Measurement of the Tumor-to-Normal Ratio for Radioembolization of Hepatocellular Carcinoma: A Prospective Study Comparing 2-Dimensional Perfusion Angiography, Technetium-99m Macroaggregated Albumin, and Yttrium-90 SPECT/CT.

PURPOSE: To calculate the preradioembolic tumor-to-normal (T:N) ratio in hepatocellular carcinoma (HCC) using 2-dimensional (2D) perfusion angiography and compare it with that calculated using technetium-99m macroaggregated albumin (99mTc MAA) single-photon emission computed tomography (SPECT)/computed tomography (CT). MATERIALS AND METHODS: This prospective single-arm study enrolled 15 participants with HCC who underwent 2D perfusion angiography immediately before the enrollment and with the microcatheter located at the same location as 99mTc MAA injection, after which SPECT/CT was performed. Quantitative digital subtraction angiography was used to calculate the area under the curve for the tumor and normal hepatic parenchyma and subsequently calculate the T:N ratio. The T:N ratio was calculated from the 99mTc MAA SPECT/CT and post-yttrium-90 bremsstrahlung SPECT/CT using dosimetry software. RESULTS: The mean participant age was 64.1 years ± 9.8, and the study included 14 (93%) men and 1 (7%) woman. The mean tumor size was 4.1 cm (SD ± 2.4), and all participants received segmental treatments with glass microspheres. The mean T:N ratio calculated by 99mTc MAA SPECT/CT was 2.28 (SD ± 0.89) vs 2.25 (SD ± 0.99) calculated by 2D perfusion angiography (P = .45). For the 13 participants who underwent selective internal radiation therapy (transarterial radioembolization), there was no significant difference between the T:N ratios calculated by 2D perfusion angiography and post-90Y SPECT/CT (2.25 [SD ± 1.05] vs 1.91 [SD ± 0.39]; P = .12). CONCLUSIONS: The T:N ratio calculated by 2D perfusion angiography correlated well with that calculated by 99mTc MAA SPECT/CT.

Percutaneous Radiofrequency Ablation to Occlude the Thoracic Duct: Preclinical Studies in Swine for a Potential Alternative to Embolization.

PURPOSE: To investigate the feasibility of percutaneous radiofrequency (RF) ablation to occlude the thoracic duct (TD) in a swine model with imaging and histologic correlation. MATERIALS AND METHODS: Six swine underwent TD RF ablation. Two terminal (4 hours, 1 open and 1 percutaneous) and 4 survival (30 days, all percutaneous) studies were performed. Two 20-gauge needles were placed adjacent to the TD under direct visualization after right thoracotomy or under fluoroscopic guidance using a percutaneous transabdominal approach after intranodal lymphangiography. RF electrodes were advanced through the needles, and ablation was performed at 90°C for 90 seconds. Lymphangiography was performed, and the TD and adjacent structures were resected and examined microscopically at the end of each study period. RESULTS: Four of 6 subjects survived the planned study period and underwent follow-up lymphangiography. Two subjects in the survival group were euthanized early-1 after developing an acute chylothorax and 1 because of gastric volvulus 14 days after ablation. Occlusion of the targeted TD segment was noted on lymphangiography in 3 of the 4 remaining subjects (2 acute and 1 survival). Histology 4 hours after RF ablation demonstrated necrosis of the TD wall and hemorrhage within the lumen. Histology at 14 and 30 days revealed fibrosis with hemosiderin-laden macrophages replacing the ablated TD. Collagen degeneration within the aortic wall involving a maximum of 60% thickness was noted in 5 of the 6 subjects. CONCLUSIONS: Percutaneous RF ablation can achieve short-segment TD occlusion. Further study is needed to improve safety and demonstrate clinical efficacy in treating TD leaks.

Clinical and Dosimetric Implications of Calculating Lung Shunt Fraction for Hepatic 90Y Radioembolization Using SPECT/CT Versus Planar Scintigraphy.

