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86% and specificity of 100%. In particular, levels of miR-15b, miR-21, and miR-23a correlated strongly with
2
2
tumor nodule volume (miR-15b, R = 0.86; miR-21 R = 0.92; miR-23a, R = 0.86) and returned to normal
2
levels within 24 h of gross total tumor resection. Interestingly, patients with tumors situated more deeply
within the brain parenchyma demonstrated higher ratios of miRNA to tumor nodule volume than those
[41]
more peripherally situated . These results further support the notion that oncologic miRNA serum levels
may be affected by tumor anatomic location, just has been speculated with CSF biomarkers [Figure 1].
This pilot study evaluating the potential utility of serum miRNA as a biomarker for pediatric brain tumors
is encouraging, but this initial work also highlighted significant barriers to serum miRNA development,
including: (1) normalization of miRNA profiles; (2) low miRNA yields compared to tissue or CSF sources;
(3) and a poor understanding of relative contributions tumor and host tissues make to the final serum
miRNA signatures [41,71] . One significant example of these challenges can be demonstrated in observing the
effect that general anesthesia has on select serum miRNA levels. miR-125b, which has been implicated as
an oncomir in gliomas and medulloblastomas [80,81] , is suppressed in humans and rodents after exposure
to general anesthetic agents [41,82] . Yet, few miRNA biomarker studies have controlled for the effects of
anesthesia miRNA levels. Indeed, controlling for anesthesia in pediatric clinical trials is an ethically and
technically complicated matter that adds a layer of complexity to serum miRNA interpretation of which
clinical researchers must be cognizant. This example highlights the importance of developing a thorough
understanding of the interplay between oncologically-relevant miRNA and the normal functions they
regulate so that confounding host and external forces acting on miRNA of interest can be controlled.

Protein/small molecule
As mentioned previously, protein and small molecule serum biomarkers have been extensively studied,
and they represent, perhaps, the most significant cohort of potential biomarkers for pediatric brain tumors.
An exhaustive list of all proteins and small molecules implicated in pediatric brain tumor diagnostics and
prognostics is beyond the scope of this brief review, but we will touch on some of the more widely reported
biomarkers in the literature.

Osteopontin is an extracellular matrix protein expressed in a wide variety of tissues and involved in
[83]
mineralization, immune modulation, cell migration, and anti-apoptosis . It has been shown to be
overexpressed in atypical teratoid/rhabdoid tumors (AT/RT), as well as several other CNS tumors. In a series
of 39 pediatric patients with AT/RT, medulloblastoma, epilepsy, or hydrocephalus, serum and CSF levels of
osteopontin were shown to be significantly elevated in AT/RT patients versus medulloblastoma patients (~2:1
in serum) and versus control patients (~4:1 in serum). Serum osteopontin levels also correlated with AT/
[84]
RT response to therapy, and higher serum levels were associated with a more malignant disease course .
This work raises the possibility that osteopontin may be a highly specific and reliable biomarker for risk-
stratifying AT/RT patients and gauging their response to therapy.

Another protein involved in a variety of carcinogenic signaling pathways, including proliferation,
immunomodulation, migration, anti-apoptosis, and chemotherapy resistance, is metallothionein. Different
isomers of metallothionein have been implicated in vitro in inducing chemoresistance in neuroblastoma,
melanoma, rhabdomyosarcoma, and medulloblastoma cell lines [85-87] . A group of researchers, using differential
pulse voltammetry to measure serum metallothionein levels, attempted to exploit metallothionein’s association
with oncogenesis to see if it could be reliably detected at supernormal levels in pediatric solid tumor patients,
including in 10 medulloblastoma patients and 4 ependymoma patients. All 38 pediatric solid tumor patients
[88]
in this study had serum levels of metallothionein roughly 6-8-fold higher than adult controls (P < 0.05) . This
work strongly suggests that serum metallothionein may be useful as a non-specific oncologic biomarker in
pediatric patients, though additional work is needed to confirm the results with age-matched controls.