YKL-40 and matrix metalloproteinase-9 as potential serum biomarkers for patients with high-grade gliomas.

Abstract

Biomarkers can facilitate diagnosis, monitor treatment response, and assess prognosis in some patients with cancer. YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins highly differentially expressed by malignant gliomas. We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers.
Serum samples were obtained concurrently with magnetic resonance imaging scans. YKL-40 and MMP-9 were determined by ELISA and the values correlated with the patient's radiographic status and survival.
High-grade glioma patients who underwent a surgical resection of their tumor had transient increase of both YKL-40 and MMP-9 serum levels in the postoperative period. Glioblastoma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients, 50 samples) had a significantly lower level of YKL-40 and MMP-9 than patients with active tumor (n = 66 patients, 209 samples; P = 0.0003 and 0.0002, respectively). Anaplastic glioma patients with no radiographic evidence of disease (n = 32 patients, 107 samples) also had a significantly lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199 samples; P = 0.04). There was a significant inverse association between YKL-40 and survival in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard ratio, 2.2; P = 0.05).
YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients. YKL-40 can be used as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger patient population are needed to confirm these findings.

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YKL-40 and Matrix Metalloproteinase-9 as Potential Serum
Biomarkers for Patients with High-Grade Gliomas
AdI¤lia Hormigo,2Bin Gu,1Sasan Karimi,3Elyn Riedel,4Katherine S. Panageas,4MarkA. Edgar,5
Meena K.Tanwar,6Jasti S. Rao,7Martin Fleisher,1Lisa M. DeAngelis,2and Eric C. Holland2,6
Abstract
Purpose: Biomarkers canfacilitate diagnosis,monitor treatment response, andassessprognosis
in some patients with cancer.YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins
highly differentially expressed by malignant gliomas.We obtained prospective longitudinal serum
samples from patients with gliomas to determine whetherYKL-40 or MMP-9 could be used as
serum markers.
Experimental Design: Serum samples were obtained concurrently with magnetic resonance
imaging scans.YKL-40 and MMP-9 were determined by ELISA and the values correlated with
the patient’s radiographic status and survival.
Results: High-grade glioma patients who underwent a surgical resection of their tumor had
transient increase of bothYKL-40 and MMP-9 serumlevels in the postoperative period.Glioblas-
toma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients,
50 samples) hadasignificantlylowerlevelofYKL-40 and MMP-9 thanpatientswithactivetumor
(n = 66 patients, 209samples; P =0.0003 and 0.0002, respectively).Anaplasticgliomapatients
with no radiographic evidence of disease (n = 32 patients,107 samples) also had a significantly
lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199
samples; P = 0.04). There was a significant inverse association betweenYKL-40 and survival
in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard
ratio, 2.2; P = 0.05).
Conclusions: YKL-40 and MMP-9 can be monitored in patients’ serum and help confirm the
absence ofactive disease in GBMandYKL-40 in anaplastic glioma patients.YKL-40 canbeused
as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger
patient population are needed to confirm these findings.
The current pathologic classification of high-grade gliomas
[glioblastoma multiforme (GBM) and anaplastic glioma]
encompasses a heterogeneous population of tumors with
variable sensitivity to treatment. Tumor grade generally predicts
prognosis, but for an individual patient, predictions are often
inaccurate. For anaplastic oligodendroglioma, detection of 1p
and 19q loss is an indicator of chemotherapy sensitivity and
improved overall prognosis (1). There is no molecular indicator
of treatment response or predictor of survival for anaplastic
astrocytomas. The identification of promoter methylation of
the O6-methylguanine-DNA methyltransferase (MGMT) DNA
repair gene in some GBM patients was recently reported to
confer a favorable treatment response to temozolomide
chemotherapy and longer survival (2); however, this analysis
must be done on tumor tissue that is frequently unavailable or
noninformative.
Currently, tumor response is evaluated by noninvasive
imaging, usually magnetic resonance imaging (MRI). However,
MRI may be unreliable when assessing novel cytocidal
therapies, in discerning radionecrosis from tumor progression,
and in predicting malignant transformation from a low-grade
glioma. In other cancers, such as prostate cancer, serum tumor
markers are used to diagnose malignancy, assess treatment
response, and even predict survival. No such serum markers
have been identified for brain tumors although ongoing
research has identified potential candidate proteins (3, 4).
