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.

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.

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.

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.

Mitral valve replacement complicated by iatrogenic left ventricular outflow obstruction and paravalvular leak: case report and review of literature.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction and paravalvular leak (PVL) are relatively uncommon, but are serious complications of prosthetic valve replacement. CASE PRESENTATION: We present a case that displays the unique therapeutic challenges of treating a patient who developed both LVOT obstruction and mitral PVL after undergoing surgical aortic and mitral valve replacement (MVR). We also describe the use of alcohol septal ablation and albumin-glutaraldehyde (BioGlue) for septal ablation to percutaneously treat the patient's LVOT obstruction, followed by use of an Amplatzer vascular plug for percutaneous closure of an antero-medial mitral PVL associated with severe regurgitation. CONCLUSION: Percutaneous interventional management of these entities may be considered as an initial therapeutic option, especially in high-risk patients with significant morbidity and mortality of repeat surgical operations.

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.

Tilsotolimod: an investigational synthetic toll-like receptor 9 (TLR9) agonist for the treatment of refractory solid tumors and melanoma.

INTRODUCTION: Cancer immunotherapy has seen tremendous strides in the past 15 years, with the introduction of several novel immunotherapeutic agents. Nevertheless, as clinical practice has shown, significant challenges remain with a considerable number of patients responding sub-optimally to available therapeutic options. Research has demonstrated the important immunoregulatory role of the tumor microenvironment (TME), with the potential to either hinder or promote an effective anti-tumor immune response. As such, scientific efforts have focused on investigating novel candidate immunomodulatory agents with the potential to alter the TME toward a more immunopotentiating composition. AREAS COVERED: Herein, we discuss the novel investigational toll-like receptor 9 agonist tilsotolimod currently undergoing phase II and III clinical trials for advanced refractory cancer, highlighting its mode of action, efficacy, tolerability, and potential future applications in the treatment of cancer. To this effect, we conducted an exhaustive Web of Science and PubMed search to evaluate available research on tilsotolimod as of August 2021. EXPERT OPINION: With encouraging early clinical results demonstrating extensive TME immunomodulation and abscopal effects on distant tumor lesions, tilsotolimod has emerged as a potential candidate immunomodulatory agent with the possibility to augment currently available immunotherapy and provide novel avenues of treatment for patients with advanced refectory cancer.

Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101).

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. RESULTS: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. CONCLUSIONS: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007.

Gallbladder Cryoablation: A Novel Option for High-Risk Patients with Gallbladder Disease.

Management of high-risk surgical patients with cholecystitis poses a significant clinical problem. These patients are often left with the options of permanent cholecystostomy tube drainage or high-risk surgery. Numerous attempts have been made over the past 4 decades to fulfill the need for a minimally invasive, definitive treatment option for such gallbladder disease. These attempts have largely focused on endoluminal ablation with a variety of sclerosants and have been unable to reliably achieve permanent gallbladder devitalization. The advent of modern percutaneous devices and techniques have provided further opportunity to develop minimally invasive treatment options for high-risk patients. Cryoablation, a thermal ablation modality that induces cell death through tissue freezing, has recently emerged as a promising potential option to treat gallbladder disease. Early studies have demonstrated good technical and clinical success, and a prospective trial is ongoing. This manuscript explains the clinical need for gallbladder cryoablation, briefly revisits historical minimally invasive treatments, describes cryoablation technology and why it is well suited for the gallbladder, and reviews the preclinical and clinical studies evaluating the safety and efficacy of gallbladder cryoablation.

Cardiac MRI for Evaluation of Right Heart Function before and after Catheter-directed Therapy in Submassive Pulmonary Embolism: A Prospective Study of Feasibility and Potential Utility.

Cardiac MRI is clinically feasible in the setting of submassive pulmonary embolism and is able to demonstrate measurable differences of right heart function before and after catheter-directed therapy.

Using FDA-approved drugs as off-label fluorescent dyes for optical biopsies: from in silico design toex vivoproof-of-concept.

Optical biopsies bring the microscope to the patient rather than the tissue to the microscope, and may complement or replace the tissue-harvesting component of the traditional biopsy process with its associated risks. In general, optical biopsies are limited by the lack of endogenous tissue contrast and the small number of clinically approvedin vivodyes. This study tests multiple FDA-approved drugs that have structural similarity to research dyes as off-labelin situfluorescent alternatives to standardex vivohematoxylin & eosin tissue stain. Numerous drug-dye combinations shown here may facilitate relatively safe and fastin situor possiblyin vivostaining of tissue, enabling real-time optical biopsies and other advanced microscopy technologies, which have implications for the speed and performance of tissue- and cellular-level diagnostics.

Effects of nonselective internal iliac artery angioembolization on pelvic venous flow in the swine model.

BACKGROUND: Pelvic angioembolization (AE) is a mainstay in the treatment algorithm for pelvic hemorrhage from pelvic fractures. Nonselective AE refers to embolization of the bilateral internal iliac arteries (IIAs) proximally rather than embolization of their tributaries distally. The aim of this study was to quantify the effect of nonselective pelvic AE on pelvic venous flow in a swine model. We hypothesized that internal iliac vein (IIV) flow following IIA AE is reduced by half. METHODS: Nine Yorkshire swine underwent nonselective right IIA gelfoam AE, followed by left. Pelvic arterial and venous diameter, velocity, and flow were recorded at baseline, after right IIA AE and after left IIA AE. Linear mixed-effect model and signed rank test were used to evaluate significant changes between the three time points. RESULTS: Eight swine (77.8 ± 7.1 kg) underwent successful nonselective IIA AE based on achieving arterial resistive index of 1.0. One case was aborted because of technical difficulties. Compared with baseline, right IIV flow rate dropped by 36% ± 29% (p < 0.05) and 54% ± 29% (p < 0.01) following right and left IIA AE, respectively. Right IIA AE had no initial effect on left IIV flow (0.37% ± 99%, p = 0.95). However, after left IIA AE, left IIV flow reduced by 54% ± 27% (p < 0.01). Internal iliac artery AE had no effect on the external iliac arterial or venous flow rates and no effect on inferior vena cava flow rate. CONCLUSION: The effect of unilateral and bilateral IIA AE on IIV flow appears to be additive. Despite bilateral IIA AE, pelvic venous flow is diminished but not absent. There is abundant collateral circulation between the external and internal iliac vascular systems. Arterial embolization may reduce venous flow and improve on resuscitation efforts in those with unstable pelvic fractures. LEVEL OF EVIDENCE: Prognostic, level IV.