Prostatic Artery Embolization in Patients with Refractory Lower Urinary Tract Symptoms after a Prior Minimally Invasive Surgical Treatment.

The purpose of this study was to report on prostatic artery embolization (PAE) outcomes in patients with refractory or recurrent lower urinary tract symptoms (LUTSs) due to benign prostatic hyperplasia (BPH) who had previously undergone a minimally invasive surgical technique (MIST). A single-center retrospective study identified 16 eligible patients. Baseline prostate volume at the time of PAE was 112.9 mL (SD ± 52.7). There were no adverse events throughout the follow-up period. There was significant improvement in International Prostate Symptom Score and quality of life from baseline of 23.5 (SD ± 5.1) and 4.9 (SD ± 0.9), respectively, to the last follow-up of 11.6 (SD ± 7.2) and 2 (SD ± 1.6), respectively. There was nonsignificant improvement in sexual function after PAE compared with baseline after MIST. PAE can be a safe and effective treatment in patients who have undergone prior MIST without negatively impacting erectile or ejaculatory function.

Yttrium-90 Radioembolization in the VX2 Rabbit Model: Radiation Safety and Factors Influencing Delivery Efficiency.

The purpose of this study was to define the optimal infusion parameters and operator radiation exposure for yttrium-90 (90Y) radioembolization in the VX2 rabbit model of liver cancer. Forty-one rabbits with VX2 were treated with glass microspheres with vial sizes of 1, 3, and 5 GBq. The mean administered activity was 51.5 MBq (95% CI, 39.1-63.9). Delivery efficiency improved with 1 GBq versus with 3 GBq (residual 11.0% vs 46.4%, respectively; P = .0013) and improved with 1 GBq versus with 5 GBq (residual 11.0% vs 33.8%, respectively; P = .0060). The mean operator extremity exposure was 41.7 µSv/infusion. The optimal minimum infusion volume and rate was 49 mL and 21 mL/min, respectively. Fecal elimination occurred with microsphere uptake in the gallbladder at 1 and 2 weeks. 90Y radioembolization can be safely and efficiently performed in the VX2 rabbit model. Methodological considerations as a "how-to" for the setup of a preclinical 90Y laboratory are included to support future translational research.

Correlation and Agreement of Yttrium-90 Positron Emission Tomography/Computed Tomography with Ex Vivo Radioembolization Microsphere Deposition in the Rabbit VX2 Liver Tumor Model.

PURPOSE: To demonstrate a stronger correlation and agreement of yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) measurements with explant liver tumor dosing compared with the standard model (SM) for radioembolization. MATERIALS AND METHODS: Hepatic VX2 tumors were implanted into New Zealand white rabbits, with growth confirmed by 7 T magnetic resonance imaging. Seventeen VX2 rabbits provided 33 analyzed tumors. Treatment volumes were calculated from manually drawn volumes of interest (VOI) with three-dimensional surface renderings. Radioembolization was performed with glass 90Y microspheres. PET/CT imaging was completed with scatter and attenuation correction. Three-dimensional ellipsoid VOI were drawn to encompass tumors on fused images. Tumors and livers were then explanted for inductively coupled plasma (ICP)-optical emission spectroscopy (OES) analysis of microsphere content. 90Y PET/CT and SM measurements were compared with reference standard ICP-OES measurements of tumor dosing with Pearson correlation and Bland-Altman analyses for agreement testing with and without adjustment for tumor necrosis. RESULTS: The median infused activity was 33.3 MBq (range, 5.9-152.9). Tumor dose was significantly correlated with 90Y PET/CT measurements (r = 0.903, P < .001) and SM estimates (r = 0.607, P < .001). Bland-Altman analyses showed that the SM tended to underestimate the tumor dosing by a mean of -8.5 Gy (CI, -26.3-9.3), and the degree of underestimation increased to a mean of -18.3 Gy (CI, -38.5-1.9) after the adjustment for tumor necrosis. CONCLUSIONS: 90Y PET/CT estimates were strongly correlated and had better agreement with reference measurements of tumor dosing than SM estimates.

Yttrium-90 Radioembolization to the Prostate Gland: Proof of Concept in a Canine Model and Clinical Translation.

