Prognosis Prediction of Measurable Enhancing Lesion after Completion of Standard Concomitant Chemoradiotherapy and Adjuvant Temozolomide in Glioblastoma Patients: Application of Dynamic Susceptibility Contrast Perfusion and Diffusion-Weighted Imaging
November
Prognosis Prediction of Measurable Enhancing Lesion after Completion of Standard Concomitant Chemoradiotherapy and Adjuvant Temozolomide in Glioblastoma Patients: Application of Dynamic Susceptibility Contrast Perfusion and Diffusion- Weighted Imaging
Jae Hyun Kim 0 1 2 3
Seung Hong Choi 0 1 2 3 4
Inseon Ryoo 0 1 2 3
Tae Jin Yun 0 1 2 3
Tae Min Kim 0 1 2 5
Il Han Kim 0 1 2
0 Competing Interests: The authors have declared that no competing interests exist
1 Funding: This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120300), the Korea Healthcare technology R&D Projects, Ministry for Health, Welfare & Family Affairs (A112028 and HI13C0015), and the Research Center Program of IBS (Institute for Basic Science) in Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manu- script
2 Editor: James Bradley Elder, The Ohio State University Medical Center , United States of America
3 Department of Radiology, Seoul National University College of Medicine , Seoul , Korea,
4 Center for Nanoparticle Research, Institute for Basic Science, and School of Chemical and Biological Engineering, Seoul National University , Seoul , Korea,
5 Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine , Seoul, Korea, 4. Department of Neurosurgery, Seoul National University College of Medicine , Seoul, Korea, 5. Department of Pathology, Seoul National University College of Medicine , Seoul, Korea, 6. Department of Radiation Oncology, Cancer Research Institute, Seoul National University College of Medicine , Seoul , Korea
Purpose: To assess the prognosis predictability of a measurable enhancing lesion using histogram parameters produced by the normalized cerebral blood volume (nCBV) and normalized apparent diffusion coefficient (nADC) after completion of standard concomitant chemoradiotherapy (CCRT) and adjuvant temozolomide (TMZ) medication in glioblastoma multiforme (GBM) patients. Materials and Methods: This study was approved by the institutional review board (IRB), and the requirement for informed consent was waived. A total of 59 patients
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with newly diagnosed GBM who received standard CCRT with TMZ and adjuvant
TMZ for six cycles underwent perfusion-weighted and diffusion-weighted imaging.
Twenty-seven patients had a measurable enhancing lesion and 32 patients lacked
a measurable enhancing lesion based on the Response Assessment in
NeuroOncology (RANO) criteria in the follow-up MRI, which was performed within 3
months after adjuvant TMZ therapy was completed. We measured the nCBV and
nADC histogram parameters based on the measurable enhancing lesion. The
progression free survival (PFS) was analyzed by the Kaplan-Meier method with the
use of the log-rank test.
Results: The median PFS of patients lacking measurable enhancing lesion was
longer than for those with measurable enhancing lesions (17.6 vs 3.3 months,
P,.0001). There was a significant, positive correlation between the 99th percentile
nCBV value of a measurable enhancing lesion and the PFS (P5.044, R25.152). In
addition, the median PFS was longer in patients with a 99th percentile nCBV value
4.5 than it was in those with a value ,4.5 (4.4 vs 3.1 months, P5.036).
Conclusion: We found that the nCBV value can be used for the prognosis
prediction of a measurable enhancing lesion after the completion of standard
treatment for GBM, wherein a high 99th percentile nCBV value (4.5) suggests a
better PFS for GBM patients.
Glioblastoma multiforme (GBM) is the most common primary brain tumor in
adults; it is also extremely aggressive. In spite of enormous treatment efforts, the
prognosis is grave, with the median survival rate ranging from 9 to 18 months [1
4]. The standard treatment for newly diagnosed GBM consists of maximal surgical
resection and concurrent chemoradiotherapy (CCRT) with temozolomide
(TMZ), followed by 6 cycles of adjuvant TMZ [57]. The radiologic assessment,
especially via magnetic resonance imaging (MRI), plays an important role in the
evaluation of the GBM response to treatment. In 1990, Macdonald introduced
radiological and clinical response criteria for malignant brain tumors [8]. These
criteria provide a standardized radiological assessment of the tumor response and
are based on measuring the enhancing component of the tumor. The enhancing
portion of GBM is a key factor for using these criteria to predict the prognosis of
GBM patients. Furthermore, recently, the Response Assessment in
NeuroOncology (RANO) Working Group proposed new standardized criteria for
accurately assessing the tumor response in high-grade glioma patients [9]. The
RANO criteria emphasize not only the evaluation of the non-enhancing
component but also precise examination of measurable enhancing tumor
components. The measurable enhancing lesions are defined as bidimensionally
contrast-enhancing lesions with clearly defined margins by computed tomography
(CT) or MRI scans and two perpendicular diameters of at least 10 mm visible on
two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip
[9]. The presence of a measurable enhancing lesion is an important requirement
for defining GBM progression with the RANO criteria.
