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Ishikawa T.,Kyoto Prefectural University of Medicine | Kokura S.,Kyoto Prefectural University of Medicine | Sakamoto N.,Iseikai Hyakumanben Clinic | Okajima M.,Kyoto Prefectural University of Medicine | And 15 more authors.
Clinical Biochemistry | Year: 2012

Objective: To investigate the relation between functional impairments of cancer patients and circulating cytokines using a multiplex technique. Design and methods: 50 patients with cancer were assessed using the quality of life (QOL) questionnaire. 27 plasma cytokine levels were determined by using the Bio-Plex array system. The relation to QOL scores was assessed using Chi-square test for categorical variables and univariate linear regression analysis for cytokine levels. Results: Multivariate analysis showed that interleukin-6 (IL-6) level is a significant independent determinant of physical (β = - 0.238, P = 0.0126) and cognitive functioning (β = - 0.462, P = 0.0006) and that vascular endothelial growth factor (VEGF) level is a significant independent determinant of emotional functioning (β = - 0.414, P = 0.039). Conclusion: This study, in which 27 cytokines are simultaneously tested with cutting edge technology, demonstrates that plasma IL-6 and VEGF are significant independent determinants of functional impairments in patients with cancer. © 2011 Elsevier B.V.. Source


Ishikawa T.,Kyoto Prefectural University of Medicine | Kokura S.,Kyoto Prefectural University of Medicine | Sakamoto N.,Iseikai Hyakumanben Clinic | Okayama T.,Kyoto Prefectural University of Medicine | And 15 more authors.
International Journal of Cancer | Year: 2013

A core challenge in administering immune-based treatments for cancer is the establishment of easily accessible immunological assays that can predict patients' clinical responses to immunotherapy. In this study, our aim was to predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer. To do this, we evaluated whole blood cytokine levels and peripheral regulatory T cells (Tregs) in 46 patients with unresectable or recurrent pancreatic cancer who received adoptive T-cell therapy at 2-week intervals. To test immune function, venous blood was obtained from patients before the start of therapy and 2 weeks after the 4th treatment. Whole blood interferon (IFN)-α levels (after stimulation with the Sendai virus) were evaluated, as well as the levels of 9 cytokines stimulated with phytohemagglutinin [interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, tumor necrosis factor-α, IFN-γ, and granulocyte-monocyte colony-stimulating factor]. Peripheral Tregs were analyzed by flow cytometry. Using the obtained data, we then observed the relationship between these immunological parameters and clinical outcome of patients. We found that the whole blood production of IFN-γ, IL-2, IL-4, IL-5 and IL-13 significantly increased after adoptive T-cell therapy, whereas the number of peripheral Tregs did not change. Multivariate Cox proportional hazards analyses indicated that the number of peripheral Tregs before receiving adoptive T-cell therapy and the change in IFN-γ levels after adoptive T-cell therapy were independent variables predicting overall survival. The findings of this study indicate that the assay of whole blood IFN-γ production offers promise for evaluating the clinical response of patients to cancer immunotherapy. What's new? The study addresses a critical challenge in immune-based treatments of cancers: finding an easily accessible blood test that can predict a patient's responsiveness to treatment. The authors tested various cytokine and T cell parameters in patients afflicted with pancreatic cancer after receiving adoptive T cell therapy. They find that changes in whole blood interferon-gamma (IFN-γ) levels were independent variables predicting overall survival. Although a whole blood IFN-γ assay is considered a "nonspecific" immunological test, it faithfully reflected the patients' actual immune responses and should be especially valuable in situations where the relevant target antigen of the adoptively transferred T cells is not known. By combining measurements of whole blood IFN-γ with antigen-specific immunological assays, the authors hope to even better predict clinical outcome in cancer immunotherapy. Copyright © 2013 UICC. Source


Ishikawa T.,Kyoto Prefectural University of Medicine | Kokura S.,Kyoto Prefectural University of Medicine | Sakamoto N.,Iseikai Hyakumanben Clinic | Matsumoto S.,Kyoto Prefectural University of Medicine | And 11 more authors.
Experimental and Therapeutic Medicine | Year: 2011

It remains to be clarified whether adoptive cellular therapy (ACT) in patients with advanced cancer, in whom strong immunosuppression and immune-escape mechanisms are established, has the potential to alter cytokine secretion from blood cells and affect the number of regulatory T cells (Tregs). In this study, the secretion of cytokines from peripheral blood cells and the number of peripheral blood Tregs were analyzed before and after ACT. Blood samples were collected from 109 consecutive cancer patients who received ACT, which consisted of anti-CD3 stimulated lymphokine-activated killer cells. For testing immune function, venous blood was obtained from patients before the start of therapy and after they had received 4 cycles of ACT. Of the 109 patients, 76 received ACT four times or more. All 109 blood samples at baseline and 76 follow-up samples were available. The secretion ability of various cytokines from peripheral blood cells was measured, as well as the number of peripheral blood Tregs. We found that the secretion ability of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was enhanced significantly after treatment, while the number of Tregs and the ratio of Treg to CD4 was significantly decreased. Overall survival in patients with increased IFN-γ and TNF-α secretion after ACT was significantly longer. These findings suggest a potential therapeutic role for ACT in cancer immunotherapy. Source


Matsumoto T.,Kyoto Prefectural University of Medicine | Kokura S.,Kyoto Prefectural University of Medicine | Ishikawa T.,Kyoto Prefectural University of Medicine | Funaki J.,Kyoto Prefectural University of Medicine | And 11 more authors.
Oncology Research | Year: 2012

We examined the effects of adoptive T-cell transfer (ACT) on the population of regulatory T cells (Tregs) in a mouse colorectal cancer transplant model. In an in vivo study, Treg populations in Balb/c mice colon26 transplant model after ACT were analyzed in peripheral blood, local lymph node, and tumor. In an in vitro study CD4 + cells were cultured in medium containing TGF-β to induce Tregs. LAK cells were added or not in this Treg induction system. Treg induction after coculture with LAK was investigated. We also studied the role of IFN-γ in the mechanism of Treg induction. Tregs in the draining lymph nodes and tumor were significantly suppressed by ACT. The induction of Tregs in vitro was inhibited by coculture with LAK cells. Furthermore, Tregs in the cultured cells were significantly inhibited by addition of exogenous IFN-γ. Moreover, Tregs were increased by addition of IFN-γ mAb. ACT may decrease Tregs in tumor-bearing hosts. One of the mechanisms is considered to be IFN-γ inhibiting the induction of Tregs. Copyright © 2012 Cognizant Comm. Corp. Source

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