YKL-40 is an extracellular matrix glycoprotein of unknown
function, initially detected as a protein secreted by a human
osteosarcoma cell line (5). Its name is based on its molecular
weight of 40 kDa and three NH2-terminal amino acids,
tyrosine, lysine, and leucine, and is also known as human
cartilage glycoprotein 39 (5). It is a chitinase-like protein that
has no catalytic activity against chitinase substrates due to
amino acid substitutions in the region corresponding to the
active site of chitinases (6). There is evidence that it may be
involved in tissue remodeling (7). YKL-40 is secreted by
Imaging, Diagnosis, Prognosis
Authors’ Affiliations:1Clinical Laboratories, Departments of2Neurology,
3Radiology,4Epidemiology and Biostatistics,5Pathology, and6Cancer Biology and
Genetics, Neurosurgical Service, Department of Surgery, Memorial Sloan-Kettering
Cancer Center, New York, New York; and7Department of Biomedical and
Therapeutic Sciences, College of Medicine, Universityof Illinois, Peoria, Illinois
Received1/25/06; revised 7/11/06; accepted 7/31/06.
Grant support: Accelerate Brain Cancer Cure award (E. Holland).
The costs of publicationof this article were defrayedinpartby thepaymentof page
charges.This article must therefore be hereby marked advertisement in accordance
with18 U.S.C. Section1734 solely toindicate this fact.
Requests for reprints: AdI¤lia Hormigo, Department of Neurology, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY 10021. Phone:
212-639-7330; Fax: 917-432-2310; E-mail: hormigoa@mskcc.org.
F2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0181
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articular chondrocytes and is detected in synovia and cartilage
of patients with rheumatoid arthritis (7). YKL-40 expression
promotes adhesion and migration of vascular smooth muscle
cells in vitro, and it has been detected in vivo in atherosclerotic
plaques and in the developing heart (8). It participates in
differentiation of circulating monocytes into macrophages (9).
In the central nervous system, it may be produced by activated
macrophages in meningitis and encephalitis (10). A gene
expression profile of gliomas showed that YKL-40 was highly
differentially expressed compared with pooled normal brain
using cDNA microarray analysis. YKL-40 was elevated in the
serum of patients with GBM (11) and immunohistochemistry
of high-grade gliomas showed increased YKL-40 expression in
GBMs (12). Comparative genomic hybridization studies and
gene expression array analysis of GBM tumor tissue revealed
that YKL-40 was associated with chromosome-10 loss and poor
clinical outcome (13).
Matrix metalloproteinase-9 (MMP-9) is a well-known matrix
metalloproteinase associated with tumor infiltration and
angiogenesis (14–17). MMP-9 belongs to the gelatinase
subclass of MMPs and its expression has been detected both
in tumor and endothelial cells in glioma (18). Increasing level
of MMP-9 in glioma specimens correlates with higher tumor
grade (14).
YKL-40 and MMP-9 are two secreted proteins that are central
to glioma biology, making them candidates for serum markers
of this disease. We studied serial serum samples from patients
with high-grade gliomas to ascertain the usefulness of YKL-40
and MMP-9 as potential serum markers.
Materials and Methods
Patients.
collected prospectively from patients with histologically confirmed
gliomas to assay YKL-40 and MMP-9 levels. Patients were allowed to
enroll any time during the course of their illness. Patients with known
glioma or suspected brain tumor identified by imaging, who had not
yet undergone resection, were eligible for the study. Those patients
enrolled before their initial surgical procedure and were retained in the
study only after histologic confirmation of a glioma. Serum samples
and imaging studies were obtained every 2 to 3 months when patients
were evaluated in their follow-up visit. Serum samples would not be
obtained or discarded if the patients had a concurrent inflammatory
illness at the time of their appointment. All blood samples were
obtained within 4 weeks of MRI scans with 118 samples (45%)
obtained on the same day as the MRI and 93 samples (35%) within a
week. In patients who underwent surgical resection, samples were
obtained within 14 days preoperatively and serially 1 to 14 days
postoperatively to determine the effect of surgery on the marker levels.
Patients with rheumatic disease, acute infection, HIV, or other types of
cancer were excluded from participating in the study. Pathology
specimens from all patients enrolled in the study were centrally
reviewed at our institution using the WHO classification scheme (19).
