A new single-center retrospective study published in the European Journal of Nuclear Medicine and Molecular Imaging aims to change that. Researchers at Beijing Tsinghua Changgung Hospital analyzed 290 consecutive patients with unresectable hepatocellular carcinoma who underwent yttrium-90 selective internal radiation therapy between October 2022 and December 2025. Among them, 91 were flagged on pre-treatment imaging as potentially receiving tumor blood flow from the inferior phrenic artery, and 78 ultimately had angiographically confirmed supply from that vessel. The team then compared the two main ways interventional radiologists handle the artery: threading microspheres directly through it into the tumor, or deliberately plugging it with coils so that tumor blood flow is redirected back into the liver’s own arterial network.

The technical foundation of the study lies in meticulous pre-procedural mapping. Every patient underwent hepatic digital subtraction angiography combined with cone-beam computed tomography, a pairing that allows physicians to see not just the two-dimensional course of the vessels but the full three-dimensional territory each artery perfuses. A technetium-99m macroaggregated albumin injection followed by SPECT/CT simulation calculated the lung shunt fraction, ensuring that too many microspheres would not escape to the lungs, and post-treatment PET/CT verified where the radioactive spheres actually landed. Using a 2.1 French goose-neck microcatheter, the team achieved superselective catheterization of the inferior phrenic artery in 88.6 percent of attempted cases, demonstrating that even this small, tortuous vessel can be reliably accessed when combined angiographic and tomographic guidance is used.

The decision-making algorithm the researchers propose hinges on two variables: the volume of tumor fed by the inferior phrenic artery and the anatomy of any non-target branches that could carry microspheres into dangerous territory. When the artery perfused at least 20 milliliters of tumor and risky branches could be managed, the team favored direct infusion of yttrium-90 microspheres through the vessel, reserving prophylactic coil embolization for high-risk offshoots such as suprarenal, esophageal, pericardial, or pulmonary shunt branches. When the perfused tumor volume fell below 20 milliliters or non-target vessels could not be safely catheterized, the team simply embolized the artery trunk with coils, wagering that intrahepatic arteries would compensate. Forty-five patients landed in the infusion group and 33 in the embolization group, with the infusion cohort predictably carrying heavier tumor burdens and more advanced disease.

The anatomical findings reinforce how distinctive the inferior phrenic artery can be. The right inferior phrenic artery dominated as the parasitic feeding vessel in 89.8 percent of cases, with the left artery accounting for only 7.7 percent and dual supply appearing in 2.5 percent. Most of these arteries originated from the celiac trunk or directly from the abdominal aorta, though a striking 21.8 percent arose from the renal artery. The median radioactivity delivered through the inferior phrenic artery was a modest 0.3 gigabecquerels, yet the dosimetric payoff was substantial: the median tumor-absorbed dose in the infusion group reached 92 Gy, with three-quarters of those patients receiving at least 61 Gy, approaching the 100 to 250 Gy window widely recommended for hepatocellular carcinoma.

Perhaps the most eye-catching result concerns the embolization strategy, which has always rested on an assumption that had never been carefully quantified. If you plug the parasitic artery, does tumor blood flow really reroute to intrahepatic vessels in time to matter? By comparing intra-procedural cone-beam CT with post-treatment PET/CT, the researchers found that approximately 88 percent of the territory originally supplied by the inferior phrenic artery received yttrium-90 microspheres through compensatory intrahepatic pathways, with more than half of lesions achieving complete hemodynamic compensation. Critically, the compensatory rate held steady regardless of tumor size, suggesting that flow redistribution after coil embolization is a robust phenomenon rather than a fortunate accident, and providing quantitative reassurance comparable to the 83.8 percent redistribution rate previously reported with glue embolization.

On efficacy, direct infusion through the inferior phrenic artery consistently outperformed embolization. Using the modified Response Evaluation Criteria in Solid Tumors, the objective response rate in the infusion group climbed from 60.0 percent at one month to 82.3 percent at three months, whereas the embolization group moved from 48.5 percent to 69.7 percent over the same intervals. The gap between the groups widened to 12.6 percentage points by three months, and the complete response rate in the infusion group surged from 17.8 percent to 46.7 percent, an absolute gain of 28.9 percentage points that far outpaced the 21.2 percent rise seen in the embolization cohort. Disease control rates exceeded 93 percent at one month in both groups, underscoring that neither strategy leaves patients behind.

Safety is where lingering fears about extrahepatic radiation have historically been most vocal, and the study directly confronts them. Mean whole-lung absorbed dose was 9.53 Gy, comfortably below the 20 Gy clinical threshold, with no significant differences between groups in lung volume, lung shunt fraction, or lung dose. The overall adverse event rate was 17.8 percent in the infusion group and 9.1 percent in the embolization group, a difference that was not statistically significant, and every reported event was a mild to moderate, reversible thoracic complaint. No severe treatment-related complications occurred in either arm, an outcome the authors attribute to the discipline of combined DSA-CBCT anatomical evaluation paired with prophylactic embolization of non-target branches whenever they were visualized.

