1. NEWS & VIEWS
DIAGNOSIS
Novel prognostic biomarkers in hepatocellular
carcinoma
Roberta W. C. Pang and Ronnie T. P Poon
.
Hepatocellular carcinoma (HCC) is a heterogeneous cancer with variable outcomes after treatment. Prognosis of
HCC cannot be accurately predicted by current clinical staging systems. Development of prognostic biomarkers
is critical to improve treatment outcome. Recent studies indicate that inflammatory and immunological markers
might provide reliable prognostic classification in HCC.
Hepatocellular carcinoma (HCC) is a
common cancer worldwide, related to the
high prevalence of HBV and HCV infec­
tion. Despite advances in surgical and non­
surgical treatments, the prognosis for patients
with HCC remains unsatisfactory compared
with many other common human cancers.
A major obstacle hindering improvement in
treatment outcome is the difficulty in predict­
ing treatment response, owing to the hetero­
geneity of not only the cancer itself but also
the underlying chronic liver disease. Although
current clinical staging systems provide a
rough framework of prognostic classification
and treatment decision for HCC, identifica­
tion of prognostic biomarkers could further
enhance outcome prediction and treatment
selection. Thus far, most research has focused
on mol­ cular biomarkers based on tumour
e
molecular biology. Two recent papers have
highlighted the relevance of inflammatory
and immunological responses of the host
in predicting prognosis of HCC. Sieghart
et al.1 reported that high levels of C‑reactive
protein (CRP) at the time of diagnosis pre­
dicts poor long-term survival of patients
with HCC, whereas Fu et al.2 showed that
impairment of CD4+ cytotoxic T lympho­cytes
(CTLs) predicts poor outcome.
The study of inflammatory markers is of
particular relevance in HCC as the develop­
ment of this cancer is usually associated with
chronic inflammation. CRP is an acute-phase
protein produced by the liver in inflammatory
conditions and it has a role in linking innate
immunity and inflammation. The importance
of serum levels of CRP to prognosis has been
evaluated previously in HCC.3,4 Raised levels
of CRP have been shown to predict early
recurrence and poor survival in patients
Photodisc/Getty
Pang, R. W. C. & Poon, R. T. P Nat. Rev. Gastroenterol. Hepatol. 9, 691–692 (2012); published online 13 November 2012; doi:10.1038/nrgastro.2012.208
.
undergoing surgical resection for HCC.3
Furthermore, raised levels of CRP have also
been demonstrated to predict recurrence
and poor survival after liver transplantation
for HCC.4 In the new study, Sieghart et al.1
studied the prognostic importance of serum
levels of CRP in patients with HCC under­
going nonsurgical treatment. They used a
training cohort of 466 patients in one institu­
tion to identify the optimum cut-off CRP level
(1 mg/dl, equivalent to 95.2 nmol/l), and then
evaluated the influence on prognosis of high
versus low CRP levels according to this cut-off
value in a validation cohort of 252 patients
treated at another institution.1 The study
showed that raised levels of CRP was a pre­
dictor of poor survival in multivariate analy­
sis independent of other clinical factors. More
importantly, CRP level was demonstrated to
have independent prognostic value after strat­
ification by the Barcelona Clinic Liver Cancer
classification, suggesting that CRP level can be
added to the clinical staging system to further
subcategorize patients in terms of prognosis.
