566, P = 0.018) (Table 1), suggesting that more patients with relapse should receive CIK cells immunotherapy.
Demographic and clinical characteristics of patients after CIK cells immunotherapy
No statistical difference was observed in sex and age of the patients, tumor site, histological type, invasion depth, lymph node metastasis, pathological grade or tumor size after CIK cells immunotherapy (0, 1-10, 11-25, and over 25 frequencies). However, a significant difference was found in cancer recurrence and stage after CIK cells immunotherapy (Table 2).
Table 2 Distribution of demographic and clinical characteristics in group II.
The survival time of gastric cancer patients in group II was much longer than that of those in group I (χ2 = 10.907, P = 0.001, Figure 1). The median survival time of patients in group II was also longer than that of those in group I (49 mo vs 27 mo).
Figure 1 Survival rates of patients after cytokine-induced killer cells immunotherapy plus chemotherapy and chemotherapy alone.
CIK: Cytokine-induced killer.
Two- and 5-year survival rates of patients in two groups
The 2- and 5-year survival rates of patients in group II were significantly higher than those of patients in group I (73.5% vs 52.6%, 40.4% vs 23.9%, P <0.05) (Table 3).
Table 3 Two- and five-year survival rates of gastric cancer patients in two groups.
Groups
Survival rate (%)
95% CI
u-value
P
2-yr
Chemotherapy
52.6
41.7-63.6
2.721
0.007
CIK treatment
73.5
63.3-83.7
5-yr
Chemotherapy
23.9
13.5-34.3
1.913
0.0526
CIK treatment
40.4
27.1-53.7
Survival time of patients after CIK cells immunotherapy
Because the CIK cells immunotherapy seemed effective against gastric cancer, whether the frequency of CIK cells immunotherapy affects its efficacy was determined. The survival curve was obviously higher for the patients after CIK cells immunotherapy plus chemotherapy than after chemotherapy alone. The survival time of gastric cancer patients was significantly longer after CIK cells immunotherapy than after chemotherapy (χ2 = 14.534, P = 0.002, Figure 1).
Time-dependent Cox model analysis of CIK cells immunotherapy and prognosis of patients
The frequency of CIK cells immunotherapy was a strong time-dependent variable. A significant difference was observed in the survival time and the frequency of CIK cells immunotherapy between the two models (χ2 = 27.990, P < 0.0001). However, it could not stratify the theoretical hypothesis of proportional hazard model. Hence, we tried to improve the analyzing results of the Cox model by dividing the patients into two stages with a relatively short survival time. Because of the relatively short interval time, the frequency of CIK cells immunotherapy may be a time-independent variable and can satisfy the assumption of proportional hazard model. The median survival time (36 mo) of the patients was used as the optimum cut-point.
In the first stage Cox model, the frequency of CIK cells immunotherapy was not a time-dependent variable, thus refusing the hypothesis of non proportional hazard model by Pearson correlation test between Schoenfeld residual of CIK cells immunotherapy frequency and survival time (r = 0.04, F = 0.10, P = 0.751). After the patients who remained alive beyond 36 mo after treatment were defined as survivors, the frequency of CIK cells immunotherapy was significantly associated with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients, tumor stage and relapse (HR = 0.54, 95% CI: 0.36-0.80) (Table 4).
Table 4 First stage time-dependent multivariate Cox model analysis of cytokine-induced killer cells immunotherapy at different frequencies and prognosis of the patients1,2 (n = 1543).
In the second stage Cox model, the frequency of CIK cells immunotherapy was not a time-dependent variable (r = 0.307, F = 1.98, P = 0.176).When the second stage Cox model involving only 56 patients with a survival time of over 36 mo was fitted, no association was observed between the frequency of CIK cells immunotherapy and the survival time of gastric cancer patients (HR = 1.09, 95% CI: 0.63-0.89) (Table 5).
Table 5 Second stage time-dependent multivariate Cox model analysis of cytokine-induced killer cells immunotherapy at different frequencies and prognosis of patients1,2 (n = 56).
In China, gastric cancer patients are usually diagnosed at a relatively advanced stage with metastasis to other organs[24]. A number of treatment modalities are available for gastric cancer, such as surgical resection combined with chemotherapy[25,26], radiotherapy[27,28], thermotherapy[29,30] and/or traditional Chinese medicine[31,32]. However, the 5-year survival rate of advanced gastric cancer patients is still very poor[33]. It has been shown that cellular immunotherapy can promote host anti-cancer immunity, thus prolonging the survival time of gastric cancer patients[34]. Treatment of gastric cancer with autologous CIK cells is one of the promising cellular immunotherapies[35].
