Voxel-based tumor dose correlates to complete pathologic necrosis after transarterial radioembolization for hepatocellular carcinoma.

PURPOSE: The transarterial radioembolization (TARE) dose is traditionally calculated using the single-compartment Medical Internal Radiation Dose (MIRD) formula. This study utilized voxel-based dosimetry to correlate tumor dose with explant pathology in order to identify dose thresholds that predicted response. METHODS: All patients with HCC treated with TARE using yttrium-90 [90Y] glass microspheres at a single institution between January 2015 - June 2023 who underwent liver transplantation were eligible. The [90Y] distribution and dose-volume histograms were determined using Simplicity90 (Mirada Medical, Oxford UK) with a Bremsstrahlung SPECT/CT. A complete response was assigned if explant pathology showed complete necrosis and the patient had not undergone additional treatments to the same tumor after TARE. Logistic regression and receiver operator characteristic (ROC) curves were constructed to evaluate dose thresholds correlated with response. RESULTS: Forty-one patients were included. Twenty-six (63%) met criteria for complete response. Dose to 95% (D95), 70% (D70), and 50% (D50) of the tumor volume were associated with likelihood of complete response by logistic regression (all p < 0.05). For lesions with complete response versus without, the median D95 was 813 versus 232 Gy, D70 was 1052 versus 315 Gy, and D50 was 1181 versus 369 Gy (all p < 0.01). A D95 > 719 Gy had the highest accuracy at 68% (58% sensitivity, 87% specificity) for predicting complete response. Median percent of tumor volume receiving at least 100 Gy (V100), 200 Gy (V200), 300 Gy (V300), and 400 Gy (V400) also differed by pathologic response: the median V100, V200, V300, and V400 was 100% versus 99%, 100% versus 97%, 100% versus 74%, and 100% versus 43% in the complete response versus non-complete response groups, respectively (all p < 0.05). CONCLUSION: Voxel-based dosimetry was well-correlated with explant pathology. The D95 threshold had the highest accuracy, suggesting the D95 may be a relevant target for multi-compartment dosimetry.

Point-of-care magnetic resonance technology to measure liver fat: Phantom and first-in-human pilot study.

PURPOSE: To assess feasibility and accuracy of point-of-care (POC) NMR-proton density fat fraction (PDFF) in phantoms and in a human pilot study in a POC setting. METHODS: POC NMR (LiverScope, Livivos, San Diego CA) PDFF measurements were obtained of certified phantoms with known PDFF values (0%-40%). In an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant prospective human study, a convenience sample of participants from an obesity clinic was enrolled (November 2020 to June 2021). The inclusion criteria required body mass index (BMI) = 27-40 kg/m2 and willingness to undergo POC NMR and MRI-PDFF measurements. Liver PDFF was measured by POC NMR and, within 35 days after, by a confounder corrected CSE MRI PDFF acquisition and reconstruction method. The adverse events were documented and linear regression analyses were performed. RESULTS: POC NMR-PDFF measurements agreed with known phantom PDFF values (R2  = 0.99). Fourteen participants were enrolled in the pilot human study. MRI-PDFF could not be obtained in 4 participants (claustrophobia reaction, n = 3, exceeded size of MR scanner bore, n = 1). POC NMR was unevaluable in 2 participants (insufficient signal penetration depth, n = 1, failure to comply with instructions, n = 1). Technical success was 11 of 13 (85%) for POC NMR PDFF. In 7 participants (4 female; 31-74 years old; median BMI 35 kg/m2 ), MRI-PDFF (range, 2.8%-18.1%), and POC NMR-PDFF (range, 3%-25.2%), agreed with R2  = 0.94. POC NMR had no adverse events. CONCLUSION: POC NMR measures PDFF accurately in phantoms and, in a first-in-human pilot study, is feasible and accurate in adults with obesity. Further testing to determine precision and accuracy across larger and more diverse cohorts is needed.

Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis.

