Navigation value of intraoperative ultrasound combined with indocyanine green fluorescence in complex hepatocellular carcinoma resection

Table 1 Comparison of baseline characteristics between two groups, mean ± SD/n (%)/median (interquartile rage)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
General demographic characteristics
Age (years)	54.3 ± 10.7	55.8 ± 11.2	t = 0.978	0.329
Gender (male)	86 (83.5)	79 (81.4)	χ2 = 0.168	0.682
BMI (kg/m2)	23.8 ± 3.2	24.1 ± 3.4	t = 0.654	0.514
Underlying liver disease
HBV infection	89 (86.4)	82 (84.5)	χ2 = 0.156	0.693
HCV infection	8 (7.8)	9 (9.3)	χ2 = 0.156	0.693
Cirrhosis			χ2 = 0.824	0.662
No cirrhosis	28 (27.2)	24 (24.7)
Mild cirrhosis	51 (49.5)	51 (52.6)
Moderate to severe cirrhosis	24 (23.3)	22 (22.7)
Preoperative liver function indicators
Child-Pugh A	91 (88.3)	87 (89.7)	χ2 = 0.092	0.762
TBIL (μmol/L)	16.8 ± 6.3	17.2 ± 6.8	t = 0.431	0.667
ALB (g/L)	41.2 ± 4.6	40.8 ± 4.9	t = 0.601	0.548
ALT (U/L)	42 (28-68)	45 (30-71)	Z = 0.721	0.471
AST (U/L)	38 (26-59)	40 (28-62)	Z = 0.683	0.495
PT-INR	1.08 ± 0.12	1.09 ± 0.13	t = 0.567	0.571
ICG-R15 (%)	12.4 ± 5.8	12.9 ± 6.1	t = 0.603	0.547
Tumor characteristics
Maximum tumor diameter (cm)	7.8 ± 3.2	7.6 ± 3.4	t = 0.431	0.667
Tumor number			χ2 = 0.412	0.814
Single	67 (65.0)	66 (68.0)
2 lesions	24 (23.3)	21 (21.6)
≥ 3 lesions	12 (11.7)	10 (10.3)
Central tumor	58 (56.3)	52 (53.6)	χ2 = 0.147	0.701
Large vessel involvement	47 (45.6)	42 (43.3)	χ2 = 0.109	0.741
AFP > 400 ng/mL	52 (50.5)	46 (47.4)	χ2 = 0.191	0.662
Imaging evaluation
Tumor volume (cm3)	286 (145-512)	273 (138-498)	Z = 0.512	0.609
Estimated resection liver volume (cm3)	618 (425-856)	602 (410-841)	Z = 0.621	0.535
Residual liver volume percentage (%)	58.3 ± 12.4	57.6 ± 13.1	t = 0.394	0.694
ECOG score			χ2 = 0.286	0.867
0 points	64 (62.1)	62 (63.9)
1 point	32 (31.1)	28 (28.9)
2 points	7 (6.8)	7 (7.2)
Comorbidities
Hypertension	31 (30.1)	27 (27.8)	χ2 = 0.127	0.722
Diabetes	18 (17.5)	15 (15.5)	χ2 = 0.147	0.701
Cardiovascular and cerebrovascular disease	12 (11.7)	10 (10.3)	χ2 = 0.093	0.761

BMI: Body mass index; HBV: Hepatitis B virus; HCV: Hepatitis C virus; TBIL: Total bilirubin; ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; PT-INR: Prothrombin time-international normalized ratio; ICG-R15: Indocyanine green-minute retention rate; AFP: Alpha-fetoprotein; ECOG: Eastern Cooperative Oncology Group.

