Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(L-lactic acid) microspheres in healthy pigs

M A D Vente, J F W Nijsen, T C de Wit, J H Seppenwoolde, G C Krijger, P R Seevinck, A Huisman, B A Zonnenberg, T S G A M van den Ingh, A D van het Schip, M A D Vente, J F W Nijsen, T C de Wit, J H Seppenwoolde, G C Krijger, P R Seevinck, A Huisman, B A Zonnenberg, T S G A M van den Ingh, A D van het Schip

Abstract

Purpose: The aim of this study is to evaluate the toxicity of holmium-166 poly(L-lactic acid) microspheres administered into the hepatic artery in pigs.

Methods: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n=5) or with holmium-166-loaded microspheres ((166)HoMS; n=13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken.

Results: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n=2), preexisting gastric ulceration (n=1), and endocarditis (n=1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements.

Conclusion: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.

Figures

Fig. 1
Fig. 1
MR arteriography of the thorax and abdomen of a pig, anteroposterior projection (a); excerpt of a (b): common hepatic artery (1), splenic artery (2), caudal phrenic artery (3), gastroduodenal artery (4), (branches of the) proper hepatic artery (5), right hepatic artery (6), medial hepatic arteries (7), left hepatic artery (8), and right gastric artery (9)
Fig. 2
Fig. 2
Liver enzymes serum activities. Time in between samples was 3 or 4 days, and value 1 was derived from samples taken before microsphere administration: serum activities of GGT (a), serum activities of ALP (b), serum activities of ALT (c), serum activities of AST (d)
Fig. 3
Fig. 3
Hematological values. Time in between samples was 3 or 4 days, and value 1 was derived from samples taken before microsphere administration: hemoglobin concentrations (a), platelet counts (b), leukocyte counts (c), prothrombin time (d)
Fig. 4
Fig. 4
a Liver of pig 3 (165HoMS): aggregate of microspheres within a hepatic artery with fibrosis and multinucleated giant cells. b Liver of pig 3 (165HoMS): large portal area with necrosis surrounded by macrophages and multinucleated giant cells and a fibrous capsule with large aggregates of microspheres. c Liver of pig 8 (166HoMS): a confined moderate-sized aggregate, probably within a hepatic artery, surrounded by hepatic necrosis and hemorrhage of the surrounding parenchyma and partial necrosis of the portal structures. d Stomach of pig 10 (166HoMS): submucosal artery with microspheres associated with fibrinoid deposition and necrosis of the arterial wall. e Liver of pig 11 (166HoMS): large area with yellow necrosis and a large aggregate of microspheres within a necrotic hepatic artery. f Gallbladder of pig 16 (166HoMS): lumen filled with necrotic debris, macrophages, and some neutrophils. Marked fibrosis of the wall with an aggregate of microspheres within an artery
Fig. 5
Fig. 5
Nuclear images of pigs administered 166HoMS. Planar nuclear scan of pig 15, demonstrating highly selective deposition of 166HoMS microspheres in the liver (a); planar nuclear scan of pig 18, on which a substantial amount of 166Ho (17.4%) is revealed to be present in the gastric wall (b); planar nuclear scan of pig 10, demonstrating excessive amounts of radioactivity (52.5% of injected dose) present in the stomach. An intense hotspot in the lesser curvature of the stomach is depicted by the arrow (c)
Fig. 6
Fig. 6
In vivo coronal (a–c) and transverse (d–f) MR images of pig 17. The anatomical images are found in a and d (T1-weighted SE), and b and e (T2-weighted SE images). c and f The holmium-sensitive T2*-weighted GE images. In the T1-weighted SE images, the vessels and gallbladder show up as hypo-intense structures and as hyperintense structures in the T2-weighted SE images. In the T2*-weighted GE images, the clusters of microspheres are visualized as additional focal regions of signal loss, especially in the dorsal region

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