Superstable homogeneous lipiodol-ICG formulation: initial feasibility and first-in-human clinical application for ruptured hepatocellular carcinoma

Abstract

The most common treatment of spontaneous tumor rupture hemorrhage (STRH) is transcatheter arterial embolization (TAE) followed by liver resection, and surgical navigation using near-infrared fluorescence is effective method for detecting hidden lesions and ill-defined tumor boundaries. However, due to the blockage of the tumor-supplying artery after effective TAE treatment, it is difficult to deliver sufficient fluorescent probes to the tumor region. In this study, we report on the successful application of superstable homogeneous intermixed formulation technology (SHIFT) in precise conversion hepatectomy for ruptured hepatocellular carcinoma (HCC). A homogeneous lipiodol-ICG formulation obtained by SHIFT (SHIFT-ICG) was developed for clinical practice for STRH. A ruptured HCC patient received the combined protocol for embolization and fluorescence surgical navigation and exhibited excellent hemostatic effect. Lipiodol and ICG were both effectively deposited in the primary lesion, including a small metastatic lesion. In follow-up laparoscopic hepatectomy, SHIFT-ICG could clearly and precisely image the full tumor regions and boundaries in real time, and even indistinguishable satellite lesions still expressed a remarkable fluorescence intensity. In conclusion, the simple and green SHIFT-ICG formulation can be effectively used in emergency embolization hemostasis and later precise fluorescence navigation hepatectomy in patients with ruptured HCC bleeding and has high clinical application value.

Keywords: conversion therapy; fluorescent navigation; hepatectomy; spontaneous tumor rupture.

Graphical abstract

Figure 1.

An overview of the preparation and research processes of SHIFT-ICG. The system of SHIFT was used to make SHIFT-ICG formulation under supercritical carbon dioxide (SC-CO₂). Subsequently, SHIFT-ICG deposited in the tumor-feeding artery through TAE, and then achieving acute hemostatic therapy and subsequent precise fluorescence-guided resection.

Figure 2.

Construction of a superstable homogeneous lipiodol–ICG formulation. (A) The photograph of the two formulations with conventional three-way stopcock (MIX) and SHIFT methods. (B) The viscosity value was measured by rheology test. (C) DSA imaging and the relative signal intensity, the two-tailed t-test was subjected to compare the statistical difference between two groups and P values were 0.67, which was considered no significant statistical difference. (D) The cumulative ICG release of the two formulations (MIX and SHIFT groups) at indicated times, two-way analysis of variance was subjected to test the statistical difference between two groups at different time. *P < 0.05 was considered significant statistical difference.

Figure 3.

The computed tomography and TAE findings. (A–C) The right lobe of the liver was observed to have a tumor measuring 4.1 × 3.5 cm² in diameter, and bloody ascites was also observed. The situation with the DSA angiography and SHIFT-ICG embolization: (D) before embolization, (E) during embolization and (F) after embolization. White arrow: primary lesions, red arrow: small metastatic lesion.

Figure 4.

The surgical navigation effect of SHIFT-ICG after successful conversion. The tumor state before surgical resection was measured by magnetic resonance imaging: (A) coronal plane, (B) horizontal plane and (C) small metastatic lesion. (D) Fluorescence imaging before surgical resection (white arrow: primary tumor lesions; red arrow: small metastatic lesion). (E) Whole resected tumor lesions imaged by fluorescence. (F) An image showing the resected liver tumor lesions (red arrow) and the fluorescence imaging (white arrow). Postoperative histological examination: (G) H&E staining was subjected to evaluate the pathological evaluation, (H) Oil red staining was used to test the lipiodol deposition and (I) ICG retention in tumor cells was observed by fluorescence confocal microscopy imaging.

Figure 5.

Follow-up treatment and re-examination. (A) One week after hepatectomy, the patient received the angiographic imaging. (B) The angiographic images of the patient with the treatment of infusion chemotherapy and TACE. The contrast-enhanced CT of the patient after hepatectomy three months: (C) venous phase and (D) arterial phase.