Table 2 Comparison of intraoperative indicators between two groups, mean ± SD/n (%)/median (interquartile rage)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
Operation time (minutes)	298.5 ± 68.3	276.2 ± 71.6	t = 2.255	0.012
Intraoperative blood loss (mL)	420 (280-680)	550 (350-850)	Z = 2.891	0.004
Intraoperative transfusion	28 (27.2)	41 (42.3)	χ2 = 5.343	0.021
Red blood cell units (U)1	4 (2-6)	4 (2-8)	Z = 1.234	0.217
Plasma volume (mL)1	200 (100-400)	300 (150-450)	Z = 1.156	0.248
Hepatic hilar blocking time (minutes)	48 (28-72)	54 (32-78)	Z = 1.421	0.156
Tumor localization time (minutes)	12.6 ± 4.3	18.9 ± 6.7	t = 7.831	< 0.001
Intraoperative detection of occult lesions2	24 (23.3)	6 (6.2)	χ2 = 12.358	< 0.001
Number of lesions detected3	1 (1-2)	1 (1-1.5)	Z = 1.156	0.248
Surgical procedure adjustment	31 (30.1)	14 (14.4)	χ2 = 7.296	0.007
Surgical procedure			χ2 = 7.891/Fisher	0.048
Hemi-hepatectomy	42 (40.8)	35 (36.1)
Extended hemi-hepatectomy	18 (17.5)	22 (22.7)
Segmentectomy	38 (36.9)	28 (28.9)
Local resection	5 (4.9)	12 (12.4)
Anatomical resection	98 (95.1)	85 (87.6)	χ2 = 4.218	0.04

¹Only transfused patients counted.

²Occult lesions refer to lesions not shown on preoperative imaging detected immediately intraoperatively through ultrasound or fluorescence imaging (diameter ≥ 5 mm), not including small lesions found on postoperative pathology (diameter < 5 mm).

³Only patients with detected occult lesions counted.

Table 3 Comparison of oncological indicators between two groups, mean ± SD/n (%)/median (interquartile rage)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
Positive margin	3 (2.9)	13 (13.4)	χ2 = 7.621	0.006
Margin distance (cm)	1.2 (0.8-1.8)	0.8 (0.5-1.3)	Z = 3.912	< 0.001
Margin distance grouping1			χ2 = 14.328	0.001
< 0.5 cm	8 (7.8)	22 (22.7)
0.5-1.0 cm	32 (31.1)	35 (36.1)
> 1.0 cm	63 (61.2)	40 (41.2)
R0 resection	100 (97.1)	84 (86.6)	χ2 = 7.621	0.006
Pathological features
Maximum tumor diameter (cm)	7.9 ± 3.3	7.7 ± 3.5	t = 0.421	0.674
Postoperative final confirmed total tumor number2			χ2 = 0.821	0.365
Consistent with preoperative imaging	79 (76.7)	79 (81.4)
More than preoperative imaging	24 (23.3)	18 (18.6)
Among which: Detected immediately intraoperatively (≥ 5 mm)	24 (23.3)	6 (6.2)
Found on postoperative pathology (< 5 mm)	0 (0)	12 (12.4)
Pathological type			Fisher	0.782
Hepatocellular carcinoma	98 (95.1)	93 (95.9)
Cholangiocarcinoma	3 (2.9)	2 (2.1)
Mixed type	2 (1.9)	2 (2.1)
Differentiation degree			χ2 = 1.234	0.745
Well-differentiated	21 (20.4)	18 (18.6)
Moderately differentiated	56 (54.4)	54 (55.7)
Poorly differentiated	23 (22.3)	22 (22.7)
Undifferentiated	3 (2.9)	3 (3.1)
MVI grade			χ2 = 0.621	0.733
M0	48 (46.6)	42 (43.3)
M1	38 (36.9)	38 (39.2)
M2	17 (16.5)	17 (17.5)
Liver capsule invasion	42 (40.8)	37 (38.1)	χ2 = 0.149	0.7
Satellite nodules	28 (27.2)	24 (24.7)	χ2 = 0.156	0.693
Intact tumor capsule	67 (65.0)	61 (62.9)	χ2 = 0.101	0.751

¹Among the 3 cases and 13 cases with positive margins, 2 cases and 11 cases respectively had margin distance < 0.5 cm, and the remaining 1 case and 2 cases had margin distance of 0.5-1.0 cm but were microscopically margin positive.

²Postoperative final confirmed total tumor number = number of lesions shown on preoperative imaging + number of occult lesions detected immediately intraoperatively (diameter ≥ 5 mm) + number of small lesions additionally found on postoperative pathological examination (diameter < 5 mm).

