PMC6127913_01
Hematoxylin and eosin (H&E) staining shows moderately differentiated intrahepatic cholangiocarcinoma (magnification ~ x200)
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Fig1
The patient is a 72-year-old man with histologically confirmed moderately differentiated intrahepatic cholangiocarcinoma (Fig. 1).
MRI tumor evaluation during treatment. Tumor area is highlighted on the left panel. Raw images are provided on the right panel. a Tumor evaluation at the stage of the initial CCA diagnosis (October 2015, was done with liver vein contrasting (7.5 ml Gadovist). Sum of diameters of target lesions equals 221 mm; b tumor progression after the best clinical practice care (July 2016). Sum of diameters of target lesions equals 278 mm (26% increase); c tumor growth during Sorafenib treatment (October 2016). Sum of diameters of target lesions equals 314 mm (16% increase); d tumor growth after Sorafenib treatment prior to start of Pazopanib (January 2017). Sum of diameters of target lesions equals 392 mm (35.3% increase). e Tumor progression after Pazopanib treatment (July 2017). Sum of diameters of target lesions equals 471 mm (35.7% increase if counting a as a reference or 20% increase if counting d as a reference)
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Fig2
MRI image at the time of diagnosis is shown on Fig. 2a. The treatment was poorly effective, and the tumor increased in size according to MRI (Fig. 2b); additional metastatic nodules appeared in the left and the right lobes with the spread to the bile duct, holedoch and into the gallbladder. MRI analysis in October 2016 revealed moderate tumor growth, corresponding to disease stabilization (Fig. 2c). MRI performed in January 2017 revealed progression of tumor growth and additional nodule in the left lung (Fig. 2d). Trametinib in CCA did not report hand-foot syndrome as a side effect. Pazopanib administration (800 mg daily) started since January 2017. The control MRI in July 2017 revealed progression in the lung nodes and 20% increase in sum of diameters of target lesions, which is a borderline between stabilization and progression according to RECIST (Fig. 2e).
Serum gamma glutamyltranspeptidase levels during treatment
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Fig3
Serum gamma glutamyltranspeptidase (GGT) level, which is associated with poor prognosis and tumor aggressiveness, was significantly increased, when compared to pre-treatment levels (Fig. 3). In addition, start of Pazopanib treatment coincided with a start of a trend towards decrease of serum GGT level (Fig. 3).
ERK and Ras signaling pathways were hyperactivated in the biopsy CCA tissue. Visualization was provided by Oncobox software. The pathways are shown as an interacting network, where green arrows indicate activation, red arrows:inhibition. Color depth of each node of the network corresponds to the logarithms of the case-to-normal (CNR) expression rate for each node, where "normal" is a geometric average between normal tissue samples, the scale represents extent of up/downregulation. The molecular targets of Sorafenib and Pazopanib are shown by black arrows
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Fig4
Ras molecular signaling pathways were highly activated in the CCA patient's tumor biopsy (Fig. 4), the predicted rating of the most effective target drugs is shown in Table 2. Regorafenib, a multi-tyrosine kinase inhibitor was on the top position of the rating.