The study’s authors are candid about its limits. As a single-center retrospective analysis, it carries inherent selection bias, and the infusion group’s higher tumor burden and greater proportion of Barcelona Clinic Liver Cancer stage C patients may confound the efficacy comparison. Only three-month tumor response was assessed, leaving progression-free survival and overall survival unmeasured, and the team calls for long-term follow-up and multicenter prospective validation before the algorithm becomes standard practice. Even so, the work represents the largest head-to-head comparison of inferior phrenic artery strategies in yttrium-90 radioembolization to date, and it delivers something the field has lacked: a concrete, volume-based decision rule. Direct infusion when the artery feeds at least 20 milliliters of tumor and the plumbing cooperates; embolization when it does not. For the roughly one in three hepatocellular carcinoma patients whose tumors recruit this diaphragmatic artery, that clarity could mean the difference between an incomplete treatment and a truly definitive one.

Subject of Research: Inferior phrenic artery management strategies during yttrium-90 selective internal radiation therapy for hepatocellular carcinoma.

Article Title: Interventional strategies for inferior phrenic artery management in yttrium‑90 selective internal radiation therapy for hepatocellular carcinoma: A single‑center retrospective study

Article References: Liao, Y., Huang, X., Liang, Z., Ma, J., Feng, X., Fu, W., Liang, B., Yang, S., Li, G., Bao, L., Zhang, T., Zheng, L., Liu, C., Tang, M., Zhang, L., & Dong, J. (2026). Interventional strategies for inferior phrenic artery management in yttrium‑90 selective internal radiation therapy for hepatocellular carcinoma: A single‑center retrospective study. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08170-0

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08170-0

Keywords: yttrium-90, selective internal radiation therapy, hepatocellular carcinoma, inferior phrenic artery, radioembolization, interventional radiology, cone-beam computed tomography, lung shunt fraction, mRECIST, extrahepatic collateral supply, tumor response, coil embolization

Malignant ascites, the pathological accumulation of fluid in the peritoneal cavity, is a hallmark of advanced disease and signals rapid progression and metastatic spread. Standard interventions, including cytotoxic agents such as cisplatin and anti-angiogenic drugs like bevacizumab, typically provide only transient relief, and fluid reaccumulation remains common. The researchers sought a strategy that could simultaneously attack the tumor and suppress fluid production, while sidestepping the toxicity that limits conventional regimens. Their attention turned to the PI3K/AKT/mTOR signaling pathway, a master circuit governing tumor proliferation, survival, angiogenesis, and metastasis that is frequently hyperactivated in hepatocellular carcinoma through gene mutations, epigenetic changes, and upstream receptor dysregulation. Because the pathway is also implicated in treatment resistance, it represents an attractive therapeutic bullseye.

The team’s mechanistic insight centered on choline metabolism, a well-documented hallmark of cancer. Rapidly dividing malignant cells ramp up phosphocholine biosynthesis to meet relentless demands for new membrane material. Choline kinase alpha, the rate-limiting enzyme in this pipeline, is markedly overexpressed in hepatocellular carcinoma and is functionally entwined with PI3K/AKT signaling, where it mediates interactions between the epidermal growth factor receptor and mTORC2 that promote drug resistance and tumor progression. Disrupting the choline-metabolic axis, the researchers reasoned, could starve tumors of structural building blocks while severing their survival signaling. What they needed was a delivery platform that would keep the drug where it was needed, inside the peritoneal cavity, for as long as possible.

The answer emerged from an unlikely corner of pharmacological history. Euphorbia pekinensis Rupr. and Radix Glycyrrhizae have been prescribed together for centuries in traditional Chinese medicine for edema, fluid accumulation, and ascites, appearing in classical formulations such as Da Wu Yin Wan. Yet the pairing belongs to the classic eighteen incompatible medicaments, a traditional prohibition rooted in severe organ toxicity when the herbs are prepared conventionally. Modern investigations had hinted that the combination could mitigate ascites associated with hepatocellular carcinoma, but how to harness its synergy while avoiding organ damage remained unresolved. The new study resolved this tension through supramolecular engineering rather than simple co-administration.

To build the hydrogel, the researchers extracted an ethyl acetate fraction from Euphorbia pekinensis using reflux extraction with 95 percent ethanol, then combined it with glycyrrhizic acid in a one-to-one ratio and co-decocted the mixture. Heating to 65 degrees Celsius produced a sol, and on cooling to room temperature the solution gelled within minutes. Electron microscopy revealed why the combination behaves so differently from either component alone: whereas the Euphorbia fraction forms heterogeneous, irregular particles, the co-decocted material self-assembles into a homogeneous gel of uniformly distributed spherical nanoparticles roughly 200 nanometers in diameter. Rheological testing confirmed a stable gel state at low shear strain, with shear-thinning behavior that allows the material to be extruded cleanly through a syringe, a property essential for clinical injectability.