“Consistent with preoperative imaging” means the postoperative final confirmed tumor number is the same as the number reported on preoperative imaging. MVI: Microvascular invasion.

Table 4 Comparison of postoperative complications between two groups, n (%)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
Overall complications	19 (18.4)	28 (28.9)	χ2 = 4.123	0.042
Clavien-Dindo grade1			χ2 = 6.821	0.078
Grade I-II	13 (12.6)	16 (16.5)
Grade III	4 (3.9)	9 (9.3)
Grade IV	2 (1.9)	2 (2.1)
Grade V	0 (0)	1 (1.0)
Grade III-V complications	6 (5.8)	12 (12.4)	χ2 = 4.128	0.042
Total complication episodes	26	46
Specific complication types (counted by episodes)
Bile leakage	5 (4.9)	10 (10.3)	χ2 = 4.178	0.041
Grade A	3 (2.9)	5 (5.2)
Grade B	1 (1.0)	4 (4.1)
Grade C	1 (1.0)	1 (1.0)
Abdominal infection	4 (3.9)	6 (6.2)	χ2 = 0.628	0.428
Abdominal hemorrhage	2 (1.9)	5 (5.2)	Fisher	0.133
Liver failure	1 (1.0)	3 (3.1)	Fisher	0.354
Pleural effusion	6 (5.8)	8 (8.2)	χ2 = 0.521	0.47
Pulmonary infection	4 (3.9)	6 (6.2)	χ2 = 0.628	0.428
Wound infection	2 (1.9)	4 (4.1)	Fisher	0.428
Renal insufficiency	1 (1.0)	2 (2.1)	Fisher	0.607
Other complications	1 (1.0)	2 (2.1)	Fisher	0.607
Postoperative reoperation	2 (1.9)	6 (6.2)	Fisher	0.104
30-day postoperative mortality	0 (0)	1 (1.0)	Fisher	0.485
90-day postoperative mortality	1 (1.0)	3 (3.1)	Fisher	0.354

¹Patients categorized by most severe complication grade, P value for overall Clavien-Dindo grade distribution comparison (grade I-II, grade III, grade IV, grade V) was 0.078, not reaching statistical significance; but when comparing grade III-V (severe complications) with grade I-II (mild complications), the difference between the two groups was statistically significant (P = 0.042). Specific complication types counted by episodes, some patients may experience multiple complications simultaneously, so total complication episodes (26 in combined navigation group, 46 in conventional surgery group) is greater than total patients with complications (19 in combined navigation group, 28 in conventional surgery group).

Table 5 Comparison of postoperative liver function indicators and recovery indicators between two groups, mean ± SD/n (%)/median (interquartile rage)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
Postoperative day 1
TBIL (μmol/L)	28.6 ± 12.4	31.2 ± 14.8	t = 1.342	0.181
ALT (U/L)	286 (198-412)	312 (218-445)	Z = 1.523	0.128
AST (U/L)	268 (182-385)	295 (201-421)	Z = 1.612	0.107
ALB (g/L)	35.8 ± 4.2	35.2 ± 4.6	t = 0.962	0.337
PT-INR	1.28 ± 0.18	1.32 ± 0.21	t = 1.456	0.147
Postoperative day 3
TBIL (μmol/L)	32.4 ± 14.6	38.7 ± 17.2	t = 2.781	0.006
ALT (U/L)	156 (98-238)	198 (128-285)	Z = 2.634	0.008
AST (U/L)	142 (88-215)	178 (112-256)	Z = 2.512	0.012
ALB (g/L)	34.6 ± 4.1	33.8 ± 4.5	t = 1.321	0.188
PT-INR	1.24 ± 0.16	1.29 ± 0.19	t = 2.012	0.045
Postoperative day 5
TBIL (μmol/L)	28.3 ± 12.8	34.6 ± 15.4	t = 3.112	0.002
ALT (U/L)	98 (62-148)	128 (82-186)	Z = 2.891	0.004
AST (U/L)	86 (54-132)	112 (72-165)	Z = 2.734	0.006
ALB (g/L)	35.2 ± 4.3	34.6 ± 4.6	t = 0.962	0.337
PT-INR	1.18 ± 0.14	1.23 ± 0.17	t = 2.234	0.027
Postoperative day 7
TBIL (μmol/L)	22.4 ± 9.6	26.8 ± 12.3	t = 2.812	0.005
ALT (U/L)	68 (45-102)	82 (56-125)	Z = 2.123	0.034
AST (U/L)	58 (38-88)	72 (48-108)	Z = 2.234	0.026
ALB (g/L)	36.4 ± 4.2	35.8 ± 4.5	t = 0.981	0.328
PT-INR	1.12 ± 0.12	1.16 ± 0.14	t = 2.156	0.032
Postoperative recovery indicators
Postoperative hospital stays (days)	12 (9-16)	15 (11-20)	Z = 3.012	0.003
Time to first ambulation (days)	2 (1-3)	2 (2-3)	Z = 1.823	0.068
Time to first liquid diet (days)	2 (2-3)	3 (2-4)	Z = 2.234	0.026
Time to drainage tube removal (days)	5 (4-7)	6 (5-9)	Z = 2.567	0.01