The results of the present study demonstrate that CIK cells immunotherapy plus chemotherapy for gastric cancer has more potential benefits than chemotherapy alone. Therefore, the effect of adjuvant cellular therapies for gastric cancer has drawn more attention of oncologists. It has been shown that adjuvant radiotherapy and chemotherapy for gastric cancer after curative resection can improve the disease-free and overall survival time of gastric cancer patients[25,36]. Residual tumor cells after chemotherapy can be removed by the host immune system[37]. However, several cycles of chemotherapy can decrease the immune functions of gastric cancer patients[38], and have been suspected to be one of the reasons for the high relapse rate of gastric cancer after postoperative systemic chemotherapy. Immunotherapy can directly kill cancer cells and boost the immune responses against the tumor[39]. Therefore, immunotherapy should be beneficial for gastric cancer patients, and not conducive to the growth of tumor cells.
In the present study, CIK cells were obtained upon culturing PBMC in the presence of IFN-γ, IL-2, anti-CD3MAb, and IL-1α[13]. This method allows us to generate a large number of CIK cells. In addition, the anti-tumor cell activity of CIK cells is stronger than that of anti-tumor effector cells[16]. The effector cells in our culture are believed to be CD3+CD56+. CIK cells have a higher survival rate, proliferation capacity, and killing activity than their target cells[40,41], and can secrete a variety of cytokines, which further enhance the cytotoxicity of immune effector cells[42] and change the tumor microenvironment to favor cancer eradication. In addition, CIK cells can kill both autologous and allogeneic tumor cells[43,44], as well as multi-drug resistance cells and FasL-positive cells[45,46]. Accordingly, CIK cells immunotherapy combined with chemotherapy may have a synergistic effect.
Several studies[17,47-49] showed that CIK cells immunotherapy can significantly improve the immune functions of cancer patients, such as an increase in CD3+CD56+ level. However, the clinical data are not enough to demonstrate the effectiveness of CIK cells immunotherapy. The results of this retrospective study, based on the follow-up of 156 gastric cancer patients, show that the frequency of CIK cells immunotherapy can significantly prolong the survival time of gastric cancer patients.
However, the frequency of CIK cells immunotherapy may significantly decrease the risk of cancer-related death in gastric cancer patients. The common Cox model was not preferred in our analysis because the balance test showed that tumor relapse and stage were different in patients of the two groups. There are two reasons that support our conclusion. First, except for tumor relapse and stage, the balance test showed the following factors, including age and sex of the patients, tumor size, site and invasiveness, lymph node metastasis and pathological grade did not affect us to assign the gastric cancer patients into groups I and II. Second, due to the fact that the frequency of CIK cells immunotherapy was a time-dependent variable in the Cox model, a two-stage time-dependent Cox model adjustment was made for some confounding factors (tumor relapse and stage), thus the false results were avoided when the common Cox model was used to make our analysis more reliable.
After the postoperative adjuvant chemotherapy, most residual tumor cells sensitive to chemotherapy were removed. Chemotherapy may suppress the immune function and therefore immunotherapy is necessary for boosting immunity. It was reported that the number of CD3+ cells and the CD4+/CD8+ ratio are significantly lower in most gastric cancer patients than in healthy controls after chemotherapy[17]. In the present study, the number of CD3+ and CD4+ cells was significantly increased, while the number of CD8+ cells was declined and the CD4+/CD8+ ratio was increased after CIK cells immunotherapy, suggesting that CIK cells also have an immune modulating function in addition to their anti-tumor function[50]. Single CIK cells immunotherapy has an in vivo effect against gastric cancer for about one month[51]. In contrast, the number of CD3+ cells and the CD4+/CD8+ ratio maintain at a high level after three cycles of CIK cells immunotherapy[17].
Our study has a few limitations. First, it was a retrospective cohort/observational study rather than a strictly-designed randomized trial. Since the patients were not assigned into CIK cells immunotherapy group and chemotherapy group, imbalance of certain clinical factors between the two groups could not be avoided. Second, there were some unknown potential reasons for choice of treatment regimens, which might affect our conclusion, despite the fact that the balance test was performed and some confounding factors were adjusted in the Cox model. Therefore, a randomized clinical trial is necessary to justify the benefit of CIK cells immunotherapy for gastric cancer. The benefit of radiochemotherapy and S1 chemotherapy for gastric cancers, established in a recent clinical trial[52], is important to determine whether CIK cells immunotherapy provides additional benefit when it is used in combination with radiotherapy and chemotherapy.