BACKGROUND. Accurate assessment of hepatopulmonary shunting, typically performed by planar scintigraphy, is critical in planning 90Y radioembolization. High lung shunt fractions (LSFs) may alter treatment. OBJECTIVE. The purpose of this study is to compare LSFs calculated from planar scintigraphy versus SPECT/CT in patients with high planar LSFs (> 15%) and to describe the potential clinical and dosimetric implications of SPECT/CT LSF calculations. METHODS. This retrospective study included 36 patients (29 men and seven women; mean age, 62.4 ± 9.8 [SD] years) who underwent 99mTc-macroaggregated albumin (MAA) planar scintigraphy for planning hepatic radioembolization, had a planar LSF greater than 15%, and underwent concurrent SPECT/CT. Clinically reported planar LSFs were recorded. SPECT/CT LSFs were retrospectively calculated using automatically generated volumetric ROIs around the lungs and liver with subsequent manual adjustments. Total lung and perfused liver doses were calculated using a medical internal radiation dose model. Values derived from planar and SPECT/CT data were compared using Mann-Whitney U tests. Multivariable regression analysis was performed of factors associated with the discrepancy in LSF between the techniques. RESULTS. Mean planar LSF was 25.1% ± 11.6%, and mean SPECT/CT LSF was 16.0% ± 9.3% (p < .001). Mean lung dose was 18.8 ± 8.0 Gy for planar LSF versus 12.3 ± 7.2 Gy for SPECT/CT LSF (p < .001). Mean perfused liver dose was 92.9 ± 36.1 Gy using planar LSF versus 102.7 ± 39.1 Gy using SPECT/CT LSF (p < .001). In multivariable analysis, a larger discrepancy in LSF between planar scintigraphy and SPECT/CT was associated with a body mass index (weight in kilograms divided by the square of height in meters) of 26 or higher (p = .02), maximum tumor size of less than 9 cm (p = .05), and left hepatic intraarterial injection (p = .02). Fourteen of 36 patients did not undergo upfront radioembolization due to a planar LSF greater than 20% and instead underwent shunt-reducing embolization with subsequent radioembolization (n = 7), transarterial chemoembolization (n = 5), or no treatment (n = 2). Five of these 14 patients had a SPECT/CT LSF of less than 20% and would have been eligible for upfront radioembolization based on SPECT/CT LSF. Seven of 29 patients treated with radioembolization underwent prescribed dose reductions based on planar LSF; six of these patients would have qualified for standard radioembolization without dose reduction using SPECT/CT LSF. CONCLUSION. Planar scintigraphy yields greater LSFs compared with SPECT/CT, possibly leading to unnecessary shunt-reducing procedures and prescribed dose reductions. CLINICAL IMPACT. SPECT/CT should be considered for clinical LSF calculations before radioembolization in patients with high LSFs.

Quantitative Assessment of the Hemodynamic Effects of Intra-Arterial Nitroglycerin on Hepatocellular Carcinoma using Two-Dimensional Perfusion Angiography.

PURPOSE: To determine the hemodynamic effects of intra-arterial nitroglycerin on hepatocellular carcinoma (HCC) using 2-dimensional (2D) perfusion angiography. MATERIALS AND METHODS: Two-dimensional perfusion angiograms obtained prior to radioembolization from September 2019 to February 2020 were retrospectively reviewed. The inclusion criteria were the presence of Liver Imaging Reporting and Data System-5 tumors and angiographically distinguishable tumor and background liver. The exclusion criteria were previously treated tumors and motion-degraded studies. Thirteen patients with 2D perfusion angiograms obtained before and 2 minutes ± 1 after the administration of intra-arterial nitroglycerin were analyzed. The mean patient age was 72 years ± 9 and 11 of 13 (85%) had cirrhosis. The mean maximum tumor dimension was 4.6 cm ± 2.1. Eight tumors were in the right lobe and 5 were in the left lobe. The tumor and background liver 2D perfusion data were processed and the areas under the time-density curves were calculated. The relative perfusion of HCC to background liver was compared before and after nitroglycerin administration using a 2-tailed paired t-test. RESULTS: The mean rate of contrast administration was 1.4 mL/s ± 0.7 and the mean volume administered was 7.1 mL ± 3.3. The mean nitroglycerin dose was 281 µg ± 69. Ten of 13 patients (77%) demonstrated a relative increase in tumor perfusion. The mean HCC to background liver area under the curve ratio was 1.94 ± 0.76 before and 2.40 ± 0.89 after nitroglycerin administration (P < .05). CONCLUSIONS: Intra-arterial nitroglycerin increases previously untreated HCC perfusion relative to background liver as measured by 2D perfusion angiography, but this effect is variable among patients and should be validated with 3-dimensional imaging techniques.

