Catching metastasizing cells in the act


Coumans, F.A.W. (2012) Catching metastasizing cells in the act. thesis.

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Abstract:Distant metastases are formed by tumor cells that shed from the primary
tumor into the bloodstream. These circulating tumor cells (CTC) may be
enumerated in a patients¿ blood. The number of CTC provides a prognosis,
predicts a response to therapy and the expression of certain molecules
in the CTC allows for determination of the most appropriate therapy.
CellSearch, the standard assay for CTC enumeration from 7.5 mL of blood
has shown feasibility of both these concepts, but finds no CTC in up to
50% of metastatic carcinoma patients. In this thesis we investigate several
approaches to improve recovery of CTC. Archive data from several large
clinical CTC trials were used to test alternative CTC definitions resulting
in a higher number of CTC for similar or better prognostic value than
the CellSearch definition. Flow cytometry was compared to CellSearch
to evaluate whether a higher number of CTC is achievable by improved
enrichment. The distribution function of CTC in metastatic patients was
determined to estimate the effect of increased sample volume. The increase
of sample volume by filtration of apheresis samples was investigated. An
improvement to the CellSearch analyzer is presented to allow more accurate
measurement of treatment targets on CTC. Increasing the number of CTC
by a more inclusive CTC definition reduces the prognostic value of the
CTC count when evaluating effectiveness of therapy. A potential threefold
increase in EpCAM+CK+DNA+CD45- CTC by improved recovery will not
be sufficient to find CTC in all metastatic carcinoma patients. Extrapolation
of the EpCAM+CK+DNA+CD45- CTC distribution function in patients,
predicts that increasing the sample volume to 5 liters of blood will result
in recovery of CTC in 99% of metastatic patients. CTC enrichment by
filtration of apheresis samples may allow for the sampling of such a blood
volume, but we could not reach the required assay conditions due to sample
age. It is critical for CTC enumeration that any cell included in the count
is a CTC, even if this means that a large fraction of tumor cell (fragments)
are not counted. To recover CTC in all patients, the sample volume must
be increased dramatically. Sample age is critical, and CTC recovery in
an extracorporeal circuit using antibody or physical based enrichment can
circumvent this issue.
Item Type:Thesis
Science and Technology (TNW)
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