Hepatic Artery

TACE was performed according to our previously reported protocol [16 (link)]. Chemolipiodolization was performed using 50 mg of epirubicin (pharmorubicin; Pfizer, Wuxi, Jiangsu, China), 50 mg of lobaplatin (Hainan Changan International Pharmaceutical Co. Ltd., Haikou, Hainan, China), and 6 mg of mitomycin C (Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, Zhejiang, China) mixed with 10 mL of lipiodol (Lipiodol Ultra-Fluide; Guerbet Laboratories, Aulnay Sous Bois, Paris, France). If necessary, up to 20 mL of additional pure lipiodol was injected. The injection was stopped when stasis of blood flow in the target artery was observed. Subsequently, embolization was performed with the injection of polyvinyl alcohol particles that were 300–500 μm in diameter through the catheter to reach stasis in the tumor-feeding artery. Repeated TACE was performed at intervals of 6 weeks.
In the HAIC group, patients were treated using a 3-week cycle regimen. A catheter was advanced into the hepatic artery according to our previously reported protocol [16 (link)]. A microcatheter was selectively placed into the feeding arteries of the tumor. The gastroduodenal artery was occluded by a coil when necessary. Then, the microcatheter was connected to the artery infusion pump to administer the following treatment: OXA, 85 mg/m² intra-arterial infusion on day 1; LV, 400 mg/m² intra-arterial infusion on day 1; and 5-FU, 400 mg/m² bolus infusion on day 1 and 2400 mg/m² continuous infusion over 46 h. After HAIC was completed, the indwelling catheter and the sheath were removed, and manual compression was performed to achieve hemostasis.
HAIC and TACE were discontinued when disease progression (including vascular invasion or the development of extrahepatic spread) or intolerable AEs occurred or when the patient was eligible for another treatment (surgical resection) or withdrew consent. Additionally, the study treatment was suspended when the following conditions occurred: technical difficulty in repeating the treatment (stenosis or occlusion of the tumor-feeding artery or an artery only supplied by the extrahepatic collateral arteries) or unsuitable characteristics (neutrophil count < 1200/μL, platelet count < 60,000/μL, total bilirubin > 30 mmol/L, or albumin < 3.0 mg/dL). The study treatment was stopped if no recovery occurred after a 30-day delay.
If the study treatment was discontinued, the following treatment was defined as subsequent treatment. The subsequent treatment decisions of both groups would be made according to the same protocol by the same multidisciplinary team, based on the tumor burden, liver function, and the patient’s request. Basically, hepatic resections were performed on patients whose tumor shrank to be resectable. For patients with tumor progression without contraindications to TACE, repeating TACE was recommended. For patients whose residual tumors could not be embolized due to technical problems, radiofrequency ablations were used to destroy residual tumors when it was feasible. Conservative treatments were given to patients with terminal HCC, Child–Pugh C liver function, or Eastern Cooperative Oncology Group (ECOG) score > 2 [32 (link)].

Automated segmentation of the stomach, liver, GB, pancreas, spleen, rib, skin, and abdominal wall was performed on the portal phase CT image using a deep learning algorithm based on fine-tuned 3D U-Net. 3D U-Net is a specialized deep learning algorithm for biomedical image segmentation, and this algorithm used its own fine-tuned model with learning from radiologists-annotated clinical data. On the early arterial and the portal phase CT images, biomedical engineers used semi-automatic segmentation software (AVIEW, Coreline Soft, Seoul, Korea) and segmented upper abdominal vessels which were essentially needed for making a surgery-oriented 3-D model as follows: aorta, celiac artery, left and right gastric arteries, splenic artery, common hepatic artery, proper hepatic artery, left hepatic artery, right hepatic artery, aberrant hepatic artery if present, gastroduodenal artery, left and right gastroepiploic arteries, inferior vena cava, portal vein, splenic vein, left gastric vein, and left and right gastroepiploic veins. For 3-D reconstruction, 3-D masks of organs and vessels were obtained from this segmentation process and inspected by one radiologist with 19 years of experience in abdominal imaging.

The embolization procedure was performed under the guide of digital subtraction angiography (Siemens AXIOM Artis FA DSA, Siemens Medical Systems, Erlangen, Germany). Rabbits were anesthetized as described earlier. Vascular access was achieved in the femoral artery through surgical cut down. Celiac angiography was performed to identify the hepatic arterial anatomy and the feeder artery of the tumor using a 3-F catheter (Cook, Bloomington, India). The left hepatic artery, which exclusively supplies blood flow to the tumor, was catheterized selectively. When the catheter was adequately positioned in the left hepatic artery after celiac arteriography was performed, MVLs or 0.9% sodium chloride was injected carefully into the artery according to different groups. Digital spot images were obtained after embolization. The catheter was then removed, and the femoral artery was ligated.