|Year : 2016 | Volume
| Issue : 1 | Page : 259-266
Diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain
Yu-Fang Wang, Bo Hou, Su-Jun Yang, Xiao-Rui Zhang, Xiaolei Dong, Min Zhang, Gen-Dong Yao
CT Scan Room, Han Dan Central Hospital, Han Dan, China
|Date of Web Publication||13-Apr-2016|
CT Scan Room, Han Dan Central Hospital, Zhonghua Nan Avenue No. 25, Han Dan-056 001
Source of Support: None, Conflict of Interest: None
Background: The objective of the current meta.analysis was to assess the arterial spin labeling. (ASL) perfusion imaging measurement of cerebral blood flow. (CBF) in patients with brain tumors, and assessing preoperative tumor grade in brain.
Materials and Methods: PubMed, Web of Science, Embase, China BioMedicine (CBM), CINAHL, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were chosen to evaluate the associations between ASL and brain cancer. Two reviewers separately evaluated the quality of the included trials. Standardized mean difference (SMD) at 95% confidence interval (95% CI) was also calculated.
Results: Finally, 475 patients were enrolled into this meta-analysis from 12 eligible studies and were selected for statistical analysis. Results showed that relative tumor blood flow (rTBF) and relative cerebral blood flow (rCBF) in high-grade brain cancer patients were faster than those in low-grade brain cancer patients. Subgroup analysis stratified by country implied that ASL may be the main prediction of increased rTBF in high-grade brain cancer patients among USA, Korea and China; and rCBF was faster in high-grade brain cancer using ASL in USA and China. Further reference by tissue-stratified analysis revealed a positive association of rTBF with high-grade brain cancer by utilization of ASL in all the experimental subgroups, while rCBF was only correlated in white subgroups.
Conclusion: These results showed that rTBF and rCBF were faster in high-grade brain cancer patients, suggesting that ASL may provide suitable measurement for the differential diagnosis of tumor grade in brain.
Keywords: Arterial spin labeling, brain tumor, meta-analysis, relative cerebral blood flow, relative tumor blood flow
|How to cite this article:|
Wang YF, Hou B, Yang SJ, Zhang XR, Dong X, Zhang M, Yao GD. Diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain. J Can Res Ther 2016;12:259-66
|How to cite this URL:|
Wang YF, Hou B, Yang SJ, Zhang XR, Dong X, Zhang M, Yao GD. Diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain. J Can Res Ther [serial online] 2016 [cited 2019 Nov 20];12:259-66. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/259/155978
| > Introduction|| |
A brain tumor, an intracranial solid neoplasm, is described as the abnormal growth of cells within the brain or the central spinal canal. Brain tumor is indicated to be the most common solid tumor in children causing a significant morbidity and mortality and posing great health and economic burden to the society and the patients. The most common benign tumor in adults is meningioma and the most common malignant tumor is glioblastoma; malignant brain tumors are considered rare for they merely account for 1 percent to 2 percent of all cancers in adults. Primary malignant brain tumors, which are diagnosed in clinic include lymphomas and high-grade gliomas like anaplastic astrocytomas (AAs) and glioblastoma multiformes (GBMs). In America, the incidence of brain tumors both of benign and malignant tumors is approximately 18.71 per 100,000 person each year; 11.52 and 7.19 per 100,000 person-years for benign tumors and malignant tumors, respectively. However, genetic syndromes and ionizing radiation exposure to the head or neck are the only two recognized risk factors that have involved in the mechanism of brain carcinoma up to now. Ahead of designing the optimal treatment plan for a patient, differentiating the high-grade gliomas from brain tumor in other morphologies is indispensible with an adoptable optimal imaging technique. In the attempt to overcome the dilemma for rather accurately assessing the cancer progression, arterial spin labeling (ASL) has sprung up as a novel and effective radiation therapy in recent years.,
