Risk prediction of acute variceal bleeding in hepatocellular carcinoma patients undergoing systemic therapy based on immune checkpoint inhibitors

Table 1 Statistics on baseline characteristics of the study population, n (%)

Clinical characteristics	Training cohort (n = 184)	Validation cohort (n = 102)	Z/χ2	P value
Sex			0.208	0.648
Female	39 (21.2)	24 (23.5)
Male	145 (78.8)	78 (76.5)
Age (years)			0.001	0.983
< 60	76 (41.3)	42 (41.2)
≥ 60	108 (58.7)	60 (58.8)
Etiology			0.356	0.949
Hepatitis B	143 (77.7)	78 (76.5)
Hepatitis C	18 (9.8)	9 (8.8)
Alcoholic liver disease	13 (7.1)	8 (7.8)
Other	10 (5.4)	7 (6.9)
BCLC staging			1.526	0.466
A	32 (17.4)	22 (21.6)
B	50 (27.2)	31 (30.4)
C	102 (55.4)	49 (48.0)
Immunotherapy drugs			2.028	0.363
Camrelizumab	125 (67.9)	76 (74.5)
Tislelizumab	40 (21.7)	20 (19.6)
Other	19 (10.3)	6 (5.9)
Combined antivascular drugs			1.000	0.607
TKIs	106 (57.6)	61 (59.8)
Bevacizumab	17 (9.2)	6 (5.9)
None	61 (33.2)	35 (34.3)
Bleeding events			0.044	0.833
Without	146 (79.3)	82 (80.4)
With	38 (20.7)	20 (19.6)
Bleeding time	3.00 (1.00,10.00)	4.00 (2.00,11.00)	-0.579	0.563

BCLC: Barcelona Clinic Liver Cancer; TKIs: Tyrosine kinase inhibitors.

Table 2 Comparison between the bleeding and non-bleeding groups in the training cohort, n (%)

Clinical characteristics	Non-bleeding group (n = 146)	Bleeding group (n = 38)	t/Z/χ2	P value
Sex			0.001	0.981
Female	31 (21.2)	8 (21.1)
Male	115 (78.8)	30 (78.9)
Age (years)			0.013	0.910
< 60	60 (41.1)	16 (42.1)
≥ 60	86 (58.9)	22 (57.9)
Etiology			4.141	0.233
Hepatitis B	110 (75.3)	33 (86.6)
Hepatitis C	15 (10.3)	3 (7.9)
Alcoholic liver disease	13 (8.9)	0 (0.0)
Other	8 (5.5)	2 (5.3)
Immunotherapy drugs			3.268	0.199
Camrelizumab	101 (69.2)	24 (63.2)
Tislelizumab	33 (22.6)	7 (18.4)
Other	12 (8.2)	7 (18.4)
Combined antivascular drugs			5.490	0.062
TKIs	90 (61.6)	16 (42.1)
Bevacizumab	11 (7.5)	6 (15.8)
None	45 (30.8)	16 (42.1)
Combined local treatment			0.917	0.338
Without	35 (24.0)	12 (31.6)
With	111 (76.0)	26 (68.4)
TBIL (µmol/L)			3.657	0.056
< 20	83 (56.8)	15 (39.5)
≥ 20	63 (43.2)	23 (60.5)
ALB (g/L)			1.403	0.236
≥ 35	103 (70.5)	23 (60.5)
< 35	43 (29.5)	15 (39.5)
LDH (µ/L)			3.344	0.067
< 250	100 (68.5)	20 (52.6)
≥ 250	46 (31.5)	18 (47.4)
PLT (× 109)			3.889	0.049
< 100	80 (54.8)	14 (36.8)
≥ 100	66 (45.2)	24 (63.2)
AFP (ng/mL)			4.748	0.029
< 400	104 (71.2)	20 (52.6)
≥ 400	42 (28.8)	18 (47.4)
Number of tumours, (%)			0.020	0.887
Solitary tumor	44 (30.1)	11 (28.9)
Multiple tumors	102 (69.9)	27 (71.1)
Maximum tumour diameter (cm)			10.270	0.001
< 5	99 (67.8)	15 (39.5)
≥ 5	47 (32.2)	23 (60.5)
Combined portal vein tumor thrombosis	46 (31.5)	19 (50.0)	4.514	0.034
Combined distant metastases	48 (32.9)	9 (23.7)	1.192	0.275
BCLC staging			2.080	0.353
A	27 (18.5)	5 (13.2)
B	42 (28.8)	8 (21.1)
C	77 (52.7)	25 (65.8)
Combined ascites	28 (19.2)	15 (39.5)	6.935	0.008
History of pre-treatment bleeding	10 (6.8)	19 (50.0)	42.286	< 0.001
History of endoscopy treatment	21 (14.4)	18 (47.4)	19.640	< 0.001
Child-Pugh grade			0.016	0.900
A	119 (81.5)	30 (78.9)
B	27 (18.5)	8 (21.1)
ALBI grade			8.218	0.004
Grade 1	64 (43.8)	7 (18.4)
Grades 2 and 3	82 (56.2)	31 (81.6)
FIB-4 grade			10.745	0.001
< 4.57	82 (56.2)	10 (26.3)
≥ 4.57	64 (43.8)	28 (73.7)
PNI grade			13.804	0.001
≥ 45	62 (42.5)	4 (10.5)
40-44.9	37 (25.3)	17 (44.7)
< 40	47 (32.2)	17 (44.7)

TBIL: Total bilirubin; ALB: Albumin; LDH: Lactate dehydrogenase; PLT: Platelet count; AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; ALBI: Albumin-bilirubin; FIB-4: Fibrosis-4 index; PNI: Prognostic nutritional index.

Table 3 Multifactorial logistic regression of factors affecting acute variceal bleeding

Factor	B	SE	Wald χ2	P value	OR (95%CI)
Maximum tumor diameter ≥ 5 cm	1.067	0.466	5.248	0.022	2.908 (1.167-7.246)
Combined portal vein tumor thrombosis	1.104	0.472	5.465	0.019	3.017 (1.195-7.616)
History of pre-treatment bleeding	2.829	0.533	28.143	0.000	16.923 (5.951-48.123)
FIB-4 ≥ 4.57	1.044	0.468	4.973	0.026	2.841 (1.135-7.115)
Constant	-3.587	0.530	45.817	0.000	-

Logistic regression model to predict bleeding: Ln (P/1-P) = 1.067 × maximum tumor diameter (≥ 5 = 1, < 5 = 0) + 1.104 × combined portal vein tumor thrombus (yes = 1, no = 0) + 2.829 × history of pre-treatment bleeding (yes = 1, no = 0) + 1.044 × fibrosis-4 index (≥ 4.565 = 1, < 4.565 = 0) - 3.587. FIB-4: Fibrosis-4 index.