Same-Day Repeat Hepatopulmonary Shunt Measurement during Planning Angiography for Hepatic Radioembolization.

This report describes a technique for measuring lung shunt fraction (LSF) twice in a single session during planning arteriography for radioembolization using low and standard dose technetium-99m macroaggregated albumin (99mTc-MAA). A patient with a 16.0 cm hepatocellular carcinoma and LSF of 70% was treated with lenvatinib for 4 weeks. Planning arteriography with administration of 0.5 millicuries of 99mTc-MAA was then performed. Arterial access was maintained while the LSF was calculated, which was persistently elevated at 54%. Embolization of arteriovenous shunts was performed during the same session and 5.0 millicuries of 99mTc-MAA were administered. The repeat LSF was 29%. Successful radioembolization was subsequently performed.

Gallbladder Cryoablation for Chronic Cholecystitis in High-Risk Surgical Patients: 1-Year Clinical Experience with Imaging Follow-up.

PURPOSE: To assess the short-term safety and efficacy of gallbladder cryoablation in high-risk patients. MATERIALS AND METHODS: A single-center, retrospective review of clinical and imaging follow-up from patients who were referred for gallbladder cryoablation between August 2018 and July 2019 was performed. All patients had serious pre-procedural comorbidities and were unacceptable surgical candidates (mean age, 52.5 years; mean American Society of Anesthesiologists score, 3.67). Primary efficacy measures included technical success, absence of symptoms after cholecystostomy tube removal, and imaging evidence of cystic duct obstruction and gallbladder involution. The primary safety measure was the absence of Society of Interventional Radiology moderate or greater adverse events. RESULTS: Technical success was 86%, with 1 of 7 patients unable to undergo cryoablation because of adhesions preventing hydrodissection of the colon away from the gallbladder. Mean duration of clinical follow-up after discharge was 278 days (range, 59-498 days). Abdominal pain was absent in all patients after ablation. Cholecystostomy tubes were removed immediately after ablation (n = 5) or on post-procedure day 11 (n = 1). Computed tomography or magnetic resonance imaging was obtained at 1-3 months (n = 6), 4-6 months (n = 4), and 6-12 months (n = 5) after the procedure and demonstrated gallbladder involution in 5 of 6 patients. One patient had asymptomatic distention of the gallbladder on follow-up imaging. Hepatobiliary iminodiacetic acid scans were completed in 5 of 6 patients 1 month after ablation and demonstrated cystic duct occlusion in all 5 patients. One moderate adverse event (infection) and 1 life-threatening adverse event (hemorrhage) occurred. CONCLUSIONS: Gallbladder cryoablation might be a viable treatment option for high-risk patients with gallbladder disease and warrants further investigation.

Exploring the internal and external wildlife gradients created by conservation fences.