Many researchers have tried to predict the prognosis of patients with
highgrade glioma with advanced MR imaging techniques, such as dynamic
susceptibility contrast (DSC) perfusion-weighted imaging (PWI) and
diffusionweighted imaging (DWI) [1016]. Although the measurable enhancing lesion is a
significant factor for assessing the tumor response in GBM patients, no clinical
studies have evaluated the impact of the presence of a measurable enhancing
lesion after the completion of standard treatment combined with adjuvant TMZ.
Therefore, the purpose of this study was to assess the prognosis predictability in
GBM patients of a measurable enhancing lesion after the completion of standard
CCRT and adjuvant TMZ using histogram parameters produced by DSC-PWI
and DWI; several studies have shown that histogram analysis of these advanced
MR imaging methods is useful in predicting early treatment response or prognosis
in patients with high-grade glioma [1721].
Materials and Methods
Our study was approved by the Institutional Review Board (IRB) at Seoul
National University Hospital (IRB No. H-1401-073-550). The institutional review
board waived the need for written informed consent from the participants because
this was a retrospective study and the data were analyzed anonymously.
From November 2006 to June 2013, 338 patients with newly diagnosed GBM who
had undergone surgical resection or stereotactic biopsy were selected. The
inclusion criteria were as follows: the patient (a) had a histopathologic diagnosis
of GBM based on the World Health Organization criteria; (b) underwent standard
CCRT with TMZ after surgery or biopsy and 6 cycles of adjuvant TMZ; (c) had
undergone a follow-up MRI study within three months (mean duration: 25 days,
range: 084 days) of completing 6 cycles of adjuvant TMZ, which included DWI
and DSC-PWI sequences; and (d) had also undergone additional regular
followup MRI studies. Finally, 59 GBM patients (42 male, 17 female; age range, 1281
years; mean age, 50 years) were enrolled in the present study. We divided these 59
patients into two groups. One group had measurable enhancing lesions, which are
defined as bidimensionally contrast-enhancing lesions with clearly defined
margins visible with MRI and two perpendicular diameters of at least 10 mm
visible on two or more axial slices that are preferably, at most, 5 mm apart with
0mm skip [9], on the first follow-up MRI study (n527; 18 male, 9 female; age
range, 1668 years; mean age, 54 years). The other group lacked measurable
enhancing lesions (n532; 24 male, 8 female; age range, 1281 years; mean age, 48
years). We divided the 27 patients with measurable enhancing lesion into the
following two subgroups: the non-progression group, which is defined as the
patients who did not show disease progression within the entire follow-up period
(n54), and the progression group (n523) (Fig. 1).
Image Acquisition
For each patient, the first follow-up MRI after the end of 6 cycles of adjuvant TMZ
was performed using 1.5 T scanners [n522, Signa Excite 1.5T (n57); Signa HDxt
1.5T (n515), GE Medical Systems, Milwaukee, WI, USA] or 3 T scanners [n537,
Verio (n528); Trio Tim (n52), Siemens Medical Solution, Erlangen, Germany;
Signa Excite 3.0T (n56), Signa HDxt 3.0T (n51), GE Medical Systems,
Milwaukee, WI, USA]. The imaging sequences for the brain included axial
spinecho T1-weighted (T1W) images, fast/turbo spin-echo T2-weighted (T2W)
images, fluid-attenuated inversion-recovery (FLAIR) images, DWI, DSC-PWI
with gadobutrol (Gadovist, Bayer Schering Pharma, Berlin, Germany) and
subsequent contrast-enhanced spin-echo T1W images. The MR imaging
parameters were as follows: 558650/820 ms/7090/3846192212 (TR/TE/FA/
matrix) for spin-echo T1W images; 45005160/91106.3 ms/90130/448
6406220348 (TR/TE/FA/matrix) for fast spin-echo T2W images; and 9000
9900/97162.9 ms/90130/1993846209220 (TR/TE/FA/matrix) for FLAIR
images. The other parameters for the three images were as follows: section
thickness of 5 mm with a 1 mm gap and a field of view (FOV) of 1992406199
240 mm.