In conclusion, more frequencies of CIK cells are necessary for gastric cancer. The survival time of gastric cancer patients is significantly longer after chemotherapy plus CIK cells immunotherapy than after chemotherapy alone.
COMMENTS
Background
Gastric cancer is one of the most common causes of cancer-related death in China. Although standardized surgical resection and numerous adjuvant therapeutic modalities are available for gastric cancer, the postoperative survival rate of advanced stage cancer patients remains very low. In recent years, immune therapy for malignant tumors has become the fourth important tumor treatment modality following surgery, radiotherapy and chemotherapy. Cellular immunotherapy can promote host anti-cancer immunity, thus prolonging the survival time of gastric cancer patients. Treatment with autologous cytokine-induced killer (CIK) cells is one of the promising cellular immunotherapies.
Research frontiers
A number of adoptive cells immunotherapy have been reported, including using lymphokine activated killer cells, tumor infiltrating lymphocytes, and anti-CD3 monoclonal antibody-induced killer cells. However, their therapeutic efficacy is limited due to their low anti-tumor activities. CIK cells, a new type of anti-tumor effector cells, can proliferate rapidly in vitro, with a stronger anti-tumor activity and a broader spectrum of tumor targets than the reported anti-tumor effector cells. Moreover, CIK cells can regulate and enhance immune function.
Innovations and breakthroughs
CIK cells immunotherapy can decrease levels of tumor markers, change immune functions, and achieve a short-term efficacy against gastric cancer. However, the relation between the frequency of CIK cells immunotherapy and its clinical efficacy has not been examined. In the present study, data obtained from 156 gastric cancer patients were used in fitting multivariate Cox model, showing that more frequencies of CIK cells immunotherapy improve the survival rate of gastric cancer patients.
Applications
The survival time of gastric cancer patients was significantly longer after chemotherapy plus CIK cells immunotherapy than after chemotherapy alone, and more frequencies of CIK cells immunotherapy benefited gastric cancer patients more. This strategy can be applied in treatment of gastric cancer.
Terminology
CIK cells are cytokine-induced killer cells and a new type of anti-tumor effector cells, which can proliferate rapidly in vitro with a stronger anti-tumor activity and a broader spectrum of tumor targets than the reported anti-tumor effector cells. Moreover, CIK cells can regulate and enhance immune function.
Peer review
This study showed beneficial effect of CIK cells immunotherapy on gastric cancer, thus improving the 2- and 5-year survival rates of gastric cancer patients. The study is well designed and the data are believable.
Footnotes
Peer reviewer: Ming Li, Associate Professor, Tulane University Health Sciences Center, 1430 Tulane Ave Sl-83, New Orleans, LA 70112, United States
S- Editor Tian L L- Editor Wang XL E- Editor Lin YP
Shang J, Pena AS. Multidisciplinary approach to understand the pathogenesis of gastric cancer.World J Gastroenterol. 2005;11:4131-4139.
[PubMed] [DOI][Cited in This Article: ]
Shen X, Zhang J, Yan Y, Yang Y, Fu G, Pu Y. Analysis and estimates of the attributable risk for environmental and genetic risk factors in gastric cancer in a Chinese population.J Toxicol Environ Health A. 2009;72:759-766.
[PubMed] [DOI][Cited in This Article: ]
Valentini V, Cellini F, Minsky BD, Mattiucci GC, Balducci M, D'Agostino G, D'Angelo E, Dinapoli N, Nicolotti N, Valentini C. Survival after radiotherapy in gastric cancer: systematic review and meta-analysis.Radiother Oncol. 2009;92:176-183.
[PubMed] [DOI][Cited in This Article: ]
Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990.Int J Cancer. 1999;83:18-29.
[PubMed] [DOI][Cited in This Article: ]
Stroncek D, Berlyne D, Fox B, Gee A, Heimfeld S, Lindblad R, Loper K, McKenna D Jr, Rooney C, Sabatino M. Developments in clinical cell therapy.Cytotherapy. 2010;12:425-428.
[PubMed] [DOI][Cited in This Article: ]
Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IG. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC).J Cancer Res Clin Oncol. 2010;Epub ahead of print.
[PubMed] [DOI][Cited in This Article: ]
Rosenberg S. Lymphokine-activated killer cells: a new approach to immunotherapy of cancer.J Natl Cancer Inst. 1985;75:595-603.
