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on this special issue [108] , although in the recent American Cancer Society Guidelines, the screening for
liver cancer is not mentioned [133] . Even in China, there are several clinical practice guidelines for liver
cancer [134] . Therefore, any users of these guidelines should be aware that the recommendations are intended
to guide clinical practice in circumstances where all possible resources and therapies are available; hence,
they should adopt the recommendations in the context of their local regulations and/or team capacities,
infrastructure and cost-benefit strategies [108,129] . Liver cancer nowadays is the second leading cause of cancer
deaths worldwide, accounting for about 8.1% of the global burden of cancer, in which China represents its
[1]
51% of this burden . The global solution to the early diagnosis and treatment of liver cancer should fully
consider the actual situation in China. We present some suggestions in summary for liver cancer screening/
surveillance.

Combined use of US and AFP are recommended
So far, AFP remains an effictive screening tool or marker for liver cancer detection, especially in undeveloped
countries/areas, on Asia, and even in some areas in developed countries [55-57,65,80,86] , because there is no a
[62]
single “all-in-one” biomarker that fits all-surveillance, diagnosis, or prediction of prognosis . In order to
improve the sensitivity and specificity of screening and prevent missed diagnosis, the combination use of
US and AFP test are strongly recommended. Since about 30% of liver cancers are negative for serum AFP,
[56]
novel diagnostic markers need to be established . There are no data to support the use of multidetector CT
or dynamic MRI for surveillance [108] , but one report [133] showed that the sensitivity estimates of CT and MRI
for liver cancer detection were 0.70 and 0.86, respectively, and the combined use was 0.94. CT or MRI could
be used for patients with cirrhosis and those suspected cases (such as with AFP positivity) requiring further
clinical ascertainment [57,130,135] .

Novel diagnostic markers are urgently needed
In addition to AFP (AFP-L3), DCP, GPC3, GP73, AFU, GGT and others are still recommended as markers
for monitoring and diagnosis of liver cancer; DKK1, MDK, and microRNA are also being used as new
markers [55,56,62,61,136-141] . For instance, a European study found that osteopontin (OPN) is a promising
marker for early detection of HCC [142] . In this study, each of 100 HCC cases was matched with 2 controls.
Conditional logistic regression model was used to calculate the multivariate OR and 95%CI for OPN
levels in relation to HCC. The results showed that OPN levels were positively correlated with HCC risk:
the multivariate OR was 1.30 (1.14-1.48) for every 10% increase. For cases diagnosed within 2 years, the
combination of OPN and AFP was best able to predict the risk of HCC, indicating that the measurement of
OPN and AFP could independently identify high-risk groups in liver diseases. In order to make up for the
deficiency of sensitivity and specificity of diagnostic markers such as AFP, novel early diagnosis and early
precursory (predictive) markers are urgently needed for research-development and verification.

Translating early detection to effective curable treatment
According to the current economic conditions and medical conditions (especially in undeveloped
countries/areas), screening in high-risk groups of liver cancer every 6 months is particularly appropriate
and acceptable. The key for a successful screening program should be a focus on individuals at high risk,
conducting repeated or periodical screening and follow-up. Some authors may suggest patients with
HCV, NAFLD or with cirrhosis should be screened, but so far there are no data from randomized trials of
[5]
surveillance to evaluate effectiveness . Liver cancer patients found in screening who fail to receive timely
treatment will not improve survival and mortality. Any guidelines for screening on liver cancer should
emphasize not only the early detection of liver cancer but also access and uptake of early curable or life-
extending treatment.

Effectiveness of screening is in anticipation
For evaluating the efficacy of population-based cancer screening modalities, the reduction of mortality
rate within the screened population is the gold-standard indicator [20,72] , but it should not be a mandatory