DWI was performed with a single-shot, spin-echo EPI sequence in the axial
plane before the injection of contrast material with a TR/TE of 690010000/55
70 ms at b50 and 1000 sec/mm2, 2540 sections, a 34 mm section thickness, a
1 mm intersection gap, a FOV of 2202406220240 mm, a matrix of 128
2406128192, three signal averages, and a voxel resolution of 1.561.563.0
4.0 mm. DWI was acquired in three orthogonal directions and combined into a
trace image. Using these data, ADC maps were calculated on a voxel-by-voxel
basis with the software incorporated into the MRI unit.
For DSC-PWI, a single-shot gradient-echo EPI sequence was used during the
intravenous injection of contrast agent. The DSC PWI imaging parameters were as
follows: TR/TE, 1500/3040 ms; FA, 3590; FOV, 2202406220240 mm; 1520
sections; matrix, 1286128; section thickness, 56 mm; intersection gap, 1
1.5 mm; and voxel resolution, 1.8661.8665 mm. For each section, 60 images
were obtained at intervals equal to the repetition time. After four to five time
points, a bolus of gadobutrol at a dose of 0.1 mmol/kg of body weight and a rate
of 4 mL/sec was injected with an MR-compatible power injector (Spectris;
Medrad, Pittsburgh, PA, USA). The bolus of contrast material was followed by a
30 mL bolus of saline, which was administered at the same injection rate.
Follow-up and Progression Assessment
The 59 patients were followed up during a median period of 10 months (range,
1.447.8 months). Clinical features and follow-up MRI were used to assess the
patients. We evaluated the disease progression and compared it with the imaging
features and clinical status of the patients at the time of the first follow-up MRI
after adjuvant TMZ. The determination of the disease progression was based on
the RANO criteria [9]. The patients who met any one of following criteria were
classified as having progressive disease: (a) 25% increase in the sum of the
products of the perpendicular diameters of enhancing lesions with the smallest
tumor measurement; (b) any new lesion; (c) clear clinical deterioration not
attributable to other causes apart from the tumor; (d) failure to return for
evaluation as a result of death or deteriorating condition; and (e) clear
progression of nonmeasurable disease. We also evaluated the pseudoprogression
based on the RANO criteria [9] in the measurable enhancing lesion (+) group
(n527), because there was a possibility that the pseudoprogression influenced the
normalized CBV (nCBV) of the measurable enhancing lesion. One patient of the
progression group was not evaluated due to lack of follow-up MRI within 12
weeks after the radiation treatment. One radiologist (S.H.C.; 12 years of brain
MRI experience) reviewed all follow-up MR images obtained from the study
population (n559).
Quantitative Image Analysis
The MR data for the ADC1000 and the DSC-PWI of the patients with measurable
enhancing lesions (n527) were digitally transferred from the picture archiving
and communication system workstation to a personal computer for further
analysis. Relative CBV (rCBV) maps were obtained by using a dedicated software
package (NordicICE and TumorEx; NordicNeuroLab, Bergen, Norway) with an
established tracer kinetic model applied to the first-pass data [22, 23]. First,
realignment was performed to minimize patient motion during the dynamic
scanning. The gamma-variate function, which is an approximation of the
firstpass response as it would appear in the absence of recirculation, was fitted to the
1/T2* curves to reduce the effects of recirculation. The dynamic curves were
mathematically corrected to reduce contrast agent leakage effects [24]. After
eliminating recirculation and contrast agent leakage, the rCBV was computed
with numeric integration of the curve. To minimize variances in the rCBV value
in an individual patient, the pixel-based rCBV maps were normalized by dividing
every rCBV value in a specific section by the rCBV value in the unaffected white
matter as defined by a neuroradiologist (S.H.C.) [25]. Coregistration between the
contrast-enhanced T1W images and the nCBV maps and between the
contrastenhanced T1W images and the ADC maps was performed based on geometric
information stored in the respective data sets with the use of a dedicated software
package (NordicICE) [26]. The differences in the slice thickness between images
were corrected automatically by re-slicing and coregistration, which was based on
the underlay and structural images. The nCBV and ADC maps were displayed as
color overlays on the contrast-enhanced T1W images. The regions of interest
(ROIs) for the measurable enhancing lesion in each section of the
contrastenhanced T1W images were determined by the semiautomatic segmentation
method using dedicated software (Nordic TumorEx), in which the
contrastenhanced T1W images were used for the structural images [27]. The ROI volumes
were also automatically calculated from the ROIs determined by the
semiautomatic segmentation method.