ASL is a functional magnetic resonance imaging (MRI) method for quantifying the cerebral blood flow (CBF) which is completely non-invasive, non-ionizing and continually evolving. The term perfusion, the blood delivered to the capillary beds and the interstitial spaces of brain, is quantified by the quantity of the blood in per unit time, per unit volume or mass of tissue, delivered to the tissue. It is an essential physiological parameter in determining both of the maximum delivery rate of oxygen and nutrients at the capillary level and the rate of waste products clearance. Perfusion quantification with ASL is carried out by inverting the longitudinal magnetization of arterial blood flowing into the tissue, and waiting for a given inflow time (TI) during which the labeled blood flow comes to the image plane, finally obtaining an image of interest that is described as the label acquisition. Apart from avoiding the use of paramagnetic contrast agents, ASL adopts an endogenous and diffusible tracer for blood flow by labeling the water magnetically in the feeding arterial blood. Similar to some invasive neuro-imaging methods, ASL can provide the quantitative measurement in the standard units of mL/100 g brain tissue/min to ensure the consistency of the different observers; besides, clinical imaging time for ASL collecting CBF data is within 5 min. As a safe technology, ASL not only allows for comfortable and repeated measurements in patients, but also avoids the possibility of nephrogenic systemic fibrosis, which is reduced by the frequent use of gadolinium-based contrast agents in renal failure patients. Perfusion measurement methods using ASL has been increasingly recognized to be available for quantitatively measuring the CBF value in the assessment of stroke as well as neurodegenerative diseases., Perfusion MRI with ASL also provides meaningful vascularization information about brain tumors by assessing the various CBF values in different types and different grades of tumor cancers. Nowadays, accumulating researches have indicated that ASL is a valuable modality for monitoring the treatment response to brain tumors,, yet, several lines of evidences have contrary outcomes., Considering the existed inconsistency, we therefore performed the current meta-analysis in order to determine the crucial role of ASL in the histopathologic grading of brain tumor.
| > Materials and Methods|| |
Related articles were identified through searching PubMed, Web of Science, Embase, CINAHL, China BioMedicine (CBM), Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for all pertinent papers, which estimated the relation between ASL and brain cancer and published up to May 31st, 2014, utilizing the search terms (”brain neoplasms” or “Astrocytoma” or “Oligodendroglioma” or “Glioblastoma” or “brain cancer” or “brain tumor” or “brain carcinoma” or “cerebral cancer” or “cerebral tumor” or “cerebral neoplasms” or “Glioma” or “glial cell tumors” or “glioma” or “gliomas” or “Astrocytoma” or “Glioblastoma Multiforme” or “GBM” or “Oligodendroglioma” or “Ependymoma” or “Embryonal Tumor” or “Medulloblastoma” or “Ependymoblastoma” or “Primitive Neuroectodermal Tumor” or “PNET” or “Meningioma” or “Craniopharyngioma” or “Schwannoma” or “Ganglioglioma” or “Pituitary Adenoma” or “Choroid Plexus Tumor”) and “Continuous arterial spin-labeled perfusion MRI” or “Arterial spin labeling” or “ASL” or “arterial spin labeling techniques” or “arterial spin labeling technique” or “continuous arterial spin labeling” or “CASL-MR” or “ASL-PI” or “arterial spin labeling MRI” for our initial search without language restrictions. Further manual search results were retrieved for additional potential relevant papers.
Any randomized human-associated cohort studies that reported the correlation of relative tumor blood flow (rTBF) and relative cerebral blood flow (rCBF) with brain cancer in different tumor grades as a chief outcome were first taken into consideration. Further, studies that had patients who were diagnosed with brain cancer confirmed by histopathologic examinations through MRI or computed tomography (CT) imaging were also included for the initial review of articles. None of the studies that do not supply the number of high-grade brain cancer and low-grade brain cancer cases, and complete information about rTBF and rCBF, were enrolled. The extracted articles with the minimum number of cases in included studies greater than 5 were not cause for exclusion. However, the extracted studies that have considerable overlap (> 50%) of study subjects or lack in complete unavailable data were cause for exclusion. If the same population belonged to previous studies, only the most recent or complete article was enrolled.
