- Department of Neurosurgery, University Hospital of Bonn, Sigmund-Freud-Strasse 25, 53105, Germany
- Department of Neurosurgery, University Hospital of Ioannina, 45500, Greece
- Department of Haematology, University Hospital of Ioannina, 45500, Greece
- Department of Rheumatology, University Hospital of Ioannina, 45500, Greece
- Department of Neurology, University Hospital of Ioannina, 45500, Greece
- Department of Psychiatry, Landschaftsverband Rheinland Klinik, Kaiser-Karl-Ring 20, Bonn, 53111, Germany
Department of Psychiatry, Landschaftsverband Rheinland Klinik, Kaiser-Karl-Ring 20, Bonn, 53111, Germany
DOI:10.4103/2152-7806.134104Copyright: © 2014 Gousias K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Gousias K, Voulgaris S, Vartholomatos G, Voulgari P, Kyritsis AP, Markou M. Prognostic value of the preoperative immunological profile in patients with glioblastoma. Surg Neurol Int 07-Jun-2014;5:89
How to cite this URL: Gousias K, Voulgaris S, Vartholomatos G, Voulgari P, Kyritsis AP, Markou M. Prognostic value of the preoperative immunological profile in patients with glioblastoma. Surg Neurol Int 07-Jun-2014;5:89. Available from: http://sni.wpengine.com/surgicalint_articles/prognostic-value-of-the-preoperative-immunological-profile-in-patients-with-glioblastoma/
Background:Aim of our study was to determine the predictive impact of certain serum immunological markers on overall survival (OS) in patients with glioblastoma multiforme (GBM).
Methods:We assayed prospectively values of interleukin 2 (IL-2), immunoglobulin G (IgG), C4, CD3+, CD4+ and CD8+ cells via flow cytometry, enzyme-linked immunosorbent assay (ELISA) and radial immunodiffusion in preoperative sera of adult patients with de novo histologically confirmed supratentorial GBM. Kaplan-Meier method and Cox proportional hazards models were used to assess clinical, laboratory, and treatment prognostic factors for OS.
Results:Twenty-six consecutive patients were identified with a mean age of 59.6 years. Median follow up was 12 months. Lower IL-2 values (P = 0.029) und CD4+ counts (P P = 0.011). Further independent prognostic factors for OS were type of resection (resection vs. biopsy) and administration of radiotherapy (yes/no).
Conclusion:Preoperative values IL-2 and CD4+ cells in sera may carry a prognostic impact. Novel diagnostic models prior to histopathological confirmation may be used to predict prognosis of patients with GBM. Future studies should investigate whether targeting immune factors, such as CD4+ and IL-2, may improve the prognosis of patients with GBM.
Keywords: CD4+ cells, glioblastoma multiforme, IL-2, overall survival, serum
Several studies have been focused on the immunity of glioma, in order to investigate its poor prognosis and to potentially include immunotherapy in its treatment.[
To date, a variety of clinical and treatment parameters have been identified as beneficial prognostic factors for survival in patients with GBM, such as younger age, higher Karnofsky score (KPS), aggressive degree of resection, administration of adjuvant chemotherapy, and radiotherapy.[
In order to further improve the prognosis of patients with GBM, some novel potential alterable prognostic factors are required. Suitable candidates may be some of the immune parameters of the sera, since they may be easily influenced (i.e. antagonized/substituted/stimulated). To the best of our knowledge, except for the counts of CD4+ cells,[
We prospectively examined preoperative fasting morning sera from patients with subsequently histologically confirmed de novo supratentorial GBM, operated at the Department of Neurosurgery of the University Hospital of Ioannina between June 1, 2005 and January 31, 2008. Twenty-six patients fit our inclusion criteria (age over 18 years, no previous history of brain tumor, immunological or hematological disease and no previous administration of steroids or antiepileptic drugs for more than 3 days) Median follow up was estimated at 12 months. Mean age was 59.6 years (range 20-78). A total of 18 (69.2%) patients demonstrated preoperative KPS ≥70%. Postoperative KPS ≥70% (see below) was seen in 17 (65.3%) patients. A positive history of epilepsy was present in nine (34.1%) patients. A frontal location of the tumor was seen in 9 (34.1%) cases, whereas the preoperative maximal tumor diameter was over 4 cm in 10 (38.4%) patients [
The following clinical and treatment parameters were studied as potential prognostic factors; age, gender, tumor location, preoperative maximal tumor diameter and KPS, short-term functional outcome as reflected by KPS at discharge, history of epilepsy, type of resection, temozolomide (TMZ) chemotherapy, and radiotherapy. In addition, we preoperatively evaluated values of immunological parameters, which differ among WHO grades,[
The methods applied in our study have been previously described.[
The statistical analyses of the clinical and laboratory data were performed using commercially available software (SSPS version 21.0, IBM Deutschland, Ehningen, Germany) and standard procedures (Fisher's exact test, Cox regression analysis, Kaplan–Meier estimates) were followed. The immunological markers were treated as dichotomized variables with the respective median value as the cut-off. P ≤ 0.05 were considered to be statistically significant.