This study was approved by the Memorial Hospital Institutional Review
Board and all patients signed an informed consent.
Determination of level of serum marker.
collected and allowed to clot for at least 1 hour at room temperature.
They were centrifuged at 4jC for 10 minutes at 3,000 rpm. The serum
was aliquoted and stored at ?20jC. YKL-40 (Quidel Corp., San Diego,
CA) and MMP-9 (Quantikine, R&D Systems, Minneapolis, MN) levels
were determined by ELISA.
Immunohistochemistry. YKL-40 immunostains were done using
formalin-fixed, paraffin-embedded tissue. After examination of all
From August 2002 to March 2005, serum samples were
Blood samples were
available H&E sections, the corresponding paraffin block with the
most viable tumor was selected for immunostaining. Five-micron-thick
sections were cut from each paraffin block. For antigen retrieval, slides
were pretreated by steaming in citrate buffer for 30 minutes. Slides were
manually immunostained with a polyclonal anti-YKL-40 antibody
(Quidel) at 1:500 dilution with standard avidin-biotin-peroxidase.
Staining for YKL-40 was scored for the percentage of positive cells.
Determination of disease status.
assessed for each time point when a serum sample was collected. MRI
was done with 1.5-T GE scanners (GE Medical Systems, Milwaukee, WI).
All MRI studies included Fluid Attenuated Inversion Recovery,
T2-weighted and T1-weighted before and after administration of
Gadolinium contrast material (gadopentetate dimeglumine). Tumor
size was determined by using the longest diameter (Response
Evaluation Criteria in Solid Tumors criteria; refs. 20, 21) and the
product of two longest perpendicular diameters of contrast-enhancing
lesions on the gadolinium enhanced T1-weighted images. For non-
enhancing residual anaplastic gliomas, the longest diameter and the
largest cross-sectional area of expansile tumor were measured on Fluid
Attenuated Inversion Recovery images. To ensure uniformity, all MRI
scans were reviewed by two of the authors (A.H. and S.K.). Response for
high-grade gliomas was assessed as complete response (CR), partial
response (PR), stable disease (SD), or progression of disease (POD)
according to the standard of Macdonald (22).
Statistical analysis. On examination of markers by response status,
no consistent trend among PR, SD, and POD was found, which led to
the collapse of these three response groups into one category. To test the
association between marker and disease status (defined as CR versus
combined PR, SD, and POD), we used all measurements in a logit
model with generalized estimating equations that corrected for within-
patient correlations (23). Because the distributions for both YKL-40 and
MMP-9 were skewed, the data for both markers were log transformed
before all statistical testing. Overall survival was defined as time from
registration date to date of death or last follow-up. The effect of each
marker on overall survival was analyzed using each marker separately as
a time-dependent covariate in a Cox proportional hazards model (24).
Each marker was used in two ways as a time-dependent covariate: (a)
the value of the marker in the log-scale over time; (b) the change in
each marker compared with the first value collected at registration to
the protocol (difference in log values).
The patient’s disease status was
Results
Patient cohort. We enrolled a total of 143 patients (67
women and 76 men) with high-grade gliomas (Table 1).
Seventy-seven patients had a GBM and 66 an anaplastic glioma.
Among the anaplastic glioma patients, the most prevalent
subgroup was anaplastic astrocytoma with 38 (57.5%) patients.
The median age for patients with GBM was 55 years (range,
23-83 years) and for patients with anaplastic glioma, 46 years
(range, 23-81 years). The median time from tumor diagnosis to
enrollment was 1.4 months (range, 0-21 months) for GBM and
11.2 months (range, 0-137 months) for anaplastic tumors. We
have serum levels linked to imaging in 137 patients for YKL-40
and in 134 patients for MMP-9. A median of 2 samples (range,
1-13) was obtained for patients with GBM and 4 samples
(range, 1-12) for patients with anaplastic gliomas.
Normal subject YKL-40 and MMP-9 values. YKL-40 level was
measured in 93 normal subjects (46 men and 47 women),
healthy employees whose serum had been stored. The median
age of the normal subjects was 37 years (range, 21-65 years).
