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10.1038%2Fbjc.2014.162
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materials and methods
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All patients with GBM received radiotherapy and chemotherapy postoperatively according to the Stupp protocol (Stupp et al, >>2005<<).
n3:mentions
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Tumour progression and pseudoprogression were defined according to RANO criteria (Brandsma and van den Bent (>>2009<<)). In the case that the MRI changes were equivocal, the therapy was continued observing the patient closely, and MRI was repeated every 4 week. Confirming the progress in a 4-week control MRI, the initial MRI was considered as a
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Tissue microarrays were constructed using 284 glioma clinical samples and analysed by immunohistochemical staining as we previously described (Han et al, >>2013<<). Briefly, tissue microarrays were constructed with tissue microarrayer (Beecher Instruments, Silver Springs, MD, USA).
n3:mentions
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The average of CD4+, FoxP3+ and CD8+ TIL counts per field for each patient was used for statistical analysis (Sato et al, >>2005<<).
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Methylation-specific PCR was performed as described previously (Esteller et al, >>1999<<) to detect O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation in the 90 GBMs.
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results
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This finding is consistent with previous studies that pseudoprogression is significantly correlated with MGMT status and effect of treatment (Brandes et al, >>2008<<).
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discussion
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Surgery and postoperative radiotherapy plus chemotherapy according to the Stupp protocol have improved the survival of patients with GBM; however, the outcome of most glioma patients remains poor (Stupp et al, >>2005<<). Therefore, additional therapies, including immunotherapy, are currently under intensive investigation.
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The analysis of immunological parameters at the tumour site, especially TILs, is important for the development of successful immunotherapy (Sato et al, >>2005<<). Although the brain is an immunologically privileged organ, lymphocytic infiltration into gliomas has been documented in large patient series (Brooks et al, 1978; Palma et al, 1978). However, in glioma, whether these TILs contribute to
n3:mentions
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Although the brain is an immunologically privileged organ, lymphocytic infiltration into gliomas has been documented in large patient series (Brooks et al, >>1978<<; Palma et al, 1978).
n3:mentions
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Although the brain is an immunologically privileged organ, lymphocytic infiltration into gliomas has been documented in large patient series (Brooks et al, 1978; Palma et al, >>1978<<). However, in glioma, whether these TILs contribute to host immunosurveillance (Smyth et al, 2006) and patients' reaction to combined therapy, or whether they participate in tumour-specific immuno-suppression and cancer immunoediting
n3:mentions
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However, in glioma, whether these TILs contribute to host immunosurveillance (Smyth et al, >>2006<<) and patients' reaction to combined therapy, or whether they participate in tumour-specific immuno-suppression and cancer immunoediting (Dunn et al, 2002, 2004) is generally unclear.
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glioma, whether these TILs contribute to host immunosurveillance (Smyth et al, 2006) and patients' reaction to combined therapy, or whether they participate in tumour-specific immuno-suppression and cancer immunoediting (Dunn et al, >>2002<<, 2004) is generally unclear. The infiltration of lymphocytes and the prognostic value of TILs may partly indicate their role in glioma tissues.
n3:mentions
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whether these TILs contribute to host immunosurveillance (Smyth et al, 2006) and patients' reaction to combined therapy, or whether they participate in tumour-specific immuno-suppression and cancer immunoediting (Dunn et al, 2002, >>2004<<) is generally unclear. The infiltration of lymphocytes and the prognostic value of TILs may partly indicate their role in glioma tissues.
n3:mentions
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have higher levels of CD4+ TILs than low-grade gliomas, which in combination with decreased levels of CD8+ TILs indicate a decreased CD8+/CD4+ ratio in high-grade glioma patients, consistent with the results reported by Yu et al (>>2003<<). Waziri et al (2008) reported that most of the CD4+ TILs present in glioblastoma suppress the cellular immune response.
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Waziri et al (>>2008<<) reported that most of the CD4+ TILs present in glioblastoma suppress the cellular immune response.
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Previous studies have reported that CD8+ TILs have favourable effects on the survival of patients with breast cancer (Mahmoud et al, >>2011<<), ovarian cancer (Sato et al, 2005) and colorectal cancer (Galon et al, 2006; Pages et al, 2009).
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Previous studies have reported that CD8+ TILs have favourable effects on the survival of patients with breast cancer (Mahmoud et al, 2011), ovarian cancer (Sato et al, >>2005<<) and colorectal cancer (Galon et al, 2006; Pages et al, 2009).
n3:mentions
n2:16344461
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Previous studies have reported that CD8+ TILs have favourable effects on the survival of patients with breast cancer (Mahmoud et al, 2011), ovarian cancer (Sato et al, 2005) and colorectal cancer (Galon et al, >>2006<<; Pages et al, 2009).
n3:mentions
n2:17008531
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Previous studies have reported that CD8+ TILs have favourable effects on the survival of patients with breast cancer (Mahmoud et al, 2011), ovarian cancer (Sato et al, 2005) and colorectal cancer (Galon et al, 2006; Pages et al, >>2009<<). However, in the present study, we showed that the number of CD8+ TILs alone cannot effectively predict patient outcome in GBM.
n3:mentions
n2:19858404
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Consistent with our results, Kim et al (>>2012<<) reported that CD8+ TILs were not an independent predictor in an analysis of 61 glioblastomas .