BACKGROUND & AIMS: Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation. METHODS: Herein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-ß agonist mimetic, which was used to promote repopulation. RESULTS: The non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE-/- mice. This regimen led to robust liver repopulation by transplanted hepatocytes, which was associated with significant reductions in serum cholesterol levels after transplantation. Additionally, in mice receiving this regimen, ApoE was detected in the circulation 4 weeks after treatment and did not induce an immunological response. Importantly, the normalization of serum cholesterol prevented the formation of atherosclerotic plaques in this model. CONCLUSIONS: Significant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver. LAY SUMMARY: Hepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.

Singlet oxygen generation on porous superhydrophobic surfaces: effect of gas flow and sensitizer wetting on trapping efficiency.

We describe physical-organic studies of singlet oxygen generation and transport into an aqueous solution supported on superhydrophobic surfaces on which silicon-phthalocyanine (Pc) particles are immobilized. Singlet oxygen ((1)O2) was trapped by a water-soluble anthracene compound and monitored in situ using a UV-vis spectrometer. When oxygen flows through the porous superhydrophobic surface, singlet oxygen generated in the plastron (i.e., the gas layer beneath the liquid) is transported into the solution within gas bubbles, thereby increasing the liquid-gas surface area over which singlet oxygen can be trapped. Higher photooxidation rates were achieved in flowing oxygen, as compared to when the gas in the plastron was static. Superhydrophobic surfaces were also synthesized so that the Pc particles were located in contact with, or isolated from, the aqueous solution to evaluate the relative effectiveness of singlet oxygen generated in solution and the gas phase, respectively; singlet oxygen generated on particles wetted by the solution was trapped more efficiently than singlet oxygen generated in the plastron, even in the presence of flowing oxygen gas. A mechanism is proposed that explains how Pc particle wetting, plastron gas composition and flow rate as well as gas saturation of the aqueous solution affect singlet oxygen trapping efficiency. These stable superhydrophobic surfaces, which can physically isolate the photosensitizer particles from the solution may be of practical importance for delivering singlet oxygen for water purification and medical devices.

Superhydrophobic photosensitizers. Mechanistic studies of (1)O2 generation in the plastron and solid/liquid droplet interface.

We describe here a physical-organic study of the first triphasic superhydrophobic sensitizer for photooxidations in water droplets. Control of synthetic parameters enables the mechanistic study of "borderline" two- and three-phase superhydrophobic sensitizer surfaces where (1)O2 is generated in compartments that are wetted, partially wetted, or remain dry in the plastron (i.e., air layer beneath the droplet). The superhydrophobic surface is synthesized by partially embedding silicon phthalocyanine (Pc) sensitizing particles to specific locations on polydimethylsiloxane (PDMS) posts printed in a square array (1 mm tall posts on 0.5 mm pitch). In the presence of red light and oxygen, singlet oxygen is formed on the superhydrophobic surface and reacts with 9,10-anthracene dipropionate dianion (1) within a freestanding water droplet to produce an endoperoxide in 54-72% yields. Control of the (1)O2 chemistry was achieved by the synthesis of superhydrophobic surfaces enriched with Pc particles either at the PDMS end-tips or at PDMS post bases. Much of the (1)O2 that reacts with anthracene 1 in the droplets was generated by the sensitizer "wetted" at the Pc particle/water droplet interface and gave the highest endoperoxide yields. About 20% of the (1)O2 can be introduced into the droplet from the plastron. The results indicate that the superhydrophobic sensitizer surface offers a unique system to study (1)O2 transfer routes where a balance of gas and liquid contributions of (1)O2 is tunable within the same superhydrophobic surface.

Ratchetlike slip angle anisotropy on printed superhydrophobic surfaces.

The fabrication and properties of superhydrophobic surfaces that exhibit ratchet-like anisotropic slip angle behavior is described. The surface is composed of arrays of poly(dimethylsiloxane) (PDMS) posts fabricated by a type of 3D printing. By controlling the dispense parameters, regular arrays of asymmetric posts were deposited such that the slope of the posts was varied from 0 to 50 relative to the surface normal. Advancing and receding contact angles as well as slip angles were measured as a function of the post slope and droplet volume. Ratchetlike slip angle anisotropy was observed on surfaces composed of sloped features. The maximum slip angle difference (for a 180° tilt angle variation) was 32° for 20 µL droplets on surfaces with posts fabricated with a slope of 50°. This slip angle anisotropy is attributed to an increase in the triple contact line (TCL) length as the droplet is tilted in a direction against the post slope whereas the TCL decreases continuously when the drop travels in a direction parallel to the post slope. The increasing length of the TCL creates an increased energy barrier that accounts for the higher slip angles in this direction.