To minimize the bias from the use of multiple MR scanners, we used the
normalized ADC (nADC) value to define the foci with diffusion restriction in the
measurable enhancing lesion [28]. The nADC value of each voxel was defined as
the ADC value of the voxel divided by the ADC value of normal periventricular
white matter. The ADC values of the normal periventricular white matter were
measured at the contralateral side of the main tumor.
Then, one radiologist (J.H.K.; 2 years of brain MRI experience) performed
histogram analysis in the manner described below. The nCBV histograms were
plotted with the nCBV on the x-axis, with a bin size of 0.2, and the y-axis was
expressed as a percentage of the total lesion volume by dividing the frequency in
each bin by the total number of analyzed voxels. For further quantitative analysis,
cumulative nCBV histograms were obtained from the nCBV histograms, in which
the cumulative number of observations in all of the bins up to the specified bin
was mapped on the y-axis as percentages. The following parameters were derived
from the nCBV histograms: (a) the mean and (b), in the cumulative nCBV
histograms, the 99th percentile points (the Xth percentile point is the point at
which X% of the voxel values that form the histogram are found to the left of the
histogram) [27, 29, 30]. The nADC histograms were plotted with the nADC values
on the x-axis, with a bin size of 0.1, and the y-axis was expressed as a percentage of
the total lesion volume by dividing the frequency in each bin by the total number
of analyzed voxels. In the same manner as for the cumulative nCBV histograms,
the cumulative nADC histograms were obtained from the nADC histograms. The
mean nADC was derived from the nADC histograms. The 5th percentile point of
the cumulative nADC histograms was also derived [29, 30] (Fig. 2).
All statistical analyses were performed with SPSS software, version 21.0 (IBM). All
reported P values were two-sided; a P value of less than 0.05 was considered
statistically significant.
The measurable enhancing lesion (+) and (2) group clinical characteristics
were compared using Students t-test for non-categorical variables and Fishers
exact or chi-square tests for categorical variables. Students t-test was also used to
evaluate the difference in the histogram parameters and ROI volumes between the
non-progression and progression groups of patients with measurable enhancing
lesions. The proportion of patients who experienced the pseudoprogression
between the non-progression and progression groups was assessed by Fishers
exact test. Survival curves for the PFS were constructed using the Kaplan-Meier
method, and log-rank tests were carried out to evaluate the differences between
the two groups, which were divided by the presence of a measurable enhancing
lesion or the nCBV cutoff value (4.5). With the simple linear regression model, the
ROI volume of the measurable enhancing lesion, 99th percentile nCBV value and
5th percentile nADC value were correlated with the PFS of patients with
measurable enhancing lesions.
Patient Clinical Characteristics
The characteristics of the patients in the two groups (with or without measurable
enhancing lesion) were comparatively well balanced. The mean age of the 59
patients was 50 years, and 57 patients (97%) underwent gross total resection. Two
patients, who only received stereotactic biopsy without surgical resection, were
divided equally between the two groups. Additionally, the Karnofsky performance
scores were more than 70 in 56 patients (95%) at the time of the first follow-up
MRI after adjuvant TMZ. MGMT promoter methylation was less in the
measurable enhancing lesion (+) group than in the measurable enhancing lesion
(2) group, but this difference was not statistically significant (56% vs 71%)
(Table 1).
PFS according to the Presence of a Measurable Enhancing Lesion
The median PFS was shorter in patients with measurable enhancing lesions than
in those lacking a measurable enhancing lesion, 3.3 months [95% confidence
interval (CI), 1.7 to 5.0] vs 17.6 months (95% CI, 11.9 to 23.4), P,.0001 by the
log-rank test (Table 2) (Fig. 3). Additionally, the one-year PFS rate was lower in
patients with measurable enhancing lesions than in those without measurable
enhancing lesions, 11.1% (95% CI, 0 to 25.2) vs 60.2% (95% CI, 41.4 to 79.0)
(Table 2).
Note. Unless otherwise indicated, data are given as the number of patients.
*Data are the meanstandard deviation.
