To establish magnetic resonance (MR)-based molecular imaging paradigms for the noninvasive monitoring of extracellular pH (pH
) as a functional surrogate biomarker for metabolic changes induced by ...locoregional therapy of liver cancer.
Thirty-two VX2 tumor-bearing New Zealand white rabbits underwent longitudinal imaging on clinical 3T-MRI and CT scanners before and up to 2 weeks after complete conventional transarterial chemoembolization (cTACE) using ethiodized oil (lipiodol) and doxorubicin. MR-spectroscopic imaging (MRSI) was employed for pH
mapping. Multiparametric MRI and CT were performed to quantify tumor enhancement, diffusion, and lipiodol coverage of the tumor posttherapy. In addition, incomplete cTACE with reduced chemoembolic doses was applied to mimic undertreatment and exploit pH
mapping to detect viable tumor residuals. Imaging findings were correlated with histopathologic markers indicative of metabolic state (HIF-1α, GLUT-1, and LAMP-2) and viability (proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase dUTP nick-end labeling).
Untreated VX2 tumors demonstrated a significantly lower pH
(6.80 ± 0.09) than liver parenchyma (7.19 ± 0.03,
< 0.001). Upregulation of HIF-1α, GLUT-1, and LAMP-2 confirmed a hyperglycolytic tumor phenotype and acidosis. A gradual tumor pH
increase toward normalization similar to parenchyma was revealed within 2 weeks after complete cTACE, which correlated with decreasing detectability of metabolic markers. In contrast, pH
mapping after incomplete cTACE indicated both acidic viable residuals and increased tumor pH
of treated regions. Multimodal imaging revealed durable tumor devascularization immediately after complete cTACE, gradually increasing necrosis, and sustained lipiodol coverage of the tumor.
MRSI-based pH
mapping can serve as a longitudinal monitoring tool for viable tumors. As most liver tumors are hyperglycolytic creating microenvironmental acidosis, therapy-induced normalization of tumor pH
may be used as a functional biomarker for positive therapeutic outcome.
Objectives
To compare 1D and 3D quantitative tumor response criteria applied to DCE-MRI in patients with advanced-stage HCC undergoing sorafenib therapy to predict overall survival (OS) early during ...treatment.
Methods
This retrospective analysis included 29 patients with advanced-stage HCC who received sorafenib for at least 60 days. All patients underwent baseline and follow-up DCE-MRI at 81.5 ± 29.3 days (range 35–140 days). Response to sorafenib was assessed in 46 target lesions using 1D criteria RECIST1.1 and mRECIST. In addition, a segmentation-based 3D quantification of absolute enhancing lesion volume (vqEASL) was performed on the arterial phase MRI, and the enhancement fraction of total tumor volume (%qEASL) was calculated. Accordingly, patients were stratified into groups of disease control (DC) and disease progression (DP). OS was evaluated using Kaplan-Meier curves with log-rank test and Cox proportional hazards regression model.
Results
The Kaplan-Meier analysis revealed that stratification of patients in DC vs. DP according to mRECIST (
p
= 0.0371) and vqEASL (
p
= 0.0118) successfully captured response and stratified OS, while stratification according to RECIST and %qEASL did not correlate with OS (
p
= 0.6273 and
p
= 0.7474, respectively). Multivariable Cox regression identified tumor progression according to mRECIST and qEASL as independent risk factors of decreased OS (
p
= 0.039 and
p
= 0.006, respectively).
Conclusions
The study identified enhancement-based vqEASL and mRECIST as reliable predictors of patient survival early after initiation of treatment with sorafenib. This data provides evidence for potential advantages 3D quantitative, enhancement-based tumor response analysis over conventional techniques regarding early identification of treatment success or failure.
Key Points
• Tumor response criteria on MRI can be used to predict survival benefit of sorafenib therapy in patients with advanced HCC.
• Stratification into DC and DP using mRECIST and vqEASL significantly correlates with OS (p = 0.0371 and p = 0.0118, respectively) early after initiation of sorafenib, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively).
• mRECIST (HR = 0.325, p = 0.039. 95%CI 0.112–0.946) and qEASL (HR = 0.183, p = 0.006, 95%CI 0.055–0.613) are independent prognostic factors of survival in HCC patients undergoing sorafenib therapy.
Objectives
The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and ...immunological tumor microenvironment in a rabbit VX2 tumor model.
Methods
VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pH
e
) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann–Whitney
U
test.
Results
pH
e
mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pH
e
compared to control (
p
= 0.0175) and cTACE alone (
p
= 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR
+
antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups.
Conclusions
The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pH
e
and the ability of immune cells to accumulate and infiltrate the tumor tissue.
Key Points
•
Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pH
e
towards a more physiological value (p
=
0.0025).
•
Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen.
•
Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR
+
-cells and 0.62 for CD3
+
-cells).
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