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remained suppressed after tumor patients went into remission, so it is unlikely that this protein would be
[64]
useful for longitudinal screening of pediatric brain tumor patients .

Limitations to CSF-based biomarkers
While relatively minimally invasive, accessing the lumbar cisterns in order to collect CSF samples is still
a more difficult affair than phlebotomy, saliva collection, or urine sampling. The procedures involved in
CSF sampling - lumbar puncture or ventricular puncture - require skilled, advanced practice medical
personnel with knowledge of basic anatomy and sterile technique. In the case of pediatric patients, sedation
is sometimes required in order to perform a lumbar puncture, and it is mandatory for ventricular access
procedures. These technical difficulties currently limit the availability of patient CSF as a routine diagnostic
medium and will likely frustrate attempts to use CSF-based biomarker assays for screening large populations
of pediatric patients. This limits the availability of patient CSF as a routine diagnostic medium.

As has been stated earlier, CSF may also be an inappropriate source of biomarker molecules for more
parenchymal based tumors, where tumor cells do not make direct contact with ependymal or pial surfaces
and are, therefore, less likely to release genetic material and small molecules into CSF. In reality, 70% of
pediatric brain tumors will arise in or near the 4th cerebral ventricle, making this potential limitation
[65]
applicable to a minority of cases .

In the same vein, though, the tendency of pediatric brain tumors to arise near the 4th ventricle in the
posterior fossa makes lumbar puncture more perilous for patients, as drainage of CSF from the lumbar
cistern, rarely, can create a pressure gradient across the infratentorial compartment in the setting of a large
mass lesion. These pressure gradients, in severe cases, can lead to brainstem and cerebellar herniation
[66]
through the foramen magnum, causing significant neural injury and even death . For this reason, routine
lumbar punctures for the purposes of oncologic screening may not be deemed safe in many pediatric brain
tumor patients.

Serum biomarkers
While CSF can be problematic to acquire, more peripheral biofluids, such as serum, urine, and saliva, can
and are easily acquired from pediatric patients in ambulatory settings every day. In this sense, they are far
more practical sources for pediatric brain tumor biomarker discovery than CSF; but discoveries in these
media must be approached cautiously, as biomarkers in these biofluids are subject to dilution and filtration at
multiple points between synthesis and their collection sites, sometimes greatly compromising the fidelity of
the observed biomarker concentration [67-69] .

That being said, serum remains the most successful source of clinically relevant biomarkers in practice
today. Examples of serum biomarkers in clinical use include prostate specific antigen, AFP, βHCG, alanine
aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and carcinoembryonic antigen [70,71] . As
is the case in adult oncology, most research into pediatric brain tumor peripherally circulating biomarkers
has focused on protein biomarkers, similar to those just listed, but miRNA are also beginning to show
promise as potentially specific and easily measured diagnostics for detecting, diagnosing, and tracking
pediatric brain tumors. Due to their relatively rapid turnover in the peripheral blood stream, DNA and RNA
based biomarkers are particularly well suited for gauging tumor response to therapy .
[72]
Non-coding RNA
As with CSF, serum miRNA and other forms of non-coding RNA have been targeted for potential diagnostic
and screening purposes in neuro-oncology. miR-21, miR-125b, miR-128, miR-15b, and miR-182 have all been
[73]
implicated in adult glioma studies of miRNA signatures within patient sera . Serum miR-21 and miR-15b,
in particular, have been shown to strongly predict glial tumors in adult patient populations, with combined