65 96
and accounting
for
these
relationships
in
the model might
enhance
its
validity.
Fourth,
although
the
three markers
were
independently
significant when
adjusted
for
other
base markers,
in
combination,
all
three had
to be positive
to
significantly
predict
recurrence
or
death.
Positivity
for
only one or
two of
the markers was not predictive of any of
the
three
outcomes.
The
fact
that
there
were
only
37
patients
in
the
group
with
three
positive
markers
raises
concerns
regarding
model
overfitting
in
this
subgroup. Lastly,
the
final model did not
take
into account
competing
risks
for
failure with
regard
to
cancer-specific
and
all-cause
mortality.
Since
UTUC
patients
are,
on
average, old and
comorbid,
competing
causes of mortality
are
significant
and
can
account
for
nearly
half
of
all
mortality
events
[8].
2.
Patient
selection
The
authors
included
patients
who
underwent
radical
nephroureterectomy
for
localized
UTUC,
and
excluded
patients who
had
undergone
neoadjuvant
chemotherapy.
The exclusion
criteria
create a
select group of patients and
limit
the
generalizability
of
the
findings.
Individuals with
poorer
renal
function
and
greater
comorbidity
are usually
deemed
unsuitable
for
neoadjuvant
chemotherapy.
Con-
versely, patients with a higher disease burden may be
sent
for
neoadjuvant
chemotherapy
in
an
attempt
to
down-
stage
the
disease
or
rule
out
occult
metastases
before
surgery.
Second,
the
fact
that
only
11%
of
the
cohort
underwent
lymphadenectomy
raises
concerns
regarding
differences
in
treatment
protocols
that might
have
arisen
from
the
multi-institutional
nature
of
the
study.
The
downstream
effect
of
knowing
the
lymph
node
status
of
these
patients
could
have
influenced
outcome.
Similarly,
the
indication
for
the
type
and
duration
of
adjuvant
chemotherapy
for
the
88
patients
was
unknown,
which
may
have
also
influenced
outcome.
Ultimately,
the development of a prognostic model
from
a cohort depends on
the data available
for
the cohort. There
were
no
data
regarding
environmental
exposures,
a well-
known
cause
of
urothelial
cancer,
in
this
cohort.
Cigarette
smoking
increases
the
risk
of
UTUC
and
of
recurrence
[9].
Furthermore,
cigarette
smoking
has
a well-recognized
systemic
inflammatory
effect,
and
is
thus
a
potential
confounder
of
inflammatory markers
in
this
setting
[10].
Nonetheless,
the
report
is
illuminating
and
the
authors
have
confirmed
some
important
findings.
Tumor
stage
and
lymphovascular
invasion
remain
the most
important
prognostic
factors
for
disease
recurrence
and
cancer-
specific
and
all-cause mortality.
The
inflammatory
cascade
may
have
a
role
in
predicting
outcome,
but
its mechanism
needs
to be
further understood and
its value as a prognostic
factor should be validated
in
independent cohorts. Whether
the
cumulative
marker
score
in
its
current
state
is
the
best aggregator of risk predicted by
inflammation
is unclear.
In
this
report,
its
incremental
improvement
in
prediction
was
2.7%
for
disease
recurrence,
3.9%
for
cancer-specific
mortality,
and
4.0%
for
all-cause mortality.
In
the
future,
prospective
investigation of more
inflammatory biomarkers
and
of
their
relationships
should
be
undertaken.
Of
even
greater
value
would
be
the
ability
to
predict
therapeutic
outcome
in
order
to
select
patients
for
chemotherapy,
surgery,
or
other
therapies.
Conflicts
of
interest:
The
authors
have
nothing
to
disclose.
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