{Difference between the groups was evaluated with Students t-test.
{Difference between the groups was evaluated with Fishers exact or chi-square tests.
Histogram Parameters in the Patients with Measurable Enhancing
Lesions
The ROI volumes of the measurable enhancing lesion in the non-progression
3
group (meanstandard deviation; 32.146.2 cm ) were comparable to those in
the progression group (20.221.3 cm3) (P5.646). In addition, the proportion of
patients who experienced the pseudoprogression did not differ between the two
groups (P51.000 by Fishers exact test). However, the 99th percentile nCBV value
for the non-progression group (6.171.57) was significantly higher than for the
progression group (4.441.45) (P5.039). There were no significant differences
between the two groups for other histogram parameters (Table 3).
Measurable enhancing lesion (2) (n532)
There was a statistically significant positive correlation between the 99th
percentile nCBV value of measurable enhancing lesions and the PFS (P5.044,
R25.152). However, we could not find a significant correlation between the PFS
and 5th percentile nADC value (P5.623, R25.010) (Fig. 4). Furthermore, the ROI
volume of the measurable enhancing lesion did not correlate with the PFS
(P5.290, R25.045).
PFS according to the 99th percentile nCBV value in Patients with
Measurable Enhancing Lesions
The median PFS was higher in the patients with a 99th percentile nCBV value
4.5 (n512) than in those with a 99th percentile nCBV value ,4.5 (n515), 4.4
months (95% CI, 2.8 to 6.0) vs 3.1 months (95% CI, 1.4 to 4.8), P5.036 by the
log-rank test (Fig. 5).
The ADC, nCBV maps and histograms of two representative cases were shown
in Figures 6 and 7.
One of the most important results from our study is the higher median PFS in
patients lacking measurable enhancing lesions than in the patients with
measurable enhancing lesions (17.6 vs 3.3 months). Additionally, the one-year
PFS rate was 60.2% in the group lacking measurable enhancing lesions, which was
higher than that (11.1%) of the group with measurable enhancing lesions. Several
studies have already emphasized that residual tumor after resection is an
independent prognostic factor for survival in cases of low- and high-grade gliomas
[3133]. Our study suggests that measurable enhancing lesions at the end of
standard treatment for GBM (adjuvant TMZ following gross total resection and
CCRT with TMZ) could be an important prognostic factor in GBM patients.
Therefore, the patients whose follow-up MRIs show a measurable enhancing
lesion after adjuvant TMZ might need additional therapy, such as novel
chemotherapy and surgical resection, or close observation. Additional clinical
studies are needed to evaluate the benefit of additional treatments in patients with
measurable enhancing lesions after completing standard treatment for GBM.
In our study results, we found significant positive correlation between the 99th
percentile nCBV value of a measurable enhancing lesion and the PFS (P5.044,
R25.152). Furthermore, the 99th percentile nCBV value of the non-progression
group was significantly higher than that of the progression group in patients with
measurable enhancing lesions (6.171.57 vs 4.441.45, P5.039), and the
median PFS was significantly higher in the patients with a 99th percentile nCBV
value 4.5 than in the patients with a 99th percentile nCBV value ,4.5 (4.4
months vs 3.1 months, P5.036). Our results seem to contradict previous reports.
According to several previous studies, increased rCBV or high histogram
parameters, such as the peak height position, after CCRT in GBM patients were
associated with a poor prognosis [20, 34]. Additionally, a recent study by Kim
et al. [21] demonstrated that high 99th percentile nCBV values were helpful for
detecting high-grade glioma. Furthermore, the high rCBV or histogram
parameters reflect the relative fraction of the high-grade tumor portion compared
with treatment-related brain parenchymal changes because the tumor usually
comprises a mixture of viable tumor tissue and treatment-induced necrosis [34].