To reduce the bias and strengthen the reliability, two investigators separately extracted data based on the eligibility criteria, and came to an agreement on all items after discussion as well as re-examination. The relevant data were extracted as follows: Surname of first author, year of publication, source of publication, study design, study type, sample size, sex, age, country, ethnicity and tumor grade of origin, reference tissue, ASL technique, rTBF and rCBF. Owing to different ethnicities of subjects, information was extracted independently as well as classed into Asians and Caucasians. The studies were enrolled after being approved by all authors.
The quality of included studies was assessed independently by two authors based on critical appraisal skills program (CASP) (http://www.casp-uk.net/). The questions in CASP criteria were as follows: (1) Did the study address a clearly focused issue; (2) Was the cohort recruited in an acceptable way; (3) Was the exposure accurately measured to minimize bias; (4) Was the outcome accurately measured to minimize bias; (5) (a) Have the authors identified all important confounding factors, (b) Have they taken into account the confounding factors in the design and/or analysis; (6) (a) Was the follow up of subjects complete enough, (b) Was the follow up of subjects long enough; (7) What are the results of this study; (8) How precise are the results; (9) Do you believe the results; (10) Can the results be applied to the local population; (11) Do the results of this study fit with other available evidence; (12) What are the implications of this study for practice.
For minimizing the differences of the summary, we carried out the present statistical meta-analyses applying random-effects model or fixed-effects model. A random-effects model would be applied when the presence of heterogeneity was found among studies, while a fixed-effects model would be utilized when there was no existence of statistical heterogeneity. The standardized mean differences (SMDs) at 95% confidence intervals (CI) were calculated for high-grade versus low-grade category of rTBF and rCBF by the application of Z test. The subgroup analyses by country as well as reference issued to discuss potential effect modification were also carried out, and heterogeneity among enrolled studies was assessed using the Cochran's Q-statistic (P < 0.05 was recognized as statistical significance). Due to comparatively low statistical persuasiveness of Cochran's Q-statistic, we applied I2 test to estimate the possibility of heterogeneity among studies. The sensitivity analysis was done to assess a single study could affect the final results by deleting a single study one by one to show the influence of individual data set to the pooled SMDs. The funnel plot was protracted to estimate publication bias, which might have the power to affect the validity of estimates. The symmetry of the funnel plots was evaluated applying Egger's linear regression test. All tests of included study were two-sided, as well as a P value of < 0.05 was recognized as statistical significance. To confirm the accuracy of results, two investigators inputted separately all information in the STATA software, version 12.0 (Stata Corp, College Station, TX, USA).
| > Results|| |
Baseline characteristics of included studies
The initial search yielded total 108 articles correlated to the search of keywords, and a simple flow chart of the study selection process is shown in [Figure 1]. After screening the title as well as key words, 75 studies were rejected (2 were duplicates, 16 of them were letters, meta-analysis or reviews, 27 of them were non-human studies, and 30 articles were not correlated to research topics). Full text from 33 trials were reviewed, and an additional 19 studies were rejected (3 of them were not cohort or case-control study, 6 were not related to ASL and 10 were not relevant to brain cancer), leaving 14 trials for further review. Of these, 2 were abandoned because of not supplying enough information; therefore, 12 papers,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, which incorporated a total of 475 patients (274 patients with high-grade brain cancer and 201 patients with low-grade brain cancer), were finally discovered to conform to our inclusion criteria. The year of publication ranged from 2007 to 2014. All trials were cohort studies that evaluated the correlation of rTBF and rCBF with brain cancer in different tumor grades in Asians (7 studies) and Caucasians (5 studies). Reference tissue in this current meta-analysis included gray, white, hemisphere and cerebellum. The types of ASL applied in our present meta-analysis are GE 3.0T, GE 1.5T, Siemens 3.0T, and Siemens 1.5T. All quality scores of included articles were higher than 22 (good quality). [Table 1] showed the characteristics as well as methodological quality of the extracted studies. The number of studies retrieved from those electronic databases from 2001 to 2014 is shown in [Figure 2].