However, certain issues need to be further
addressed. First, the training cohort in the
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
© 2012 Macmillan Publishers Limited. All rights reserved
Sieghart et al.1 study included a wide spec­
trum of patients: those with early-stage
cancer treated with ablation; intermediatestage cancer treated with transarterial chemo­
embolization (TACE); and advanced-stage
cancer treated with systemic therapy. By
contrast, the validation cohort included only
patients treated with TACE. Whether the
prognostic value of CRP could be extended
to patients with early cancer undergoing
ablation or those with advanced cancer
undergoing systemic therapy, and whether
the same cut-off value could be applied, is
unclear from this study. Second, although
the study showed that raised levels of CRP
were more common in patients with HCC
compared with patients with cirrhosis only,
the relative contribution by the cancer and
the underlying liver disease to the CRP level
in the patients is unclear. This aspect might
be better evaluated by correlating CRP level
with transaminase levels, which reflect levels
of inflammation in the liver. Third, assum­
ing that the increased CRP levels were related
to the tumour (as proposed by the authors),
the biological relevance of CRP in tumour
progression has not been elucidated. In the
discussion, the authors suggested that the
inflammatory response associated with high
CRP levels could be directly involved in
tumour progression of HCC. They further
proposed IL‑6—one of the main inducers of
CRP production—as a possible mediator of
tumour progression as IL‑6 has been previ­
ously shown to promote tumour growth and
metastasis. However, the study by Sieghart
and colleagues1 did not evaluate IL‑6 levels
in the participants. Another study of 110
patients undergoing locoregional therapy
for HCC did, however, evaluate serum
VOLUME 9 | DECEMBER 2012 | 691

2. NEWS & VIEWS
levels of both CRP and IL‑6.5 This study
showed that the levels of both markers were
raised in patients with HCC compared with
healthy individuals, and high levels of both
biomarkers were associated with poor sur­
vival. However, in multivariate analysis, only
IL‑6 was an independent prognostic factor.
Further studies are needed to clarify the rela­
tive influence of serum levels of CRP and IL‑6
in prognosis for patients with HCC.
The study of immunological response
to tumours is important to understand the
mechanism of tumour immune evasion,
and also to provide insight into potential
immuno­ herapy strategies. Fu et al.2 studied
t
circulating and tumour-­ nfiltrating CD4+
i
CTLs in patients with HCC and observed that
a decrease in the number of CD4+ CTLs was
closely associated with progressive stages of
HCC and poor survival.2 The authors inves­
tigated the potential regulatory mechanism
involved in the decrease in CD4+ CTLs and
showed that the number of CD4+ CTLs was
negatively correlated with the number of
T-regulatory (TREG) cells. Furthermore, they
performed in vitro experiments to demon­
strate that TREG cells inhibited release of
cytolytic molecules (such as granzyme and
perforin) by CD4+ CTLs and the genera­
tion of CD4+ CTLs. In this study, prognostic
importance of circulating and tumour CD4+
CTLs was studied in two different cohorts
of patients over different time periods: cir­
culating CD4+ CTLs were evaluated in 232
patients with HCC between 2005 and 2012;
and tumour CD4+ CTLs were evaluated
using immuno­ istochemical staining in
h
315 patients undergoing resection for HCC
between 2001 and 2004. Although both circu­
lating and tumour CD4+ CTLs were shown to
be independent prognostic factors in multi­
variate analysis in the respective cohorts, it
remained unclear whether circulating and
tumour-infiltrating CD4+ CTLs were cor­
related with each other, and which cell type
might provide the best prognostic informa­
tion. The use of circulating CD4+ CTLs is
perhaps more practical for prognostic clas­
sification as tumour samples might not be
available in patients with advanced HCC
undergoing non­ urgical therapies.
s
Immunosuppression by TREG cells was
shown to be an important immune mecha­
nism of tumour evasion in patients with HCC
by previous studies.6,7 An existing study sug­
gested that TREG cells could enhance tumour
progression through suppression of the effec­
tor function of CD8+ T cells.7 The current
study by the same group of authors provided
an additional mechanism through which TREG
692 | DECEMBER 2012 | VOLUME 9
cells might enhance tumour escape from host
immune system.2 Another study has corrobo­
rated the importance of TREG cells in restrain­
ing antitumour immunity in primary and
secondary liver cancer.8 The elucidation of the
mechanisms that underlie immune evasion
is crucial in designing immunotherapy for
HCC. Interestingly, a study published in
2010 suggested that low-dose cyclophospha­
mide might suppress TREG cells and unmask
α‑fetoprotein (AFP)-specific CD4+ T‑cell
response in patients with advanced HCC.9
AFP is a specific tumour-associated antigen
of HCC, and induction of anti-AFP CD4+
T‑cell response represents cell-mediated
immune responses to the tumour cells. TREG
cells and CD4+ T cells seem to be potential
targets in immunotherapy for HCC.