TBIL: Total bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALB: Albumin; PT-INR: Prothrombin time-international normalized ratio.

Table 6 Multivariate logistic regression analysis of factors influencing postoperative complications

Factor	β	SE	Wald χ2	OR	95%CI	P value
Combined navigation technology	-0.697	0.318	4.812	0.498	0.268-0.925	0.027
Intraoperative blood loss ≥ 600 mL	1.049	0.356	8.689	2.856	1.423-5.732	0.003
Operation time ≥ 300 minutes	0.758	0.345	4.826	2.134	1.087-4.189	0.028
Moderate to severe cirrhosis	0.988	0.371	7.098	2.687	1.298-5.563	0.008

Backward elimination method was used to screen variables, with P < 0.05 as variable retention standard. Variables included in initial model were age, body mass index, Child-Pugh grade, degree of cirrhosis, tumor diameter (≥ 8 cm vs < 8 cm), tumor number, central tumor, intraoperative blood loss (≥ 600 mL vs < 600 mL), operation time (≥ 300 minutes vs < 300 minutes), application of combined navigation technology, and other variables with P < 0.10 in univariate analysis. Tumor diameter ≥ 8 cm was excluded during variable screening process because P > 0.05, and was not retained in the final model. OR: Odds ratio; CI: Confidence interval.

Table 7 Comparison of follow-up results between two groups, n (%)/median (interquartile rage)

Indicator	Combined navigation group (n = 103)	Conventional surgery group (n = 97)	Statistic	P value
Median follow-up time (months)	29.5 (18-42)	27.8 (16-40)	Z = 0.823	0.411
1-year overall survival rate (%)	89.3	81.4
2-year overall survival rate (%)	76.8	65.2
Overall survival curve comparison1			Log-rank χ2 = 4.521	0.033
1-year disease-free survival rate (%)	72.8	61.9
2-year disease-free survival rate (%)	58.4	45.7
Disease-free survival curve comparison1			Log-rank χ2 = 5.234	0.022
Postoperative recurrence	38 (36.9)	49 (50.5)	χ2 = 3.921	0.048
Recurrence time (months)	16.8 (10.2-24.5)	13.5 (8.6-20.3)	Z = 2.012	0.044
Recurrence site classification
Intrahepatic recurrence only	26 (25.2)	34 (35.1)	χ2 = 2.512	0.113
Single	18 (17.5)	19 (19.6)
Multiple	8 (7.8)	15 (15.5)
Extrahepatic metastasis only	6 (5.8)	6 (6.2)	χ2 = 0.012	0.913
Lung metastasis	4 (3.9)	4 (4.1)
Bone metastasis	1 (1.0)	1 (1.0)
Peritoneal metastasis	1 (1.0)	1 (1.0)
Intrahepatic + extrahepatic metastasis	6 (5.8)	9 (9.3)	χ2 = 0.921	0.337
Total intrahepatic recurrence2	32 (31.1)	43 (44.3)	χ2 = 3.847	0.05
Total extrahepatic metastasis2	12 (11.7)	15 (15.5)	χ2 = 0.621	0.431

¹Log-rank test compares differences in entire survival curves, not survival rate differences at specific time points (such as 1 year or 2 years). 1-year and 2-year survival rates estimated by Kaplan-Meier method.