Spectroscopic and computational analyses illuminated the assembly mechanism at the molecular level. High-performance liquid chromatography showed that glycyrrhizic acid boosted the solubility of euphol, a marker compound of the herb, from a chromatographic peak area of 145.9 in isolation to 2530.3 in the combined preparation. Ultraviolet-visible and infrared spectroscopy located the binding interaction at hydroxyl groups, whose stretching vibrations shifted to lower wavenumbers in the assembly, and two-dimensional nuclear magnetic resonance experiments revealed close spatial contact between the hydroxyl group of euphol and the hydrophilic glucuronic acid end of glycyrrhizic acid. Molecular dynamics simulations depicted randomly dispersed molecules gradually forming binary aggregates through hydrogen bonding, which then intercalate and intertwine into an ordered supramolecular network. In short, the weak, noncovalent bonds between the two herbal molecules create a genuinely new state of matter, not a mere mixture.

The practical payoff of this architecture became apparent in live animals. Using fluorescent imaging in mice bearing ascites tumors, the team showed that the hydrogel remained concentrated in the abdominal cavity for at least 24 hours after intraperitoneal injection, whereas free fluorescent dye cleared rapidly. Enhanced retention was also observed in the liver and kidneys, with negligible accumulation in the heart, lungs, or spleen. This localized biodistribution maximizes drug exposure at the disease site while minimizing off-target toxicity, and it reduces the frequency of administration required, a meaningful advantage for patients undergoing repeated peritoneal procedures.

Therapeutic performance matched the elegant delivery design. In a subcutaneous xenograft model of H22 liver cancer, the hydrogel at 18.75 milligrams per kilogram per day achieved a tumor growth inhibition rate of 68.63 percent, approaching the 74.98 percent produced by cyclophosphamide at 20 milligrams per kilogram. Critically, the toxicology diverged sharply: cyclophosphamide significantly shrank the spleen, evidence of immune organ damage, while the hydrogel left liver, kidney, and spleen indices unchanged and produced no pathological abnormalities on histological staining. In a malignant ascites model established by intraperitoneal injection of H22 cells, hydrogel-treated mice showed markedly reduced abdominal circumference and slower weight gain driven by ascites accumulation, and organ indices that had fallen in untreated diseased animals were largely restored. The assembly appears to tame the herb’s inherent toxicity through an aggregation and assembly retention effect that concentrates the supramolecular complex at the tumor while sparing healthy tissue.

Transcriptomic and metabolomic profiling converged on a unified mechanism. RNA sequencing of treated tumors identified thousands of differentially expressed genes, with pathway enrichment pointing decisively to the PI3K-AKT and mTOR signaling cascades alongside apoptosis, hypoxia-inducible factor, and immune checkpoint pathways. Serum metabolomics revealed 119 key metabolites altered by treatment, with glycerophospholipid metabolism and choline metabolism in cancer emerging as the most significant enriched pathways, suggesting the hydrogel impairs choline utilization and phospholipid recycling and forces tumor cells toward mitochondrial fatty acid oxidation to sustain membrane homeostasis. A combined analysis of gene and metabolite shifts, applied for the first time in this ascites context, pointed to choline kinase alpha inhibition as the pivotal event.

Laboratory validation sealed the case. The hydrogel inhibited H22 cell growth in a concentration-dependent manner, elevated intracellular reactive oxygen species, collapsed mitochondrial membrane potential, and triggered apoptosis, the programmed cell death cascade that ultimately dismantles tumor cells. Choline kinase alpha activity fell dose-dependently with hydrogel treatment, and the known choline kinase inhibitor MN58b cooperated with the hydrogel at higher concentrations to amplify apoptosis. Western blotting and immunohistochemistry confirmed that treatment reduced the expression of choline kinase alpha and the phosphorylated, active forms of PI3K, AKT, and mTOR in both cells and tumor tissue. Together, the results establish the hydrogel as a choline kinase alpha inhibitor that suppresses the PI3K/AKT/mTOR axis to combat malignant ascites. Because the formulation is carrier-free, self-assembled from inexpensive natural molecules, and produced by simple co-decoction, the researchers argue it offers a practical blueprint for nature-derived, ascites-targeted precision therapeutics, though human trials will be needed to confirm whether the remarkable preclinical safety and efficacy translate to patients.

Subject of Research: A self-assembled herbal hydrogel that inhibits choline kinase alpha and the PI3K/AKT/mTOR pathway to treat hepatocellular carcinoma and malignant ascites.

Article Title: Injectable multi-component hydrogel as an inhibitor of choline kinase α achieved the treatment of malignant ascites by inhibiting PI3K/AKT/mTOR signaling pathway

Article References: Yang, Y., Qi, J., Zhu, Z., Wu, M., Zhao, Y., Wang, M., Lang, Y., Gu, Y., Liu, Y., & Cai, M. (2026). Injectable multi-component hydrogel as an inhibitor of choline kinase α achieved the treatment of malignant ascites by inhibiting PI3K/AKT/mTOR signaling pathway. Journal of Advanced Research, 87, 1105-1120. https://doi.org/10.1016/j.jare.2026.01.001

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.001

Keywords: hepatocellular carcinoma, malignant ascites, hydrogel, choline kinase alpha, PI3K/AKT/mTOR pathway, drug delivery, self-assembly, natural products, glycyrrhizic acid, Euphorbia pekinensis, metabolomics, nanomedicine