|Figure 1: A simple flow chart shows study selection procedure. A total of 12 cohort studies were included in this meta-analysis|
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|Table 1: Baseline characteristics and methodological quality of all included studies|
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|Figure 2: The assessment of the methodological quality of included studies was conducted applying the CASP scores|
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ASL in high-grade and low-grade brain cancer
A total of 12 cohort studies correlated to the ASL in brain cancer. The results of the correlation betweenthe rTBF and rCBF and different tumor stage in brain cancer by using ASL are shown in [Figure 3]. Meta-analysis results revealed that rTBF and rCBF in high-grade brain cancer patients were faster than those in low-grade brain cancer patients with ASL (rTBF: SMD = 1.81, 95% CI: 1.54–2.09, P < 0.001; rCBF: SMD = 0.74, 95% CI: 0.38–1.10, P < 0.001). Subgroup analysis by country indicated that ASL could be the main prediction of increased rTBF in high-grade brain cancer patients, rather than in low-grade brain cancer, in USA, Korea and China (P < 0.001) [Figure 4]. In addition, subgroup analysis by country also suggested that rCBF in high-grade brain cancer was faster than that in low-grade brain cancer using ASL in USA and China (both P < 0.05), but not in India, Sweden and Germany (all P > 0.05) [Figure 4]. Further subgroup analyses by reference tissue showed a positive association between rTBF and high-grade brain cancer by utilization of ASL in gray, white and hemisphere subgroups (all P < 0.05), which was also shown in [Figure 4]. Additionally, subgroup analyses by reference tissue as well as displayed that rCBF was positively correlated to high-grade brain cancer through applying ASL in white subgroups (SMD = 0.90, 95% CI: 0.44–1.36, P < 0.001), while similar association was not found in hemisphere and cerebellum subgroups (P > 0.05) [Figure 4].
|Figure 3: Forest plots of included studies for the diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain|
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|Figure 4: Subgroup analysis by country and reference tissue of the diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain|
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Sensitivity analysis and publication bias
Sensitivity analysis was carried out and the results suggested that the overall statistical significance does not change when any single study was omitted. Thus, this meta-analysis data is relatively stable [Figure 5]. The funnel plots of those 12 articles for rTBF presented to be asymmetrical suggesting a little publication bias, and further proved by classic fail-safe N and Egger's regression intercept (P = 0.005) [Figure 6]. However, the funnel plots for rCBF displayed symmetrical, and classic fail-safe N and Egger's test suggested no publication bias (P = 0.275) [Figure 6].
|Figure 5: Sensitivity analysis for the diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain in the present study|
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|Figure 6: Funnel plots, classic fail-safe N and Egger's regression intercept of publication biases on the diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain|
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| > Discussion|| |
The main purpose of this meta-analysis was to explore the diagnostic value of ASL technique in the preoperative tumor grade in brain cancer. The results in this study have shown that both rTBF value and rCBF value of high-grade tumors were obviously higher than those of low-grade tumors, suggesting that ASL technique can be a useful evaluation method for microvascular perfusion and may be propitious to the differential diagnosis of high-grade and low-grade brain cancers. Generally, brain cancer was considered to be the most common neoplasms in central nervous system, characterized by high morbidity, mortality, recurrence rates and low cure rate. It is worthwhile to note that the pathological grading of brain cancer is usually related to the severity of tumor angiogenesis and the degree of perfusion in microcirculation., Therefore, it is very important to accurately diagnose the tumor grade and the severity of tumor angiogenesis in brain cancer patients, as they may be significant for the treatment and prognosis of brain cancer. Nowadays, dynamic susceptibility contrast and ASL are the frequently used MR perfusion imaging methods for detection of tumor angiogenesis. It was widely accepted that ASL perfusion adopts magnetically tagged water in the blood as an endogenous, so that it can be diffusible tracer for blood flow and cannot be affected by the destruction of blood brain barrier. According to the MR perfusion-weighted imaging and molecular pathology of brain cancer, many researchers have found that the values of rCBF and rTBF were positively correlated with the tumor micro-vessel density and the expression of vascular endothelial growth factor.,,,,,,,,,,,,,,,,,,,,,,,,,,, In this regard, ASL perfusion can evaluate objectively the severity of angiogenesis in brain tumors and may estimate reasonably the tumor grade and the degree of malignancy. In our study, we found that ASL perfusion can differentiate the grade of brain tumors by the rTBF value and rCBF value. A previous study carried out by Yoo et al. has revealed that rTBF value calculated from ASL perfusion imaging was obviously high in high-grade gliomas, and ASL may facilitate the differential diagnosis of brain tumor grade. Thomsen et al. have also suggested that rCBF values in ASL were significantly higher in the high-grade tumors, which can be used as an effective MR perfusion imaging to evaluate the cerebral gliomas.