PURPOSE: To investigate the feasibility, safety, and absorbed-dose distribution of prostatic artery radioembolization (RE) in a canine model. MATERIALS AND METHODS: Fourteen male castrated beagles received dihydroandrosterone/estradiol to induce prostatic hyperplasia for the duration of the study. Each dog underwent fluoroscopic prostatic artery catheterization. Yttrium-90 (90Y) microspheres (TheraSphere; Boston Scientific, Marlborough, Massachusetts) were delivered to 1 prostatic hemigland (dose escalation from 60 to 200 Gy), with the contralateral side serving as a control. Assessments for adverse events were performed throughout the follow-up (Common Terminology Criteria for Adverse Events v5.0). Positron emission tomography/magnetic resonance (MR) imaging provided a confirmation after the delivery of absorbed-dose distribution. MR imaging was performed before and 3, 20, and 40 days after RE. Tissue harvest of the prostate, rectum, bladder, urethra, penis, and neurovascular bundles was performed 60 days after RE. RESULTS: All the animals successfully underwent RE. Positron emission tomography/MR imaging demonstrated localization to and good coverage of only the treated hemigland. No adverse events occurred. The MR imaging showed a significant dose-dependent decrease in the treated hemigland size at 40 days (25%-60%, P < .001). No extraprostatic radiographic changes were observed. Necropsy demonstrated no gross rectal, urethral, penile, or bladder changes. Histology revealed RE-induced changes in the treated prostatic tissues of the highest dose group, with gland atrophy and focal necrosis. No extraprostatic RE-related histologic findings were observed. CONCLUSIONS: Prostate 90Y RE is safe and feasible in a canine model and leads to focal dose-dependent changes in the gland without inducing unwanted extraprostatic effects. These results suggest that an investigation of nonoperative prostate cancer is warranted.

Streamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation.

BACKGROUND & AIMS: Pre-treatment Tc-99m macroaggregated albumin (MAA) scans are routinely performed prior to transarterial radioembolization (TARE) to estimate lung shunt fraction (LSF) and lung dose. In this study, we investigate LSF observed in early hepatocellular carcinoma (HCC) and provide the scientific rationale for eliminating this step from routine practice. METHODS: Patients with HCC who underwent Y90 from 2004 to 2018 were reviewed. Inclusion criteria were early stage HCC (UNOS T1/T2/Milan criteria: solitary ≤5 cm, 3 nodules ≤3 cm). LSF was determined using MAA in all patients. Associations between LSF and baseline characteristics were investigated. A "no-MAA" paradigm was then proposed based on a homogenous group that expressed very low LSF. RESULTS: Of 1,175 patients with HCC treated with TARE, 448 patients met inclusion criteria. Mean age was 65.6 years and 303 (68%) were males. A total of 352 (79%) had solitary lesions and 406 (91%) unilobar disease. Two-hundred and forty-three (54%), 178 (40%) and 27 (6%) patients were Child-Pugh class A, B and C, respectively. Median LSF was 3.9% (IQR 2.4-6%). Median administered activity was 0.9 GBq (IQR 0.6-1.4), for a median segmental volume of 170 cm3 (range: 60-530). Median lung dose was 1.9 Gy (IQR: 1.0-3.3). The presence of a transjugular intrahepatic portosystemic shunt (TIPS; n = 38) was associated with LSF >10% (odds ratio 12.2; 95% CI 5.2-28.6; p <0.001). Median LSF was 3.8% (IQR: 2.4-5.7%) and 6% (IQR: 3.8-15.3%) in no-TIPS vs. TIPS patients (p <0.001). CONCLUSION: LSF is clinically negligible in patients with UNOS T1/T2 HCC without TIPS. When segmental injections are planned, this step can be eliminated, thereby reducing time-to-treatment, number of procedures, and improving convenience for patients traveling from faraway. LAY SUMMARY: Transarterial radioembolization is a microembolic transarterial treatment for hepatocellular carcinoma. In our study, we found that early stage patients, where segmental injections are planned, exhibited low lung shunting, effectively eliminating the risk of radiation pneumonitis. We propose that the lung shunt study be eliminated in this subgroup, thus leading to fewer procedures, a cost reduction and improved convenience for patients.

Sodium Cholate Bile Acid-Stabilized Ferumoxytol-Doxorubicin-Lipiodol Emulsion for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Ferumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models. RESULTS: DOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion. CONCLUSIONS: SC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Are prophylactic antibiotics necessary prior to transarterial chemoembolization for hepatocellular carcinoma in patients with native biliary anatomy?