The median YKL-40 was 55.3 ng/mL (range, 13-101 ng/mL),
with a mean of 59.3 F 21.6 ng/mL. The mean value for YKL-40
established in our laboratory was higher than a previously
published mean of 28 ng/mL (range, 15-166 ng/mL; ref. 25).
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However, the prior data were obtained in women only8of
unknown age. The range of YKL-40 levels was similar in both
groups. For MMP-9, serum was available for analysis from
52 subjects (13 men and 39 women). The median age of the
normal subjects was 40 years (range, 23-64 years). The median
MMP-9 was 315 ng/mL (range, 169-705 ng/mL), with a mean
of 339 F 163 ng/mL. The normal subjects were younger than
the cancer patients and were intended to be used as a guide for
YKL-40 and MMP-9 levels and not for formal comparison with
the cancer population.
Postsurgical transient elevation of YKL-40 and MMP-9 serum
levels. In 30 patients with GBM and 14 patients with
anaplastic glioma, levels were obtained preoperatively and
serially over 2 weeks after resection. Tumor resection resulted in
transiently increased levels of both YKL-40 and MMP-9. The
levels of YKL-40 reached a peak 24 hours after resection
(median, 264 ng/mL for GBM and 295 ng/mL for anaplastic
gliomas; Fig. 1); the median levels of YKL-40 had a 4.4-fold
increase relative to the baseline level for anaplastic glioma and
a 3.2-fold increase for GBM at 24 hours. The maximum levels
for MMP-9 occurred within 48 hours postoperatively (median,
805 ng/mL for GBM and 844 ng/mL for anaplastic gliomas).
The median levels of MMP-9 had a smaller increase relative to
the baseline level (1.2-fold for anaplastic glioma and 1.3-fold
for GBM). Both YKL-40 and MMP-9 returned to baseline over
the next 96 hours to 2 weeks.
MMP-9 and YKL-40 serum levels correlate with no evidence of
disease in GBM patients and YKL-40 with no evidence of disease
in anaplastic glioma patients. Over the course of the study, 10
patients with GBM had a radiographic CR, 13 had PR, 43 SD,
and 49 POD. The median value of YKL-40 for GBM patients
with a CR was 43 ng/mL; for PR, 60 ng/mL; for SD, 86 ng/mL;
and for POD, 71 ng/mL. We found a significant difference in
YKL-40 values for GBM patients with a CR compared with
patients with evidence of disease (P = 0.0003; Fig. 2). Patients
with a GBM who had a persistent radiographic CR had durable
normal levels of YKL-40 (Fig. 3). For anaplastic glioma patients,
32 had CR, 12 PR, 39 SD, and 29 POD. The median YKL-40
value for anaplastic glioma patients with a CR was 61 ng/mL;
for PR, 76 ng/mL; for SD, 74 ng/mL; and for POD, 88 ng/mL.
For anaplastic glioma patients, YKL-40 values were also
significantly associated with disease status (P = 0.04).
ForGBMpatients, themedianvalue of MMP-9 was116ng/mL
for patients with radiographic CR, 312 ng/mL for PR, 348 ng/mL
for SD, and 360 ng/mL for POD. We found a significant
difference in MMP-9 values for GBM patients with a CR com-
pared with GBM patients with radiographic evidence of tumor
(P =0.0002;Fig.4).ThemajorityofGBMpatientswithpersistent
radiographicCRhadMMP-9levelsinthereferencerange(Fig.5).
8J. Dupont, personal communication.
Fig.1. YKL-40 levels increase substantially immediately following surgery.
Twenty-three preoperative samples and 22 samples at 24 hours, 24 at 48 hours,
27 at 72 hours,18 at 96 hours, and13 at10 to14 dayspostoperatively were used to
obtain the time point mean values and SD. Brokenline, GBM; solid line, anaplastic
glioma.