In the present study, we also attentively performed stratified analyses based upon reference tissue and country to evaluate the diagnostic value of ASL technique. The country-stratified analysis results have suggested that the rTBF values obtained by ASL in high-grade tumors were higher than those in low-grade tumors among USA, Korea and China populations. Further subgroup analyses by reference tissue have found that the rTBF values were positively correlated with the tumor grade in gray, white and hemisphere subgroups. These results we have found in this study suggested that the differences of country and reference tissues may not affect the fact that rTBF value obtained by ASL has differential diagnosis value of high-grade and low-grade brain cancers. For the value of rCBF in ASL, we also performed stratified analyses on the basis of reference tissue and country. Our study has revealed that rCBF value in high-grade tumors was higher as compared to that in low-grade tumors in USA and China, but such association was not observed in India, Sweden and Germany populations, suggesting that country differences could be the possible heterogeneity source of this outcome. The results of stratified analyses by reference tissue have displayed that there exists a positive correlation between rCBF value and the grade of brain cancer in white subgroup, while no such association was discovered in the cerebellum and hemisphere subgroups. In this regard, the differences of country as well as reference tissues may have impact on the grade of brain cancer by rCBF value. All in all, our findings in this study were in keeping with other studies that rTBF value and rCBF value were positively related to the tumor grade, indicating that ASL can be a useful MR perfusion imaging method to assess the hemodynamic information of brain cancers, and could be a suitable candidate for the preoperative assessment of tumor grade in brain.
Although this study was a practical method to generate a more powerful evaluation of true effect-size with less random error compared with individual studies, it still came with some limitations that restricted the quality as well as number of those included studies. First, the number of articles especially the relatively smaller sample sizes may be insufficient and may lead to an insufficient significant effectiveness. In addition, the relatively small sample size of included studies limited our estimation of potential publication bias and the tendency of positive research results in most magazines. Hence, the potential existence of publication bias may have a negative influence on the overestimation of the differential diagnosis effectiveness. A third limitation of our meta-analysis may be reporting and language bias, with the fact that the results of the meta-analysis might be slightly lacking reliability to some extent. Moreover, we enrolled only eligible English and Chinese studies that may relate to the occurrence of potential biases because of excluding parts of qualified studies based on language criteria. Lastly, usual reliable statistical packages (STATA) are the only way to calculate unweighted kappa coefficients for multiple raters, where they are unsuitable for ordinal scales for their treatment of all disagreements equally. And the methodological quality of those included trials was found to be poor.
In brief, our results data indicated that rTBF and rCBF value were positively correlated with the tumor grade, suggesting that ASL can be a useful MR perfusion imaging way to assess the hemodynamic information of brain cancers, and thus a useful candidate for preoperative assessment of tumor grade in brain. Taken into consideration these limitations, the combined results of the present meta-analysis should be carefully accepted and future independent high-quality RCTs with larger samples and effectiveness analyses are needed.
| > Acknowledgments|| |
We would like to acknowledge the reviewers for their helpful comments on this paper.
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