Hepatic artery stenosis angioplasty and implantation of Wingspan neurovascular stent: A case report and discussion of stenting in tortuous vessels.

BACKGROUND: Hepatic artery stenosis is a complication of orthotopic liver transplant occurring in 3.1%-7.4% of patients that can result in graft failure and need for re-transplantation. Endovascular therapy with angioplasty and stenting has been used with a high degree of technical success and good clinical outcomes, but tortuous hepatic arteries present a unique challenge for intervention. Suitable stents for this application should be maneuverable and conformable while also exerting adequate radial force to maintain a patent lumen. CASE SUMMARY: Herein we report our experience with a neurovascular Wingspan stent system in a challenging case of recurrent hepatic artery stenosis and discuss the literature of stenting in tortuous transplant hepatic arteries. CONCLUSION: Wingspan neurovascular stent is self-expanding, has good conformability, and adequate radial resistance and as such it could be added to the armamentarium of interventionalists in the setting of a tortuous and stenotic transplant hepatic artery.

Hepatocyte Transplantation: Quo Vadis?

Orthotopic liver transplantation (OLT) has been effective in managing end-stage liver disease since the advent of cyclosporine immunosuppression therapy in 1980. The major limitations of OLT are organ supply, monetary cost, and the burden of lifelong immunosuppression. Hepatocyte transplantation, as a substitute for OLT, has been an exciting topic of investigation for several decades. HT is potentially minimally invasive and can serve as a vehicle for delivery of personalized medicine through autologous cell transplant after modification ex vivo. However, 3 major hurdles have prevented large-scale clinical application: (1) availability of transplantable cells; (2) safe and efficient ex vivo gene therapy methods; and (3) engraftment and repopulation efficiency. This review will discuss new sources for transplantable liver cells obtained by lineage reprogramming, clinically acceptable methods of genetic manipulation, and the development of hepatic irradiation-based preparative regimens for enhancing engraftment and repopulation of transplanted hepatocytes. We will also review the results of the first 3 patients with genetic liver disorders who underwent preparative hepatic irradiation before hepatocyte transplantation.

Non-Invasive Targeted Hepatic Irradiation and SPECT/CT Functional Imaging to Study Radiation-Induced Liver Damage in Small Animal Models.

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging.

Catalytic, self-cleaning surface with stable superhydrophobic properties: printed polydimethylsiloxane (PDMS) arrays embedded with TiO2 nanoparticles.

Maintaining the long-term stability of superhydrophobic surfaces is challenging because of contamination from organic molecules and proteins that render the surface hydrophilic. Reactive oxygen species generated on a photocatalyst, such as TiO2, could mitigate this effect by oxidizing these contaminants. However, incorporation of such catalyst particles into a superhydrophobic surface is challenging because the particles become hydrophilic under UV exposure, causing the surface to transition to the Wenzel state. Here we show that a high concentration of hydrophilic TiO2 catalytic nanoparticles can be incorporated into a superhydrophobic surface by partially embedding the particles into a printed array of high aspect ratio polydimethylsiloxane posts. A stable Cassie state was maintained on these surfaces, even under UV irradiation, because of the significant degree of hierarchical roughness. By printing the surface on a porous support, oxygen could be flowed through the plastron, resulting in higher photooxidation rates relative to a static ambient. Rhodamine B and bovine serum albumin were photooxidized both in solution and after drying onto these TiO2-containing surfaces, and the effects of particle location and plastron gas composition were studied in static and flowing gas environments. This approach may prove useful for water purification, medical devices, and other applications where Cassie stability is required in the presence of organic compounds.