Spillover effects are an expansion of conservation benefits beyond protected areas through dispersal of species that reside within. They have been well documented in marine but not terrestrial systems. To understand the effects on wildlife created by conservation fences, we explored the internal and external gradients of activity in mammal, reptile, and bird species at a conservation reserve in arid Australia that is fenced to exclude invasive rabbits (Oryctolagus cuniculus), cats (Felis catus), and foxes (Vulpes vulpes). Two methods were used: counts of animal tracks along transects on sand dunes and captures at pitfall-trapping sites. In both cases, sites were spaced at different distances from the reserve fenceline inside and outside the reserve. We recorded a range of spillover, source-sink, step, and barrier effects that combined to create a zone within and around the reserve with fence-induced species-specific wildlife gradients. Two endemic rodents but none of the 4 mammal species reintroduced to the reserve showed positive spillover effects. Barrier effects, where activity was highest close to the fence, were recorded for the feral cat and native bettong (Bettongia lesueur), species that could not breach the fence. In comparison, some reptiles and native mammal species that could permeate the fence displayed source-sink effects; that is, their activity levels were reduced close to the fence likely due to constant emigration to the side with lower density. Activity of some reptiles was lowest at sites inside the reserve and gradually increased at outside sites with distance from the fence, a gradient likely related to trophic cascades triggered by predator exclusion. Our result shows that fenced reserves can create overlapping layers of species-specific gradients related to each species' ability to permeate the fence and its varying susceptibility to threats. Managers should be aware that these gradients may extend for several kilometers either side of the fence and that not all contained species will increase in abundance. Creating wider conservation benefits may require increased fence permeability and threat reduction outside the fence.

Exploración de los gradientes de vida silvestre internos y externos creados por las vallas de conservación. Resumen Los efectos de derrame son una expansión de los beneficios de conservación más allá de las áreas protegidas a través de la dispersión de especies que residen en su interior. Han sido bien documentados en sistemas marinos, pero no terrestres. Para entender los efectos de las vallas de exclusión sobre la vida silvestre, exploramos los gradientes internos y externos de la actividad de especies de mamíferos, reptiles y aves en una reserva de conservación en la región árida de Australia que está cercada para excluir conejos invasivos (Oryctolagus cuniculus), gatos (Felis catus) y zorros (Vulpes vulpes). Se utilizaron dos métodos: conteo de huellas de animales a lo largo de transectos en dunas de arena y captura con trampas pitfall. En ambos casos, los sitios fueron espaciados a distintas distancias dentro y fuera de la valla de la reserva. Registramos una gama de efectos de derrame, fuente-sumidero, escalón y barrera que se combinaron para crear una zona dentro y alrededor de la reserva con gradientes de vida silvestre inducidos por la valla. Dos roedores endémicos, pero ninguna de 4 especies de mamíferos reintroducidas a la reserva, mostraron efectos de derrame positivos. Los efectos de barrera, donde la actividad era mayor cerca de la valla, fueron registrados para el gato feral y la rata canguro nativa (Bettongia lesueur), especies que no pudieron franquear la valla. En contraste, algunas especies de reptiles y mamíferos nativos que pudieron permear la valla mostraron efectos de fuente-sumidero; esto es, sus niveles de actividad fueron bajos cerca de la valla probablemente debido a la emigración constante hacia el lado con menor densidad. La actividad de algunos reptiles fue menor en los sitios núcleo de la reserva e incrementaron a medida que incrementó la distancia hacia afuera, un gradiente relacionado probablemente con las cascadas tróficas desencadenadas por la exclusión de depredadores. Nuestros resultados muestran que las reservas cercadas pueden crear capas sobrepuestas de gradientes específicos relacionados con la habilidad de cada especie para permear la valla y su susceptibilidad a las amenazas. Los manejadores deber ser conscientes de que esos gradientes pueden extenderse varios kilómetros a ambos lados de la valla y que no todas las especies contenidas aumentarán en abundancia. La creación de beneficios de conservación más amplios puede requerir una mayor permeabilidad de la vallas y la reducción de amenazas fuera de la reserva.

First in-Human Gallbladder Cryoablation in a Patient with Acute Calculous Cholecystitis Initially Treated with a Cholecystostomy Tube.