n3:mentions
n2:21707245
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The lower total number of TILs in glioma (Table 2) than in other tumours such as breast cancer (Mahmoud et al, >>2011<<) and ovarian cancer (Sato et al, 2005) could be related to the blood–brain barrier or the specific local microenvironment, which requires further research.
n3:mentions
n2:21483002
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The lower total number of TILs in glioma (Table 2) than in other tumours such as breast cancer (Mahmoud et al, 2011) and ovarian cancer (Sato et al, >>2005<<) could be related to the blood–brain barrier or the specific local microenvironment, which requires further research.
n3:mentions
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Without adequate CD4+ T-cell help, CD8+ T cells frequently fail to fully function in vivo (Bos and Sherman, >>2010<<; Bos et al, 2012).
n3:mentions
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Without adequate CD4+ T-cell help, CD8+ T cells frequently fail to fully function in vivo (Bos and Sherman, 2010; Bos et al, >>2012<<). CD4+ helper T cells have been associated with better survival in breast cancer (Gu-Trantien et al, 2013) and in other malignancies. On the other hand, CD4+ Tregs can dampen anti-tumour immunity and promote tumour progression (Ruffell et
n3:mentions
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CD4+ helper T cells have been associated with better survival in breast cancer (Gu-Trantien et al, >>2013<<) and in other malignancies.
n3:mentions
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On the other hand, CD4+ Tregs can dampen anti-tumour immunity and promote tumour progression (Ruffell et al, >>2010<<; Zamarron and Chen, 2011).
n3:mentions
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On the other hand, CD4+ Tregs can dampen anti-tumour immunity and promote tumour progression (Ruffell et al, 2010; Zamarron and Chen, >>2011<<). Tregs are unfavourable prognostic markers in patients with breast cancer (Gobert et al, 2009), hepatocellular carcinoma (Gao et al, 2007) and pancreatic cancer (Hiraoka et al, 2006). In the present study, the overall fraction of CD4+
n3:mentions
n2:21647333
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Tregs are unfavourable prognostic markers in patients with breast cancer (Gobert et al, >>2009<<), hepatocellular carcinoma (Gao et al, 2007) and pancreatic cancer (Hiraoka et al, 2006).
n3:mentions
n2:19244125
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Tregs are unfavourable prognostic markers in patients with breast cancer (Gobert et al, 2009), hepatocellular carcinoma (Gao et al, >>2007<<) and pancreatic cancer (Hiraoka et al, 2006).
n3:mentions
n2:17577038
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Tregs are unfavourable prognostic markers in patients with breast cancer (Gobert et al, 2009), hepatocellular carcinoma (Gao et al, 2007) and pancreatic cancer (Hiraoka et al, >>2006<<). In the present study, the overall fraction of CD4+ TILs had no significant prognostic value, which could be associated with the complexity of its components.
n3:mentions
n2:17000676
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FoxP3+ TILs were only found in glioblastomas, but not in low-grade astrocytomas and oligodendroglial tumours, which is consistent with previous studies (Heimberger et al, >>2008<<; Lohr et al, 2011).
n3:mentions
n2:18698034
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FoxP3+ TILs were only found in glioblastomas, but not in low-grade astrocytomas and oligodendroglial tumours, which is consistent with previous studies (Heimberger et al, 2008; Lohr et al, >>2011<<). However, we did not find that the level of FoxP3+ TILs was an independent prognostic factor for survival. Our study indicates that the level of FoxP3+ TILs is low in glioma as a whole, which may influence the prognostic value of FoxP3+
n3:mentions
n2:21478334
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Consistently, Lohr et al (>>2011<<) reported that FoxP3+ Tregs were infrequently present and not associated with GBM patient outcome.
n3:mentions
n2:21478334
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CD8+/CD4+ TIL ratios have been associated with the prognosis of ovarian cancer patients (Sato et al, >>2005<<). Similarly, our results showed that high CD4+ TIL levels in combination with low CD8+ TIL levels was independently associated with shorter PFS and OS in GBM. In glioma patients, high CD4+ TIL levels with low CD8+ TIL levels may indicate
n3:mentions
n2:16344461
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Similarly, Perrin et al (>>1999<<) reported that the ultimate failure of the immune system with adequate CD8+ TILs to control high-grade glioma growth could be the consequence of a deficient CD4+ helper T-cell component of the response.
n3:mentions
n2:10421791
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gliomas have multiple mechanisms of mediating immunosuppression other than Tregs, such as immunosuppressive cytokines, antigen loss, T-cell apoptosis and induction of anergy by tumour antigen-presenting cells (Heimberger et al, >>2008<<). In addition, besides FoxP3+ TILs, other subtypes of CD4+ TILs may exert a powerful regulatory or suppressive influence upon CD8+ TILs.
n3:mentions
n2:18698034
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For example, Waziri et al (>>2008<<) reported that a significant proportion of TILs within GBM were CD4+CD56+ immunosuppressive T cells, whereas Tregs demonstrated only a modest proportional increase within GBM.
n3:mentions
n2:18490770
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Although the underlying mechanism is unclear, pseudoprogression may have a clinical impact on radiochemotherapy-treated GBM (Brandes et al, >>2008<<). Interestingly, pseudoprogression was frequently found in patients with high CD4+ TILs and high CD8+ TILs, which indicates that immune or inflammatory factors may be involved in the formation of pseudoprogression after combined therapy.
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