²“Total intrahepatic recurrence” and “total extrahepatic metastasis” include patients with “intrahepatic + extrahepatic metastasis”, meaning these patients are counted in both totals. For example, combined navigation group total intrahepatic recurrence 32 cases = intrahepatic recurrence only 26 cases + intrahepatic + extrahepatic metastasis 6 cases; conventional surgery group total intrahepatic recurrence 43 cases = intrahepatic recurrence only 34 cases + intrahepatic + extrahepatic metastasis 9 cases. P = 0.050 for total intrahepatic recurrence is at the boundary of statistical significance, suggesting the intrahepatic recurrence rate in the combined navigation group shows a marginally significant trend lower than the conventional surgery group.

Table 8 Cox multivariate regression analysis of factors influencing overall survival

Factor	β	SE	Wald χ2	HR	95%CI	P value
Combined navigation technology	-0.538	0.245	4.821	0.584	0.362-0.942	0.028
R0 resection	-0.886	0.261	11.523	0.412	0.248-0.684	< 0.001
Tumor diameter ≥ 8 cm	0.629	0.243	6.698	1.876	1.165-3.022	0.01
MVI M2 grade	0.804	0.268	8.989	2.234	1.324-3.769	0.003
AFP > 400 ng/mL	0.529	0.242	4.781	1.698	1.056-2.731	0.029

Backward elimination method was used to screen variables, with P < 0.05 as variable retention standard. Variables included in initial model were age, gender, Child-Pugh grade, degree of cirrhosis, tumor diameter (≥ 8 cm vs < 8 cm), tumor number, central tumor, vascular involvement, alpha-fetoprotein level (> 400 ng/mL vs ≤ 400 ng/mL), differentiation degree, microvascular invasion grade, R0 resection, margin distance, anatomical resection, application of combined navigation technology, and other variables with P < 0.10 in univariate analysis. Moderate to severe cirrhosis had P < 0.10 in univariate analysis, but P = 0.083 in multivariate analysis, not reaching significance standard, and was excluded during variable screening process. MVI: Microvascular invasion; AFP: Alpha-fetoprotein; HR: Hazard ratio; CI: Confidence interval.

Table 9 Cox multivariate regression analysis of factors influencing disease-free survival

Factor	β	SE	Wald χ2	HR	95%CI	P value
Combined navigation technology	-0.461	0.207	4.961	0.631	0.421-0.945	0.025
R0 resection	-0.759	0.218	12.123	0.468	0.306-0.715	< 0.001
Margin distance > 1.0 cm	-0.514	0.22	5.461	0.598	0.389-0.919	0.019
Tumor number ≥ 3	0.768	0.285	7.267	2.156	1.234-3.767	0.007
MVI M2 grade	0.911	0.235	15.021	2.487	1.568-3.945	< 0.001
Central tumor	0.485	0.208	5.436	1.623	1.078-2.443	0.02

Backward elimination method was used to screen variables, with P < 0.05 as variable retention standard. Variables included in initial model were age, gender, Child-Pugh grade, degree of cirrhosis, tumor diameter (≥ 8 cm vs < 8 cm), tumor number (≥ 3 vs < 3), central tumor, vascular involvement, alpha-fetoprotein level (> 400 ng/mL vs ≤ 400 ng/mL), differentiation degree, microvascular invasion grade, liver capsule invasion, satellite nodules, R0 resection, margin distance (> 1.0 cm vs ≤ 1.0 cm), anatomical resection, application of combined navigation technology, and other variables with P < 0.10 in univariate analysis. Tumor diameter ≥ 8 cm had P < 0.10 in univariate analysis, but P = 0.064 in multivariate analysis, showing marginally significant trend but not reaching statistical significance standard, and was excluded during variable screening process. MVI: Microvascular invasion; HR: Hazard ratio; CI: Confidence interval.