Table 1. Summary of patient cohort
GBM Anaplastic glioma
Total no. patients
Age
Median (range)
Sex (%)
Male
Female
Time from diagnosis to enrollment (mo)
Median (range)
YKL-40
Total no. samples
MMP-9
Total no. samples
YKL-40
Median no. samples (range)
MMP-9
Median no. samples (range)
YKL-40
Patients with samples correlated to MRI
MMP-9
Patients with samples correlated to MRI
n = 77
n = 66
55 (23-83)46 (23-81)
42 (55)
35 (45)
34 (52)
32 (48)
1.4 (0-21)11.2 (0-137)
273314
267315
2 (1-13) 3 (1-12)
2 (1-14)4 (1-12)
n = 71
n = 66
n = 69
n = 65
Imaging, Diagnosis, Prognosis
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For anaplastic glioma, the median value of MMP-9 was
285 ng/mL for CR, 212 ng/mL for PR, 253 ng/mL for SD, and
434 ng/mL for POD. For anaplastic glioma patients, MMP-9
values were not significantly associated with disease status
(P = 0.73).
YKL-40 and MMP-9 levels and overall survival. The median
follow-up from entry for survivors with GBM was 4.6 months
(range, 0-27 months) and for those with anaplastic glioma,
22 months (range, 0-29 months). The estimated 2-year survival
from registration was 26% [95% confidence interval (95% CI),
12-39%] for GBM and 72% (95% CI, 59-84%) for anaplastic
glioma. We analyzed YKL-40 as a time-dependent covariate in a
Cox proportional hazard model for overall survival from entry
for 75 patients with GBM (two patients with immediate
postoperative measurements only were excluded) and 68
patients with anaplastic glioma (two patients enrolled with
low-grade glioma progressed to anaplasia and were included
using measurements after progression). The analysis was done
in two ways: by using the actual value of YKL-40 and MMP-9
in the log scale and by looking at the change in the markers
compared with the first level determined for an individual
patient designated as baseline in the log scale. For GBM, there
was a significant association between actual value of YKL-40
and survival, with a hazard ratio of 1.4 (95% CI, 1.1-1.9) per
Fig. 3. GBM patients with a CRhave a durable normalYKL-40. A total of five
patientshadapersistentCR.Only threemeasurementsintwopatientsareabovethe
normal. Each line represents one patient’s measurement. Brokenline, meannormal
value plus SD.
Fig. 4. Box plot illustrating MMP-9 values innormal subjects and GBM patients.
There is a significant difference betweenno evidence of disease and presence of
disease (P = 0.0002). N, number of patients; +, mean; horizontalline, median.
Lower line of the box represents 25th percentile andupper box represents 75th
percentile.
Fig. 5. Most GBM patientswitha complete CRhave MMP-9 levels inthereference
range. A total of five patients had a persistent CR. Only two measurements in two
patients are above thenormal. Each line represents one patient’s measurements.
Brokenline, meannormal value plus SD.
Fig. 2. Box plot illustratingYKL-40 values innormal subjects and GBM patients.
There is a significant difference betweenno evidence of disease and presence of
disease (P = 0.0003). N, number of patients; +, mean; horizontalline, median.
Lower line of the box represents 25thpercentile andupper box represents 75th
percentile.
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doubling of YKL-40 values (P = 0.02; Table 2). There was no
significant association between the change in YKL-40 from
baseline and survival (P = 0.12). For anaplastic glioma, there
was a marginally significant association between the change
from baseline and survival, with a hazard ratio of 1.7 (95% CI,
0.94-3.2) per doubling of YKL-40 compared with baseline
(P = 0.08) but no significant association between the actual
value of YKL-40 and survival (P = 0.26). In the anaplastic
astrocytoma subset, we found a significant association between
the actual value of YKL-40 and survival (hazard ratio, 2.2; 95%
CI, 0.99-4.9; P = 0.05) and a marginally significant association
with change from baseline (hazard ratio, 2.3; 95% CI, 0.98-5.2;
P = 0.06).
The analysis of MMP-9 as a time-dependent covariate in a
Cox proportional hazard model for overall survival showed
that MMP-9 values were not significantly associated with
survival for either anaplastic glioma (P = 0.36) or GBM
patients (P = 0.16; Table 2). There was also no significant
association in change from baseline in MMP-9 for GBM tumors
(P = 0.29) or anaplastic gliomas (P = 0.96). In the anaplastic
astrocytoma subset, there was no significant association
between survival and actual value of MMP-9 (P = 0.34) or
change from baseline (P = 0.41).