However, the CBV produced by the DSC-PWI technique can provide physiologic
information on the tumor vascularity [3537]. Thus, decreased 99th percentile
nCBV values are indicative of decreases in vascularity and tissue perfusion, which
can induce relatively more hypoxic conditions for tumor cells. In previous studies
[3840], hypoxic cancer cells were shown to be more resistant to radiation or
cytotoxic drugs as well as more progressive and aggressive. Therefore, the low 99th
percentile nCBV values seem to indirectly reflect hypoxic conditions, which could
Figure 6. A 56-year-old male glioblastoma patient with a measurable enhancing lesion after adjuvant TMZ. The 99th percentile nCBV value and PFS
of this patient were 5.5 and 8.9 months, respectively. (A) An axial contrast-enhanced T1WI obtained within 3 months after CCRT and adjuvant TMZ shows a
measurable enhancing lesion in the left frontal cortex. (B) The nCBV map and ROIs (red color) are displayed as a color overlay on the contrast-enhanced
T1WI. (C) ADC map with ROIs (red color) are displayed as a color overlay (in hot scale) on the contrast-enhanced T1WI. (D) The volume rendering
contrastenhancement T1WI from measurable enhancing lesion shows the volume (red color) of measurable enhancing lesion at the time of progression. (E, F) The
nCBV and ADC histograms of measurable enhancing lesion.
make cancer cells more aggressive and resistant to treatment; thus, low 99th
percentile nCBV values for measurable enhancing lesions after standard GBM
treatment may be associated with poor prognosis.
In terms of the ADC values, we found no significant correlation between the 5th
percentile nADC value and PFS (P5.623) as well as no significant differences in
the mean and 5th percentile nADC value between the non-progression and
progression groups (P5.837 and.139, respectively). The ADC values reflect the
tumor cellularity; thus, ADC values are higher in cystic or necrotic areas than in
the solid component of tumors [41, 42]. In addition, in several previous studies
[12, 18, 43], recurrent tumors were shown to have significantly lower ADC values
or lower histogram parameters, such as the 5th percentile ADC value, than for
radiation injury. We found that measurable enhancing lesions after standard
treatment for GBM tend to have similar cellularity regardless of their prognosis,
Figure 7. A 60-year-old male glioblastoma patient with a measurable enhancing lesion after adjuvant TMZ. The 99th percentile nCBV value and PFS
of this patient were 2.9 and 1.1 months, respectively. (A) An axial contrast-enhanced T1WI obtained within 3 months after CCRT and adjuvant TMZ shows a
measurable enhancing lesion in the left temporal lobe. (B) The nCBV map and ROIs (red color) are displayed as a color overlay on the contrast-enhanced
T1WI. (C) ADC map with ROIs (red color) are displayed as a color overlay (in hot scale) on the contrast-enhanced T1WI. (D) The volume rendering
contrastenhancement T1WI from measurable enhancing lesion shows the volume (red color) of measurable enhancing lesion at the time of progression. (E, F) The
nCBV and ADC histograms of measurable enhancing lesion.
which is likely because enhancing lesions can consist of several
microenvironments, such as necrosis, inflammation, and viable tumor cells.
As with any retrospective analysis, this study has inherent biases and other
limitations. First, our sample size was relatively small. The statistical power was
only 5.6% to evaluate the difference in the mean nADC between the
nonprogression (n54) and progression (n523) groups by using Students t-test.
However, there may actually be no significant difference in the mean nADC
between these two groups because the difference in our study was only 0.036
considered clinically meaningless. Furthermore, though there was also a
significant difference in the 99th percentile nCBV between these two groups, a
sample size of non-progression group was only 4. Therefore, large population
studies are required to validate our results. Second, we used multiple MRI
scanners with different field strengths (e.g., 1.5 and 3.0 T scanners) from different
manufacturers, and the scan parameters were slightly different for each machine.
Although we normalized the CBV and ADC values to minimize the effects of the
different magnetic field strengths and type of MRI scanners, there could be a slight
bias in the image analysis of the ADC and nCBV maps. Third, our survival
analysis data censoring rate was relatively high, which could decrease the
reliability of the Kaplan-Meier analysis. To verify our findings, further studies
with less censoring of the data should be performed.
In conclusion, the presence of an enhancing lesion seems to be an important
factor for predicting the PFS in GBM patients who have received standard
treatments including CCRT with TMZ and adjuvant TMZ following surgery.
Additionally, an increase in the 99th percentile nCBV values of measurable
enhancing lesions has a good correlation with improved PFS.
Conceived and designed the experiments: Jae Hyun Kim SHC. Performed the
experiments: Jae Hyun Kim SHC. Analyzed the data: Jae Hyun Kim. Contributed
reagents/materials/analysis tools: IR TJY TMK SL CP Ji-Hoon Kim CS SP IHK.
Wrote the paper: Jae Hyun Kim SHC.
10. Gahramanov S, Muldoon LL, Varallyay CG, Li X, Kraemer DF, et al.. (2013) Pseudoprogression of
glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted
contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with
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