A 71-year-old poor surgical candidate with acute calculous cholecystitis was initially managed with cholecystostomy tube drainage for 28 days. He subsequently underwent gallbladder cryoablation under moderate sedation with 3 cryoprobes and 2 separate 10-8-10 freeze-thaw cycles targeting the gallbladder neck/body and fundus followed by cholecystostomy tube removal. He was discharged 1 day after ablation. Magnetic resonance and hepatobiliary iminodiacetic acid scan 1 month postablation demonstrated a thick-walled, distended gallbladder and no filling of the cystic duct. Magnetic resonance 3 months postablation demonstrated retraction of the gallbladder wall with luminal collapse. The patient denied any pain after discharge and is asymptomatic 3 months after ablation.

Endovascular Biopsy and Endothelial Cell Gene Expression Analysis of Dialysis Arteriovenous Fistulas: A Feasibility Study.

PURPOSE: To demonstrate feasibility of endothelial cell (EC) biopsy from dialysis arteriovenous fistulas (AVFs) with the use of guidewires and to characterize gene expression differences between ECs from stenotic and nonstenotic outflow vein segments. MATERIALS AND METHODS: Nine consecutive patients undergoing fistulography for AVF dysfunction from June to August 2016 were enrolled. ECs were biopsied with the use of guidewires from venous outflow stenoses and control outflow veins central to the stenoses. ECs were sorted with the use of flow cytometry, and the Fluidigm Biomark HD system was used for single-cell quantitative polymerase chain reaction (qPCR) analysis of gene expression. Forty-eight genes were assessed and were selected based on different cellular functions and previous literature. Linear mixed models (LMMs) were used to identify differential gene expression between the groups, and self-organizing maps (SOMs) were used to identify cell clusters based on gene coexpression profiles. RESULTS: A total of 219 and 213 ECs were sampled from venous outflow stenoses and control vein segments, respectively. There were no immediate biopsy-related complications. Forty-eight cells per patient were sorted for qPCR analysis. LMM identified 7 genes with different levels of expression at stenotic segments (P < .05), including AGTR-2, HMOX-2, MTHFR, SERPINC-1, SERPINE-1, SMAD-4, and VWF. SOM analysis identified 4 cell clusters with unique gene expression profiles, each containing stenotic and control ECs. CONCLUSIONS: EC biopsy from dialysis AVFs with the use of guidewires is feasible. Gene expression data suggest that genes involved in multiple cellular functions are dysregulated in stenotic areas. SOMs identified 4 unique clusters of cells, indicating EC phenotypic heterogeneity in outflow veins.

Pilot Study of the Safety and Efficacy of Gallbladder Cryoablation in a Porcine Model: Midterm Results.

PURPOSE: To investigate the midterm safety and efficacy of computed tomography (CT)-guided percutaneous gallbladder cryoablation in swine. MATERIALS AND METHODS: Three swine underwent gallbladder cryoablation. Cryoprobes were positioned percutaneously at the gallbladder margins or within the gallbladder lumen under CT guidance. Two freeze/thaw cycles were performed. One animal was euthanized on postprocedure day 4 as a result of hematemesis unrelated to the ablation. The other 2 animals were euthanized at postprocedure days 30 and 48, respectively. The gallbladder and bile ducts were resected and examined microscopically. RESULTS: Gallbladder cryoablation was completed with freeze/thaw cycle durations of 7.5-10 minutes (mean, 9.4 min ± 1.3) and ablation margins of 5.8-11.5 mm (mean, 7.8 mm ± 1.9). No nontarget ablation was observed. Laboratory values at postprocedure day 4 and the time of euthanasia were within normal limits. Two of 3 animals thrived and exhibited appropriate activity and weight gain. Contrast-enhanced CT immediately before euthanasia demonstrated delayed linear enhancement of the gallbladder wall. Gross inspection at autopsy revealed fibrotic-appearing gallbladders. Cholecystography revealed no communication to the biliary tree. Histologic examination demonstrated complete gallbladder wall fibrosis. Autopsy of the animal euthanized on day 4 revealed a gastric mucosal ulcer distant from the ablation site with no gastric serosal injury. CONCLUSIONS: Gallbladder cryoablation is a promising alternative to surgical cholecystectomy, with complete transmural gallbladder wall fibrosis and cystic duct occlusion seen at 30 and 48 days in swine. Further studies are required to establish procedural safety and long-term efficacy.