Modest correlation of YKL-40 with MMP-9 in anaplastic
gliomas but no correlation with tumor size. The correlation of
YKL-40 and MMP-9 values in the same serum sample of
patients with anaplastic gliomas was moderate (r = 0.52) but
the correlation was weaker for GBM (r = 0.24). To look at the
correlation of the serum markers with tumor size, we measured
tumor size on 225 MRI scans of GBM patients and 280 MRI
scans of anaplastic glioma patients. Neither YKL-40 nor MMP-9
values correlated with tumor size determined by one or two
dimensions for any glioma type.
No significant correlation between YKL-40 serum levels and
YKL-40 immunohistochemistry. We were able to perform
YKL-40 immunostaining in tumor specimens and compare
them with the preoperative YKL-40 serum values in 18 patients.
There was no correlation between immunostaining and
preoperative serum levels of YKL-40 (r = 0.08). Twelve of these
patients had a GBM. Comparative analysis of YKL-40 immu-
nostaining to the preoperative YKL-40 serum values in these
12 patients also showed no correlation (r = ?0.18).
Discussion
Elevated values of YKL-40 have been found in the serum
of patients with various diseases including pulmonary sarcoid-
osis (26), liver fibrosis (27), systemic sclerosis (28), active
inflammatory bowel disease (29), and bacterial endotoxemia
(30). Serum levels of YKL-40 are also elevated in patients with
cancer although its role in cancer cells is unknown. In patients
with recurrent breast cancer, elevated serum levels were related
to metastatic disease and worse survival (31). Preoperative high
serum levels of YKL-40 in patients with breast cancer were also
related to shorter overall survival and it was an independent
predictor of relapse-free survival (32). In colorectal cancer and
small-cell lung cancer patients, YKL-40 is also considered an
independent prognostic variable for poor survival (33, 34) and
it is a potential marker for detection of ovarian cancer that may
also predict recurrent disease and survival (25).
In a retrospective study, YKL-40 expression was increased in
operative specimens of GBM that progressed after radiotherapy
and was absent from tumor tissue of patients that responded to
radiotherapy (35). MMP-9 can be detected in the cerebrospinal
fluid of patients with brain tumors (36) and its expression in
tumor tissue correlates with glioma grade (37).
At the cellular level, the YKL-40 protein has been associated
with a survival advantage of GBM cells in response to hypoxia,
ionizing radiation, and p53 inhibition (38). It may have a role
in promoting cell proliferation as it was shown to promote
proliferation of connective tissue cells in vitro (39). This
mitogenic response to YKL-40 stimulation may involve both
mitogen-activated protein kinase and phosphatidylinositol
3-kinase (40), two components of a signal transduction cascade
known to be up-regulated in malignant glial cells. The presence
of heparin and hyaluronan binding motifs in the sequence
of YKL-40 suggests that it may interact with heparin-like
molecules or hyaluronan present on the cell surface or extra-
cellular matrix (8). YKL-40 may promote tumor angiogenesis
independently of angiogenic factors as it was shown to pro-
mote migration of human umbilical vein endothelial cells (41).
Our data suggest that serum levels of YKL-40 and MMP-9
differentiate between GBM patients with and without evidence
of disease; however, only YKL-40 was an indicator of survival in
GBM patients. For GBM patients, a low absolute YKL-40 value
identifies a subset that is more likely to do well. Those patients
with persistently normal values have a longer survival and
disease-free interval.
For anaplastic glioma, the YKL-40 level can also help identify
patients with no evidence of disease, and the change from
baseline is marginally predictive of survival. MMP-9 levels were
not predictive of either evidence of disease or survival in
anaplastic glioma patients. It seems that the anaplastic
astrocytoma subtype has a significant correlation of survival
with the actual value of YKL-40 and a marginally significant
correlation with change in value from baseline. This may
Table 2. Summary of statistical analysis of survival
Hazard ratio (P)
GBM Anaplastic gliomaAnaplastic astrocytoma
Total no. patients
Total no. deaths
YKL-40 per doubling in actual value
YKL-40 per doubling in value compared with baseline
MMP-9 per doubling in actual value
MMP-9 per doubling in value compared with baseline
75
32
68
17
38
10
1.4 (0.02)
1.4 (0.12)
1.2 (0.16)
1.1 (0.29)
1.3 (0.26)
1.7 (0.08)
1.2 (0.36)
0.99 (0.96)
2.2 (0.05)
2.3 (0.06)
1.3 (0.34)
0.8 (0.41)
Imaging, Diagnosis, Prognosis
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