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Hung et al. Attenuation of liver stiffness by sorafenib

diseases or interfering with receptor/ligand interactions METHODS
has been reported in clinical trials or observational
studies. [4] Patients
Patients with HCC were treated for recurrence after
The inhibition of tyrosine kinase receptors for resection or advanced HCC as stage C or stage III-
proliferative cytokines, such as PDGF, VEGF and IV according to the Barcelona Clinical Liver Cancer
fibroblast growth factors (FGF), could reverse liver staging system or the 7th edition of American Joint
fibrosis. The binding of PDGF to PDGF receptor Committee on Cancer/Union for International Cancer
(PDGFR)-b activates Ras and sequentially propagates Control) staging system respectively from May 2014
the stimulatory signal via the phosphorylation of to July 2015. [20-22] A total of 17 consecutive patients
the mitogen-activated protein kinase (MAPK)/ with advanced HCC were recruited retrospectively
[5]
extracellular-signal-regulated kinase (ERK) pathway, for this observational study in the clinic of Chang
which regulates protein synthesis, transcription of Gung Memorial Hospital (CGMH) fourteen patients
profibrogenic genes, proliferation, cell cycle control had previously undergone surgical resection and
[6]
and apoptosis in HSCs. The anti-fibrotic effect of tumor recurrence developed in the follow-up period.
imatinib, which occurs via the targeting of PDGF, has Sorafenib was administered as salvage treatment.
been observed in mouse and rat studies. Sorafenib The remaining three patients were unresectable with
[7]
is a multi-tyrosine kinase inhibitor that targets the typical imaging findings. The status of advanced HCC
receptor tyrosine kinases VEGF receptor (VEGFR) included major portal vein thrombosis (n = 5) and
and PDGFR-b and inhibits the activation of Raf/ERK distant metastasis (n = 12, 5 in the lung, 2 in the bone,
[8]
signaling pathways. Sorafenib is the standard therapy 2 in the peritoneum, 1 in the bone and peritoneum,
for the treatment of advanced hepatocellular carcinoma 1 in a lymph node and 1 in the adrenal gland). The
(HCC). [9,10] Recent studies have shown that sorafenib treatment of HCC was based on clinical practice
can induce anti-fibrotic effects by reducing HSC guidelines, [20,21] and all patients were under the care of
proliferation and enhancing apoptosis. [6,11] Sorafenib the liver cancer team of the Linkou branch of CGMH.
also attenuates liver fibrosis and injury through the The daily oral dosage of sorafenib was administered
up-regulation of signal transducer and activator of and adjusted with toxicity evaluation and without drug
transcription 3 (STAT3) phosphorylation in hepatocytes interruption in the observation period. The dosage
or through STAT3 inhibition in HSCs. [12,13] was deescalated with toxicity intolerance from 800 mg
to 400 mg.
Liver biopsy has been considered to be a “gold
standard” for the assessment of liver fibrosis. [14] This study was approved by the Institutional Review
However, a number of well-known characteristics, Board (IRB) of CGMH, Linkou branch (IRB No.
such as the associated risk of morbidity, including 103-1747B). All methods of data collection were
the risk of bleeding and perforation, inter-observer performed in accordance with the relevant guidelines
variability in the interpretation of biopsies, sampling and regulations of IRB in CGMH.
variability in the context of accurate staging, monetary
costs and the turnover time for results, limit the clinical ARFI elastography measurements
application of liver biopsy. [15] Non-invasive methods The ARFI elastography examinations were performed
that use serum biologic markers or elastography via with an Acuson S2000 ultrasound (Siemens Medical
ultrasound and magnetic resonance imaging-based Solutions, Mountain View, California, USA) with ARFI
techniques have emerged recently for the indirect technology equipment, a curvilinear array transducer
assessment of liver fibrosis. Acoustic radiation force operating at 4 MHz (4C1) and the virtual touch tissue
impulse (ARFI) elastography is an ultrasound-based quantification system every 3 months. With the liver
technique for quantifying the mechanical properties parenchyma free of visible hepatic tumors, blood
of tissue stiffness. [16,17] ARFI has been utilized in vessels and bile ducts, as confirmed by conventional
comparison with various stages of liver fibrosis and ultrasonic images, 10 valid measurements of shear
shows good diagnostic accuracy in predicting hepatic wave velocity (SWV, m/s) were made by a single
fibrosis. [18,19] experienced examiner (Chen YC) with the patients
holding their breath for a few seconds. The results of
We conducted an observational case-series study to ARFI elastography were expressed as the median of
assess liver fibrosis/stiffness using ARFI elastography the 10 SWV measurements in the liver parenchyma.
among sorafenib-treated patients with advanced HCC The SWV measurements in this study were validated
to explore anti-fibrotic effects and the correlation with using the ratio of the interquartile range (IQR) to the
non-invasive methods. median value, which is currently used to assess the
Hepatoma Research ¦ Volume 3 ¦ March 24, 2017 53