Idiopathic granulomatous mastitis associated with hyperprolactinemia: A nonoperative approach.

There is increasing evidence associating idiopathic granulomatous mastitis (IGM) with hyperprolactinemia. All documented cases have involved the patient having at least one operative procedure before the association has been made. We present a 55 year old female with IGM associated with risperidone induced hyperprolactinemia. She was successfully treated with a dopamine agonist, bromocriptine. We demonstrated that complete resolution can be achieved without surgical intervention, by targeting serum prolactin levels. We hope this will increase awareness of this rare clinically entity and avoid potentially unnecessary surgery.

Prior ablation and progression of disease correlate with higher tumor-to-normal liver 99mTc-MAA uptake ratio in hepatocellular carcinoma.

PURPOSE: Factors affecting tumor-to-normal tissue ratio (T:N) have implications for patient selection, dosimetry, and outcomes when considering radioembolization for HCC. This study sought to evaluate patient, disease specific, and technical parameters that predict T:N as measured on planning pre-90Y radioembolization 99mTc-MAA scintigraphy for hepatocellular carcinoma (HCC). METHODS: 99mTc-MAA hepatic angiography procedures with SPECT/CT over a 4-year period were reviewed. Data recorded included patient demographics, details of underlying liver disease, tumor size, history of prior treatments for HCC and technical parameters from angiography. Anatomic-based segmentation was performed in 93 cases for measurement of tumor and perfused liver volumes and SPECT counts. T:N were calculated and correlated with collected variables. RESULTS: Mean calculated T:N was 2.52. History of prior ablation was significantly correlated with higher T:N (mean 3.39 vs 2.24, p = 0.003). Cases in which mapping was being performed for treatment of disease progression was significantly correlated with higher T:N (mean 3.35 vs 2.14, p = 0.001). Larger tumor size trended toward lower T:N (p = 0.052). CONCLUSION: Patients with history of ablation and those undergoing treatment for disease progression have higher T:N and, therefore, could be considered for radioembolization preferentially over alternative treatments.

Radiofrequency Hyperthermia Enhances Locally Delivered Oncolytic Immuno-Virotherapy for Pancreatic Adenocarcinoma.

PURPOSE: To investigate the effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immuno-virotherapy on in vitro pancreatic adenocarcinoma cell line and in vivo rat pancreatic cancer model. MATERIALS AND METHODS: Rat pancreatic adenocarcinoma cell line and 24 Lewis rats with orthotopic pancreatic adenocarcinomas underwent treatment with either (1) oncolytic virotherapy (talimogene laherparepvec [T-VEC]) plus RFH at 42 °C for 30 min; (2) oncolytic virotherapy-only; (3) RFH-only; or (4) saline (control). MTS assays and flow cytometry were used to analyze tumor cell viability and apoptosis levels 24 h after treatment. In the in vivo studies, bioluminescence optical/x-ray imaging and ultrasound imaging was used to assess tumor viability and size 7 and 14 days after treatment. Histopathologic analysis was performed after hematoxylin and eosin staining, TUNEL, Ki-67, and immunohistochemical staining with CD8 and ANK61. RESULTS: Combination therapy (T-VEC + RFH) induced decreased cell viability and increased cell apoptosis compared to T-VEC alone, RFH alone, or control. Optical/x-ray imaging and ultrasound imaging demonstrated decreased tumor bioluminescent signal and tumor volume relative to baseline after combination therapy compared to T-VEC alone, RFH alone, or control. Histopathology demonstrated decreased tumor volume and cell proliferation, increased CD8+ T cell and NK cell infiltration in tumors treated with the combination therapy compared to other three groups. CONCLUSION: RFH enhances locally delivered oncolytic immuno-virotherapy for pancreatic adenocarcinoma, with decreased cell viability and increased apoptosis observed after combination therapy in vitro, and decreased cell viability and tumor volume and increased immune cell infiltrate observed after combination therapy in vivo.