To improve the management of HCC, it is
imperative to identify prognostic biomarkers
to aid clinical staging. Molecular biomarkers
based on tumour biology of HCC (such as
gene-expression profile and expression of
angiogenic factors) have been widely studied
and found to have prognostic implications.10
Inflammatory and immuno­ogical prognos­
l
tic biomarkers reflect the host response to
the tumour and therefore can supplement
tumour biology markers to provide a more
comprehensive picture of prognostic predic­
tion. However, future studies based on large
prospective cohorts are required to validate
their prognostic value before they can be
translated into clinical use.
Department of Surgery & Centre for Cancer
Research, The University of Hong Kong, Queen
Mary Hospital, 102 Pokfulam Road, Hong
Kong, China (R. W. C. Pang, R. T. P Poon).
.
Correspondence to: R. T. P. Poon
poontp@hku.hk
Acknowledgements
The authors would like to acknowledge grant support
from the Strategic Research Theme Grant of the
Centre for Cancer Research of the Faculty of
Medicine, The University of Hong Kong.
Competing interests
The authors declare no competing interests.
1.
Sieghart, W. et al. A single determination of
C‑reactive protein at the time of diagnosis
predicts long-term outcome of hepatocellular
carcinoma. Hepatology http://dx.doi.org/
10.1002/hep.26057.
2. Fu, J. et al. The impairment of CD4+ cytotoxic
T cells predicts poor survival and high recurrence
rates in patients with hepatocellular carcinoma.
Hepatology http://dx.doi.org/10.1002/
hep.26054.
3. Hashimoto, K. et al. The impact of preoperative
serum C‑reactive protein on the prognosis of
patients with hepatocellular carcinoma. Cancer
103, 1856–1864 (2005).
4. An, H. J. et al. Serum C‑reactive protein is a useful
biomarker to predict outcomes after liver
transplantation in patients with hepatocellular
carcinoma. Liver Transpl. http://dx.doi.org/
10.1002/lt.23512.
5. Jang, J. W. et al. Serum interleukin‑6 and
C‑reactive protein as a prognostic indicator in
hepatocellular carcinoma. Cytokine http://
dx.doi.org/10.1016/j.cyto.2012.07.117.
6. Fu, J. et al. Increased regulatory T cells correlate
with CD8 T‑cell impairment and poor survival in
hepatocellular carcinoma patients.
Gastroenterology 132, 2328–2339 (2007).
7. Zhou, J. et al. Increased intratumoral regulatory
T cells are related to intratumoral macrophages
and poor prognosis in hepatocellular carcinoma
patients. Int. J. Cancer 125, 1640–1648 (2009).
8. Pedroza-Gonzalez, A. et al. Activated tumorinfiltrating CD4+ regulatory T cells restrain
antitumor immunity in patients with primary or
metastatic liver cancer. Hepatology http://
dx.doi.org/10.1002/hep.26013.
9. Greten, T. F. et al. Low-dose cyclophosphamide
treatment impairs regulatory T cells and unmasks
AFP-specific CD4+ T‑cell responses in patients
with advanced HCC. J. Immunother. 33, 211–218
(2010).
10. Pang, R. W. et al. Biology of hepatocellular
carcinoma. Ann. Surg. Oncol. 15, 962–971 (2008).
ULCERATIVE COLITIS
UCCIS—a reproducible tool
to assess mucosal healing
Helmut Neumann and Markus F. Neurath
In an attempt to better characterize mucosal healing in ulcerative colitis,
various endoscopic scoring systems have been introduced. However, most
have limited interobserver agreement. A recent study has validated the
ulcerative colitis colonoscopic index of severity and found that this new
scoring system provides reproducible results among gastroenterologists.
Neumann, H. & Neurath, M. F. Nat. Rev. Gastroenterol. Hepatol. 9, 692–694 (2012);
published online 16 October 2012; doi:10.1038/nrgastro.2012.198
The ulcerative colitis colonoscopic index
of severity (UCCIS) is a newly introduced
scoring system that was developed in a
preliminary study that assessed 10 types of
mucosal lesions (that is, oedema, erythema,
stricture, loss of haustral folds, rigidity,
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© 2012 Macmillan Publishers Limited. All rights reserved