OS was defined as the time upon surgery (resection or biopsy) to death or censored at the date of last follow up. The patients’ samples and clinical data were collected after their informed consent was obtained in accordance with the tenets of the declaration of Helsinki, and after approval of the study by the Ethics Committee of the Medical Faculty of the University of Ioannina.
Median OS was estimated at 343 days (95% CI 255-431). Surgical resection (gross total or partial resection) was performed in 21 (80.7%) cases, whereas 5 cases (19.3%) had an open or stereotactic biopsy. The standard therapy for our patients consisted of combined radiotherapy (total dose 64 Gy) with TMZ followed by monthly TMZ courses up to 6 cycles or until recurrence.[
Age under 60 (P = 0.011), resection vs. biopsy (P = 0.002), TMZ chemotherapy (P = 0.005) and radiotherapy (P = 0.001) were identified as beneficial prognostic factors of OS in the univariate analysis (Log rank test). Preoperative KPS ≥ 70% (P = 0.089), female gender (P = 0.058) were recognized as trends for prolonged OS [
We used cross tabulation (Fisher's exact test) to investigate potential relations of IL-2 and CD4+ values to other clinical and treatment factors. No differences between the studied subgroups of IL-2 (<7.97 pg/ml vs. ≥7.97 pg/ml) were seen with respect to age, gender, history of epilepsy, location of tumor, preoperative and postoperative KPS, preoperative maximal tumor diameter, type of resection and administration of chemo- and radiotherapy. Similarly, the subgroups of CD4+ cells (<200 cells/μl vs. ≥200 cells/μl) were comparable regarding the clinical parameters. Interestingly, CD4+ counts did not even correlate with preoperative and postoperative KPS. A trend for correlation with preoperative maximal tumor diameter over 4 cm (P = 0.081) was found. Positive relations were found to TMZ chemotherapy (P = 0.006), whereas radiotherapy and type of resection did not correlate with CD4+ counts.
Additional support for the prognostic value of the immune parameters in patients with GBM is given by the multivariate analysis. The Cox proportional hazard models (Backward stepwise procedure) identified CD4+ counts (<200 cells/μl vs. ≥200 cells/μl; HR = 0.010, 95% CI 0.001-0.226, P = 0.011), type of resection (biopsy vs. surgical resection: HR = 0.494, 95% CI 0.264-0.924, P = 0.027) and administration of radiotherapy (no/yes: HR = 0.040, 95% CI 0.004-0.440, P = 0.009) as independent prognostic factors of OS [
Despite recent advances in diagnostic and therapy, the prognosis of patients with GBM still remains poor. The knowledge of clinical and molecular prognostic factors for these patients may recognize patients with a presumably better prognosis and therefore may permit the individualized therapy but may not improve dramatically the patients’ prognosis. This may rely on the fact that these factors are inalterable, that is, the attendant physician cannot alter for instance the age or gender of the patient as well as the MGMT/IDH1 status of the tumor.
Novel prognostic markers, which values and function may be altered in favor of the patient during adjuvant therapy, are needed in order to further affect his outcome. Some of the immunological parameters may act indeed as such prognostic markers, since they could be depleted or stimulated during the patients’ therapy.[
We have previously reported various immunological markers in sera, which differ among patients harboring high and low grade gliomas. Preoperative values of IL-2 and CD4+ were estimated as independent predictors of WHO grade. Lower values of CD4+ cells and IL-2 have been associated with a greater WHO histological grade.[
Reduced values of the proinflammatory cytokine IL-2 in patients with GBM have been well documented in the literature.[
In our series of 26 patients with GBM, also CD4+ values have been identified as prognosticators of survival. Patients with CD4+ counts <200 cells/μl showed significant shorter OS (P < 0.001) than the remaining patients. In principle, the current study validated our previous reported results.[
In summary, preoperative CD4+ cell counts may serve as diagnostic and prognostic markers for patients with GBM. However, not only the quantity but also more importantly the quality of the T cell subpopulations may reflect the immunocompetence of the patients.[
The prognostic relevance of a significant aspect of the gliomas immunity, such as the family of microglia/macrophages has not been evaluated in the present study. These cells comprise the largest population of the tumor infiltrating cells within the glioma tissue. A shift from M1 (active/cytotoxic/proinflammatory phenotype)[
Of note, our prospective study is susceptible to some limitations. We should concede that our limited population may not allow for far-reaching conclusions. However, our survival analysis also identified, similar to larger series, the same known prognostic factors, that is, age, type of resection, and administration of radiotherapy [
In conclusion, our results demonstrated that preoperative values of certain immune parameters in sera may carry a prognostic impact. Novel diagnostic models prior to histopathological confirmation may be used to predict prognosis of patients with GBM. Future studies should investigate whether targeting immune biomarkers, such as CD4+ and IL-2, may improve the prognosis of patients with GBM.
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