[PubMed] [DOI][Cited in This Article: ]
Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.Science. 1986;233:1318-1321.
[PubMed] [DOI][Cited in This Article: ]
Yun YS, Hargrove ME, Ting CC. In vivo antitumor activity of anti-CD3-induced activated killer cells.Cancer Res. 1989;49:4770-4774.
[PubMed] [DOI][Cited in This Article: ]
Takahashi H, Nakada T, Puisieux I. Inhibition of human colon cancer growth by antibody-directed human LAK cells in SCID mice.Science. 1993;259:1460-1463.
[PubMed] [DOI][Cited in This Article: ]
Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity.J Exp Med. 1991;174:139-149.
[PubMed] [DOI][Cited in This Article: ]
Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J. Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res. 2006;26:2237-2242.
[PubMed] [DOI][Cited in This Article: ]
Jiang JT, Wu CP, Shi LR, Xu N, Deng HF, Lu MY, Ji M, Zhu YB, Zhang XG. Side effects during treatment of advanced gastric carcinoma by chemotherapy combined with CIK-cell transfusion in elderly people.Chin J Clin Oncol. 2008;5:79-82.
[PubMed] [DOI][Cited in This Article: ]
Jiang J, Zhu Y, Wu C, Shen Y, Wei W, Chen L, Zheng X, Sun J, Lu B, Zhang X. Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer.Cancer Immunol Immunother. 2010;59:1707-1714.
[PubMed] [DOI][Cited in This Article: ]
Jiang JT, Wu CP, Deng HF, Lu MY, Li M, Wang H, Wu J. Compare cytotoxicity of cytokine-induced killer cells with tumor infiltrating lymphocytes in vitro.Jianyan Yixue. 2005;20:322-324.
[PubMed] [DOI][Cited in This Article: ]
De Vita F, Orditura M, Matano E, Bianco R, Carlomagno C, Infusino S, Damiano V, Simeone E, Diadema MR, Lieto E. A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients.Br J Cancer. 2005;92:1644-1649.
[PubMed] [DOI][Cited in This Article: ]
Schoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint.Biometrics. 1982;38:163-170.
[PubMed] [DOI][Cited in This Article: ]
Chen L, Tian H, Chen J, He ZG, Tao SF, Lokesh G, Peng SY. Surgical management of gastric stump cancer: a report of 37 cases.J Zhejiang Univ Sci B. 2005;6:38-42.
[PubMed] [DOI][Cited in This Article: ]
Kollmannsberger C, Budach W, Stahl M, Schleucher N, Hehr T, Wilke H, Schleicher J, Vanhoefer U, Jehle EC, Oechsle K. Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO.Ann Oncol. 2005;16:1326-1333.
[PubMed] [DOI][Cited in This Article: ]
Lin WL, Li DG, Chen Q, Lu HM. Clinical and experimental study of oxaliplatin in treating human gastric carcinoma.World J Gastroenterol. 2004;10:2911-2915.
[PubMed] [DOI][Cited in This Article: ]
Abe M, Nishimura Y, Shibamoto Y. Intraoperative radiation therapy for gastric cancer.World J Surg. 1995;19:544-547.
[PubMed] [DOI][Cited in This Article: ]
Klautke G, Foitzik T, Ludwig K, Ketterer P, Klar E, Fietkau R. Neoadjuvant radiochemotherapy in locally advanced gastric carcinoma.Strahlenther Onkol. 2004;180:695-700.
[PubMed] [DOI][Cited in This Article: ]
Zuo Y, Xu M, Shen D, Lu WD, Lu JF. [Postoperative intraperitioneal hyperthermic chemoperfusion combined with intravenous chemotherapy for 82 advanced gastric cancer patients].Zhonghua Zhongliu Zazhi. 2004;26:247-249.
[PubMed] [DOI][Cited in This Article: ]
Bozzetti F, Vaglini M, Deraco M. Intraperitoneal hyperthermic chemotherapy in gastric cancer: rationale for a new approach.Tumori. 1998;84:483-488.
[PubMed] [DOI][Cited in This Article: ]
Yu QS, Zhang FZ, Tang XR. [Clinical study on early use of Chinese medicinal herbs and chemotherapy after operation of gastric cancer].Zhongguo Zhongxiyi Jiehe Zazhi. 1995;15:459-461.
