Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities

Table 1 Utility and detection limits of existing diagnostic measures of hepatocellular carcinoma

Diagnostic methods	Definition/concept	Diagnostic limit/range	Ref.
Contrast-enhanced ultrasound	Inexpensive, non-invasive, first choice for screening HCC; Real time dynamic of blood supply.	Small HCC less than 1 cm	[101]
Multi phasic enhanced computed tomography	3 dimensional reconstructions, high sensitivity	1-2 cm HCC lesion	[102]
Magnetic resonance imaging	High resolution anatomic details, pre-contrast and multi-phasic enhanced 3D; Diffusion weighted imaging-functional imaging	2-3 cm HCC lesion	[103]
Positron emission tomography	Hepatocyte-specific PET tracer, 2-[18F] fluoro-2-deoxy-D-galactose, is used which accumulates in the liver compared with other tissues	Detection of small intrahepatic; HCC lesions	[104]
AFP	Elevated in HCC, non-specific	Range: > 500 ng/mL	[23]
α-L-fucosidase	Expressed in liver cirrhosis	Cut-off: 870 nmol/L	[105]
Des-γ-carboxy prothrombin	Sensitive; Not expressed in other liver disease	Cut-off: 40 mAU/mL	[105,106]
HSP90α + AFP +TKI	Combination of markers have improved diagnostic value	HSP90- (76.65-144.00); AFP- (5.33-2000.00); TK1- (0.57-2.30)	[26]
AFP, GPC3, and GP73	Useful markers for early diagnosis and prognosis	Upregulated	[27,107]
microRNA: miR-21, miR-199, and miR-122, miR-23a	Specific for diagnosis of HCC; Extremely sensitive	Cut-off value of ≥ 210	[108,109]

HCC: Hepatocellular carcinoma; AFP: α-fetoprotein.

Table 2 List of Food and Drug Administration approved/under trial epi-drugs

Drugs	Classification	Approved year	Indicated disease	Reference/ clinical trial number
Azacytidine	DNMT inhibitor	2004	MDS	NCT01186939
		2009	AML	NCT00887068
Decitabine	DNMT inhibitor	2006	MDS	NCT01751867
		2011	AML	NCT00260832
Vorinostat	HDAC inhibitor	2006	CTCL	NCT00773747
Romidepsin	HDAC inhibitor	2009	TCL	NCT02296398
Belinostat	HDAC inhibitor	2015	PTCL	NCT01839097
Panobinostat	HDAC inhibitor	2015	MM	NCT01023308
		2016	CML	NCT00451035
		2017	TCL	NCT00490776

MDS: Myelodysplastic syndrome; AML: Acute myeloid leukemia; CTCL: Cutaneous T cell lymphoma; TCL: T-cell lymphoma; PTCL: Peripheral T cell lymphoma; MM: Multiple myeloma; CML: Chronic myeloid leukemia; HDAC: Histone deacetylase; DNMT: DNA methyltransferase.