Effective prevention of sorafenib-related vascular damage induced adverse events and maintenance of hepatic function by dried bonito broth and histidine

Figures & data

Figure 1 Study design. The control group (n=6) was treated with SOR without DBB or HIS. The DBB+SOR group (n=6) and the HIS +S OR group (n=6) were treated with SOR with DBB and SOR with HIS.

Abbreviations: SOR, sorafenib; DBB, dried bonito broth; HIS, histidine; CT, computed tomography.

Table 1 Characteristics of the patients

Characteristics	Group			MWW test P-value
	SOR	SOR+DBB	SOR+HIS
n=6	n=6	n=6
Age (years)				0.87
Median	72.0	68.0	72.5
Range	60–80	60–77	48–79
Gender				0.62
Female	1	1	0
Male	5	5	6
BW (kg)				0.69
Median	58.7	61.4	65.5
Range	46.9–76.0	50.1–77.4	48.0–100
Etiology				1.00
HBV infection	0	1	2
HCV infection	4	2	0
Nonalcoholic steatohepatitis	1	3	4
Alcoholic steatohepatitis	1	0	0
Cirrhosis				0.79
Yes/no	5/1	5/1	4/2
Child–Pugh grade				0.85
A/B/C	3/2/0	3/2/0	0/4/0
Cancer stage				0.74
I/II/III/IVA/IVB	0/0/1/3/2	0/0/1/2/3	0/0/1/4/1
SOR (mg/body)				0.87
400/600/800	4/2/0	3/3/0	5/0/1
Period of medication (days)				0.57
Median	79.0	67.5	51.5
Range	20–494	21–1040	26–184
Antitumor response (n)				0.91
CR/PR/SD/PD	0/1/2/3	0/1/3/2	0/1/3/2
HFS (n)				0.02
	4	0	1
HFS (grade)
0/1/2/3	0/2/0/2	0/0/0/0	0/0/1/0
HT before SOR				0.76
	5	5	4
HT progression				0.11
	4	3	1
Period to CT imaging (days)				0.55
Median	33.5	35.5	30.0
Range	15–40	23–42	28–30

Abbreviations: SOR, sorafenib; HIS, histidine; DBB, dried bonito broth; MWW, Mann–Whitney–Wilcoxon test; BW, body weight; HBV, hepatitis B virus; HCV, hepatitis C virus; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; HFS, hand–foot syndrome; HT, hypertension; CT, computed tomography.

Figure 2 Impact of SOR on normal blood vessels. DSA images of a representative case. (A) before SOR administration and (B) 3 months after SOR administration. 3D images of the vascular structure reconstructed from CT images (C) before SOR administration and (D) 3 months after SOR administration.

Abbreviations: DSA, digital subtraction angiography; SOR, sorafenib; CT, computed tomography; CHA, common hepatic artery; RHA, right hepatic artery; LHA, left hepatic artery; SPA, splenic artery; CA, celiac artery.

Figure 3 Representative 3D images of vasculature in the SOR, DBB+SOR, and HIS+SOR groups. 3D images of the LHA in the SOR monotherapy group before SOR administration (A) and approximately 1 month after initiation of SOR (B). DBB+SOR group (C and D). HIS+SOR group (E and F).

Abbreviations: LHA, left hepatic artery; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.

Figure 4 Effect of DBB and HIS on the changes in vascular area dimension caused by SOR. The ratio of vascular area dimension from after to before SOR administration was compared between groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). *P<0.05; **P<0.01; NS, not significant. Kruskal–Wallis test followed by Dunn’s multiple comparison tests.

Abbreviations: CHA, common hepatic artery; RHA, right hepatic artery; LHA, left hepatic artery; SPA, splenic artery; CA, celiac artery; SMA, superior mesenteric artery; RRA, right renal artery; LRA, left renal artery; PV, portal vein; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.

Figure 5 Effect of DBB and HIS on the changes in serum biochemical factors caused by SOR.

Notes: (A–I) Changes in serum biochemical factors from before to after SOR administration were compared between the groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). N.S., not significant, Kruskal–Wallis test followed by Dunn’s multiple comparison tests.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; TBIL, total bilirubin; TC, total cholesterol; TG, triglycerides; PT, prothrombin time; BUN, blood urea nitrogen; CRE, creatinine; PLT, platelets; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine

Table 2 Background of serum biochemical analysis

Serum markers	Group			MWW test P-value
	SOR	SOR+DBB	SOR+HIS
n=6	n=6	n=6
AST (IU/L)				0.25
Median	60	45.5	52.5
Range	30–233	26–157	23–114
ALT (IU/L)				0.67
Median	43	34	52
Range	11–125	17–137	18–118
TBIL (mg/dL)				0.14
Median	1	0.75	0.8
Range	0.6–1.6	0.4–1.4	0.4–1.6
TC (mg/dL)				0.23
Median	188.5	163.5	131
Range	122–244	128–183	114–188
TG (mg/dL)				0.95
Median	51.5	66	72
Range	34–159	57–126	68–86
PT (%)				0.49
Median	84	79.5	90
Range	70–100	68–104	61–128
BUN (mg/dL)				0.10
Median	16	14.5	17.5
Range	14–27	10–20	9–25
CRE (mg/dL)				0.89
Median	0.79	0.74	0.8
Range	0.57–0.9	0.51–1.28	0.6–0.98
PLT (×10^4/μL)				0.91
Median	13.7	13.5	11.6
Range	11.4–32.9	3.8–80.4	10.5–30.5

Abbreviations: SOR, sorafenib; HIS, histidine; DBB, dried bonito broth; MWW, Mann–Whitney–Wilcoxon test; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TBIL, total bilirubin; TC, total cholesterol; TG, triglycerides; PT, prothrombin time; BUN, blood urea nitrogen; CRE, creatinine; PLT, platelets.

Figure 6 Effect of DBB and HIS on serum ALB level and PV area dimension.

Notes: (A) Changes in serum ALB from the levels before SOR administration were compared between the groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). *P<0.05. Kruskal–Wallis test followed by Dunn’s multiple comparison test. (B) Changes in serum ALB and PV area dimension. The bold black line shows the trend line, and analysis of the correlation between changes in serum ALB and PV area dimension was performed. *P<0.05, Pearson’s correlation test.

Abbreviations: ALB, albumin; PV, portal vein; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.