[PubMed] [DOI][Cited in This Article: ]
Wang GT. [Treatment of operated late gastric carcinoma with prescription of strengthening the patient's resistance and dispelling the invading evil in combination with chemotherapy: follow-up study of 158 patients and experimental study in animals].Zhongxiyi Jiehe Zazhi. 1990;10:712-716, 707.
[PubMed] [DOI][Cited in This Article: ]
Yamaguchi K, Shimamura T, Hyodo I, Koizumi W, Doi T, Narahara H, Komatsu Y, Kato T, Saitoh S, Akiya T. Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer.Br J Cancer. 2006;94:1803-1808.
[PubMed] [DOI][Cited in This Article: ]
Margolin KA, Negrin RS, Wong KK, Chatterjee S, Wright C, Forman SJ. Cellular immunotherapy and autologous transplantation for hematologic malignancy.Immunol Rev. 1997;157:231-240.
[PubMed] [DOI][Cited in This Article: ]
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.N Engl J Med. 2001;345:725-730.
[PubMed] [DOI][Cited in This Article: ]
Haynes NM, van der Most RG, Lake RA, Smyth MJ. Immunogenic anti-cancer chemotherapy as an emerging concept.Curr Opin Immunol. 2008;20:545-557.
[PubMed] [DOI][Cited in This Article: ]
Wu K, Nie Y, Guo C, Chen Y, Ding J, Fan D. Molecular basis of therapeutic approaches to gastric cancer.J Gastroenterol Hepatol. 2009;24:37-41.
[PubMed] [DOI][Cited in This Article: ]
Larmonier N, Fraszczak J, Lakomy D, Bonnotte B, Katsanis E. Killer dendritic cells and their potential for cancer immunotherapy.Cancer Immunol Immunother. 2010;59:1-11.
[PubMed] [DOI][Cited in This Article: ]
Lu PH, Negrin RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency.J Immunol. 1994;153:1687-1696.
[PubMed] [DOI][Cited in This Article: ]
Gritzapis AD, Dimitroulopoulos D, Paraskevas E, Baxevanis CN, Papamichail M. Large-scale expansion of CD3(+)CD56(+) lymphocytes capable of lysing autologous tumor cells with cytokine-rich supernatants.Cancer Immunol Immunother. 2002;51:440-448.
[PubMed] [DOI][Cited in This Article: ]
Johnson BE, Bridges JD, Sobczeck M, Gray J, Linnoila RI, Gazdar AF, Hankins L, Steinberg SM, Edison M, Frame JN. Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine.J Clin Oncol. 1996;14:806-813.
[PubMed] [DOI][Cited in This Article: ]
Scheffold C, Brandt K, Johnston V, Lefterova P, Degen B, Schöntube M, Huhn D, Neubauer A, Schmidt-Wolf IG. Potential of autologous immunologic effector cells for bone marrow purging in patients with chronic myeloid leukemia.Bone Marrow Transplant. 1995;15:33-39.
[PubMed] [DOI][Cited in This Article: ]
Verneris MR, Kornacker M, Mailänder V, Negrin RS. Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis.Cancer Immunol Immunother. 2000;49:335-345.
[PubMed] [DOI][Cited in This Article: ]
Chen FX, Liu JQ, Zhang NZ, Gong XJ, Zhang GL, Xu YM, Zhou ZH, Wang T, Huang J. [Clinical observation on adoptive immunotherapy with autologous cytokine-induced killer cells for advanced malignant tumor].Ai Zheng. 2002;21:797-801.
[PubMed] [DOI][Cited in This Article: ]
Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer.Anticancer Res. 2008;28:3997-4002.
[PubMed] [DOI][Cited in This Article: ]
Olioso P, Giancola R, Di Riti M, Contento A, Accorsi P, Iacone A. Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial.Hematol Oncol. 2009;27:130-139.
[PubMed] [DOI][Cited in This Article: ]
Kim HM, Lim J, Yoon YD, Ahn JM, Kang JS, Lee K, Park SK, Jeong YJ, Kim JM, Han G. Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma.Int Immunopharmacol. 2007;7:1793-1801.
[PubMed] [DOI][Cited in This Article: ]
Cho MY, Joh YG, Kim NR, Jung SI, Bae JW, Kim YC, Koo BH, Whang CW, Suh SO. T-lymphocyte subsets in patients with AJCC stage III gastric cancer during postoperative adjuvant chemotherapy. American Joint Committee on Cancer.Scand J Surg. 2002;91:172-177.
[PubMed] [DOI][Cited in This Article: ]
