What are potential research topics on the novel use of indocyanine dye in hepatocellular carcinoma?

Novel Research Topics on Indocyanine Green in Hepatocellular Carcinoma

The most promising research directions for ICG in HCC focus on intraoperative tumor detection, molecular characterization through fluorescence patterns, and identification of occult metastatic disease—all areas where preliminary evidence demonstrates clinical utility but lacks the large-scale validation needed for widespread adoption.

High-Priority Research Topics Based on Current Evidence Gaps

1. Standardized Fluorescence Pattern Classification and Molecular Correlation

Investigate the relationship between ICG fluorescence patterns (rim, homogeneous, heterogeneous) and specific molecular subtypes of HCC to enable real-time intraoperative molecular characterization. 1

• Preliminary data shows rim fluorescence correlates with peritumoral vascular changes, lower differentiation, and lower AFP levels, while homogeneous patterns associate with less necrosis and higher AFP 1
• Heterogeneous HCC without rim emission harbors fewer TP53 and ARID1A mutations 1
• Critical research need: Prospective multicenter trials with standardized imaging protocols, quantitative fluorescence measurements, and comprehensive genomic profiling to validate these associations and establish clinically actionable classification systems 2
• This requires strict standardization of imaging acquisition, data collection, and analysis methods similar to PET imaging protocols 2

2. Detection of Occult Intrahepatic and Extrahepatic Metastases

Determine the sensitivity and specificity of ICG fluorescence for detecting small, previously unidentified HCC nodules and extrahepatic metastases compared to current imaging standards.

• ICG fluorescence detected new HCC nodules not identified by preoperative imaging or intraoperative ultrasound in 40% of cases, with most being small, well-differentiated tumors 3
• Extrahepatic metastases (lung, lymph node, peritoneum, adrenal) demonstrated 100% positive predictive value for ICG fluorescence both in vivo and ex vivo 4
• Five additional metastatic lesions were newly identified intraoperatively using ICG fluorescence 4
• Research gap: Large prospective studies comparing ICG fluorescence to enhanced MRI, PET-CT, and intraoperative ultrasound for detection of occult disease, with long-term oncologic outcomes (recurrence-free survival, overall survival) as primary endpoints 2

3. Optimal Timing and Dosing Protocols for Tumor Visualization

Establish evidence-based protocols for ICG administration timing (days before surgery vs. intraoperative) and dosing strategies that maximize tumor-to-background ratio while maintaining liver function assessment capability.

• Current practice uses 0.5 mg/kg administered days before surgery for combined liver function testing and tumor visualization 3, 5, 4
• ICG achieves tumor targeting through enhanced permeability and retention (EPR) effect via "second window imaging" 2
• ICG is rapidly bound to plasma albumin (95%) and exclusively taken up by hepatic parenchymal cells, secreted into bile 6
• Critical research question: Comparative trials testing different administration protocols (24 hours vs. 48-72 hours vs. 1 week pre-surgery) with quantitative fluorescence measurements and correlation with tumor detection rates, particularly for small lesions (<2 cm) 2

4. Real-Time Surgical Margin Assessment and Resection Adequacy

Develop and validate quantitative fluorescence thresholds for determining adequate surgical margins during hepatectomy, potentially reducing positive margin rates.

• All patients in laparoscopic ICG-guided series achieved negative margins, compared to 3.3% positive margins in open resection controls 5
• ICG fluorescence allowed assessment of tumor resection margins and identification of additional lesions during surgery 5
• Median surgical margin of 14 mm (range 11-17 mm) was achieved for pulmonary metastases using fluorescence guidance 7
• Research need: Prospective randomized trials comparing ICG fluorescence-guided resection to standard techniques, measuring positive margin rates, local recurrence, and disease-free survival as primary outcomes 2
• Must include standardized quantitative fluorescence analysis with heat-map visualization and predetermined fluorescence intensity cutoffs for margin adequacy 2

5. Integration with Minimally Invasive Surgical Approaches

Evaluate whether ICG fluorescence imaging provides superior outcomes in laparoscopic/robotic hepatectomy compared to open surgery, particularly for cirrhotic patients.

• Laparoscopic hepatectomy with ICG fluorescence demonstrated less blood loss (125 vs 450 mL), shorter operative time (200 vs 250 min), and shorter hospital stay (5 vs 6 days) compared to open surgery 5
• ICG fluorescence enables better identification of bile duct structures and assessment of perfusion during minimally invasive procedures 5
• The 2025 EASL guidelines reference laparoscopic anatomical liver resection using ICG fluorescence imaging 2
• Research priority: Multicenter randomized controlled trials comparing laparoscopic ICG-guided hepatectomy to standard laparoscopic and open approaches, with perioperative morbidity, mortality, and long-term oncologic outcomes as endpoints 2

6. Predictive Value for Post-Hepatectomy Liver Failure

Investigate whether intraoperative ICG fluorescence patterns of remnant liver predict post-hepatectomy liver failure beyond standard ICG-R15 testing.

• ICG-R15 is established as a non-invasive predictor of portal hypertension and helps determine safe extent of resection 2, 8
• ICG clearance correlates with perioperative mortality according to Makuuchi criteria 8
• Current guidelines recommend ICG-R15 cutoffs (below 20-25% for hepatectomy, below 30-35% for segmentectomy in cirrhotic patients) 8
• Novel research angle: Real-time intraoperative assessment of remnant liver fluorescence patterns and clearance kinetics to predict post-operative liver dysfunction, potentially allowing intraoperative modification of resection extent 2, 8

7. Combination with Tumor-Specific Targeted Fluorophores

Develop and test ICG conjugated to HCC-specific targeting vehicles (antibodies, peptides) to improve tumor specificity beyond passive EPR-based accumulation.

• Current ICG use relies on non-specific EPR effect; ICG is rapidly cleared by liver and excreted in bile 2
• Most novel strategies use near-infrared dyes conjugated to tumor-specific targeting vehicles for optimal cancer-specific detection 2
• Research opportunity: Phase I/II trials testing ICG conjugated to glypican-3 antibodies, AFP-targeting peptides, or other HCC-specific ligands, comparing detection rates to unconjugated ICG 2
• Must include standardized reporting of intraoperative imaging, specimen mapping with pathology correlation, and target validation with receptor density measurements 2

Implementation Considerations for Future Studies

Standardization Requirements

All future ICG fluorescence studies must adopt standardized protocols for data acquisition and reporting to enable cross-study comparisons and regulatory approval. 2

• Qualitative analyses should include bright field images, black-and-white fluorescence images, pseudo-colored overlay images, and heat-maps displaying fluorescence intensity differences 2
• Quantitative analyses must report raw numeric fluorescence values, tumor-to-background ratios, and correlation with pathology on fresh tissue specimens 2
• Target validation should determine fluorescence intensity relative to receptor density or tumor characteristics 2

Clinical Trial Design Priorities

Phase II/III randomized controlled trials are urgently needed to demonstrate superiority over standard-of-care before widespread adoption. 2

• Early phase trials have established safety and feasibility but cannot show benefit over current standards 2
• Primary endpoints should focus on morbidity, mortality, and quality of life outcomes: positive margin rates, disease-free survival, overall survival, and post-operative complications 2
• Studies should stratify by liver function (Child-Pugh, MELD, ALBI grade), tumor stage (BCLC classification), and underlying etiology 2