61 96
along
with
an
increase
in
the
CMS
(
p
<
0.001). We
next
performed
univariate
and multivariate
analyses
to
deter-
mine
the
predictors
of
all-cause
mortality
( Table 5 ).
Multivariate
analyses
that
included
all
three
markers
separately
indicated
that
elevations
of
NLR,
plasma
fibrinogen,
and
CRP
levels
were
associated
with
worse
all-cause
mortality
following
RNU.
Similarly,
only
CRP
elevation
was
independently
associated
with
all-cause
mortality
when
all
three
markers
were
included
in
one
model.
Furthermore,
multivariate
analysis
revealed
that
the
CMS was
significantly
associated with worse
all-
cause mortality
following
RNU.
The
addition
of
CMS
to
a
standard
multivariate
model
improved
the
predictive
accuracy
by
4.0%
for
all-cause
mortality,
which
was
the
highest
among
our
prognostic models.
4.
Discussion
We
retrospectively
reviewed
a
multi-institutional
cohort
of
394
patients
who
underwent
RNU
and
analyzed
the
impact
of
CMS
on
subsequent
outcomes.
In
our
setting,
although multivariate analyses
showed
that
the use of each
inflammatory marker
alone
was
as
predictive
as
clinico-
pathologic
indices
for
prognosis,
combinations
like
CMS
provided
more
accurate
prediction
of
disease
recurrence
and
cancer-specific
and
all-cause mortality
following RNU.
Increasing
evidence
has
suggested
a
significant
inverse
association
between
systemic
inflammatory
markers
and
patient
survival with malignancies. Many
investigators have
documented
the prognostic value of
systemic
inflammatory
markers
and
then
included
those
in
their
risk models.
In
addition, guidelines
(eg,
for
renal cell carcinoma)
refer
to
the
elevation of
systemic
inflammatory markers
as a
significant
prognostic tool
[21]. Among blood-based biomarkers, we and
others
examined
the
efficacy
of
preoperative
NLR,
plasma
fibrinogen,
and
serum
CRP,
suggesting
that
all
of
these
markers are associatedwithdisease recurrence andmortality
in UTUC
following RNU
[7–12]. However, because of
the
lack
of
data
concerning
the
relationship
or
interaction
between
elevations of each
inflammatorymarker, we do not yet have a
sufficient understanding
of
the proper use
of
these
indices.
In
the
present
study,
we
found
a
significant
positive
correlation among all
three markers, especially among
the
preoperative
levels
of
plasma
fibrinogen
and
serum
CRP.
We
then
confirmed
our
hypothesis,
suggesting
that
combinations
of
the
three markers
could
be more
predic-
tive
for prognosis
than
a
single marker,
and
further
found
the
superiority
of
CMS
rather
than
combinations
of
two
(ie,
NLR
and
plasma
fibrinogen,
NLR
and
serum
CRP,
or
plasma
fibrinogen
and
serum
CRP)
of
the
three markers
(
Supplementary
Table
S1–3
).
Superior predictive value
for prognosis has been achieved
by
assessment
using
combinations
rather
than
single
markers
of
cell
cycle
regulators
and
apoptosis
markers
[20,22–25]. Using
immunostaining
including
p53,
p21,
and
p27
expression,
Shariat
et
al
reported
that
an
increased
number
of
altered
cell
cycle
regulators was
independently
associated with
the
risk of disease progression and mortality
in
bladder
UC
patients
[22,23] .Such
results
were
further
confirmed
by
prospective
analyses
in
UTUC
[25].
Karam
et
al
reported
an
assessment
of
an
altered
number
of
apoptosis
markers,
Bcl-2,
caspase-3,
p53,
and
survivin
expression,
resulting
in a significant
increase
in
the accuracy
of
survival
prediction
following
radical
cystectomy
[20] .In
addition,
combined
use
of
promoter methylation
status
in
tumors
or urine would
be
an
innovative
approach
in
the
management
of both
bladder UC
and UTUC
[26,27] .Although
such
molecules
improve
the
prediction
of
survival
for UTUC, we
propose
that
our
prognostic models
may
be
useful
for
two
different
reasons.
First,
all
three
markers
in
the
present
study
can
be
clinically
applied
for
routine measurement
because
of
their
low
cost
and
easy
accessibility.
Second,
these
three markers
can
be
available
before
surgical
intervention,
such
as
RNU.
Indeed,
neoad-
juvant
chemotherapy
has
the
advantage
of more
effective
delivery
of
chemotherapy
due
to
better
renal
function
in
UTUC
patients
[28,29].
Extended
lymph
node
dissection
at
RNU
may
have
therapeutic
potential
to
improve
disease
outcomes
[1,30].
Despite
appropriate
patient
selection
for
the
latter
two
strategies
potentially
being
challenging
for
physicians
prior
to
RNU
[6,28],
the
results may
assist
in
decision
making
when
considering
the
need
for
these
modalities
in
some
situations.
Our
study
has
several
limitations.
It
is
limited
by
its
retrospective
nature,
by
the
heterogeneous
group
of
patients due
to
a multi-institutional
study design,
by
short
median
follow-up, and by
lack of a central pathology
review
of
RNU
specimens.
In
addition,
laboratory
assays
were
performed at each
institution; however, when we
reran
the
data
set
by
including
the
data
for
the
treating
institution,
the
statistical
significance
of
the
variables
did
not
change.
Patients
with
potent
infectious
diseases
such
as
urinary
tract
infections
without
fever
may
be
included.
Not
all
patients
underwent
regional
or
extended
lymph
node
dissection, which may
have
potentially
influenced
subse-
quent
metastatic
spread.
A
wide
variety
of
adjuvant
chemotherapies were
administered
at
the
attending
phy-
sician’s
discretion;
however,
of
88
patients with
adjuvant
chemotherapy,
76
(86.4%)
were
administered
cisplatin-
based
regimens,
with
the
MVAC
regimen
for
most.
Furthermore,
the
present
data
do
not
include
information
on
surgical margins
in RNU
specimens, which may
improve
the
prediction
of
subsequent
outcome
.
External
validation
of
the present models
is warranted,
for example,
in a
future
prospective
study.
5.
Conclusions
This
retrospective
study
showed
that
a
CMS
defined
by
preoperative NLR,
plasma
fibrinogen,
and
serum
CRP was
an
independent
predictor
of
patient
survival
following
RNU. Although
the use
of
each
blood-based
inflammatory
marker
alone
provides
additional
prognostic
information,
the
addition
of
the
CMS
to multivariate
analysis
can
be
most
predictive
among
the
present
models.
These
data
confirm
our
hypothesis
and
suggest
the
potent
impact
of
the
CMS
as
a
novel
predictive
tool
for
prognosis
in UTUC
patients.
E U R O P E A N
U R O L O G Y
F O C U S
1
( 2 0 1 5
)
5 4 – 6 3
61