BACKGROUND AND OBJECTIVES: Prophylactic antibiotics are frequently administered for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). In patients without previous biliary instrumentation, infection risk from TACE is low. We hypothesized that there is a negligible rate of infection in these patients without prophylactic antibiotics. METHODS: We reviewed consecutive patients undergoing TACE between 7/1/2013-6/15/2016. All patients had an intact Sphincter of Oddi, received no peri-procedural antibiotics, and had 30+ days follow-up. Level of arterial selection was recorded. Baseline Child-Pugh (CP) and Barcelona Clinic Liver Cancer (BCLC) scores were recorded. The primary outcome measure was the absence of clinical or imaging findings of hepatic abscess within 30 days. RESULTS: A total of 171 patients underwent 235 TACE procedures. CP scores were A (n = 109), B (n = 47), and C (n = 15). BCLC scores were 0 (n = 1), A (n = 108), B (n = 47), and C (n = 15). TACE was performed segmentally (n = 208) or lobar (n = 27). Three patients died of non-infectious causes before 30 days. No hepatic abscesses developed in evaluable patients: 0/232 infusions. CONCLUSIONS: In patients with HCC and an intact Sphincter of Oddi, TACE was performed safely without prophylactic antibiotics. The majority of the patients were BCLC and CP A/B. Additional study of BCLC and CP C patients is warranted.

Analysis of the RENAL and mRENAL Scores and the Relative Importance of Their Components in the Prediction of Complications and Local Progression after Percutaneous Renal Cryoablation.

PURPOSE: To determine if modified RENAL (mRENAL) score and its individual components have superior predictive value relative to the RENAL nephrometry score in prediction of complications and recurrence after percutaneous renal cryoablation. MATERIALS AND METHODS: Primary masses treated with CT-guided percutaneous renal cryoablation between June 2007 and May 2016 were retrospectively reviewed. RENAL and mRENAL scores were used to stratify masses into low, medium, and high complexity tertiles. Complications were characterized by SIR criteria. Predictors of complications and local progression were analyzed using multivariate logistic regression and Kaplan-Meier analysis. RESULTS: There were 95 renal cryoablation procedures in 86 patients. Of ablations, 89 had at least 1 follow-up imaging study, with median follow-up of 29 months. There were 11 (12.4%) complications, including 5 (6.5%) major complications. Mass complexity, as measured by mRENAL complexity tertile, was associated with increased risk of complications on multivariate analysis (P = .045). Endophytic location was the only individual ordinal component of the RENAL and mRENAL scores associated with complications (P = .021). Local progression occurred in 7 (8.3%) masses. Complexity as measured by either scoring system was not associated with local progression. Only diameter > 3 cm was associated with increased risk of local progression (hazard ratio = 9.9, 95% confidence interval = 2.1-45, P = .003). CONCLUSIONS: mRENAL score was predictive of complications and tumor size was predictive of recurrence. Use of mRENAL score for complications and tumor size for recurrence should allow for simpler risk stratification and more accurate patient counseling.

The Role of Percutaneous Image-Guided Thermal Ablation for the Treatment of Pulmonary Malignancies.

OBJECTIVE: Image-guided thermal ablation is a minimally invasive treatment option for patients with primary and secondary pulmonary malignancies. Modalities include radiofrequency ablation, microwave ablation, and cryoablation. CONCLUSION: Although no large randomized studies exist comparing ablation to surgery or radiotherapy, numerous studies have reported safety and efficacy for the treatment of both primary and metastatic disease in select patients. Future studies will refine patient selection, procedural technique, and assessment for local recurrence and will evaluate long-term survival.

Local Arterial Therapies in the Management of Unresectable Hepatocellular Carcinoma.

OPINION STATEMENT: Most patients with hepatocellular carcinoma present with intermediate to advanced disease, where curative therapies are no longer an option. These patients with intermediate to advanced disease represent a heterogeneous population with regard to tumor burden, liver function, and performance status. While the Barcelona Clinic Liver Cancer (BCLC) staging system offers guidelines for the management of these patients, strict adherence to these guidelines may limit treatment options for these patients. Several locoregional therapies exist for these patients, including conventional transarterial chemoembolization (cTACE), transarterial embolization (TAE), drug-eluting embolization (DEE), and radioembolization. Evidence is also emerging for the role of radiation therapy including most notably stereotactic body radiation therapy and proton therapy, although at the current time, clinical trial participation is encouraged. While cTACE is traditionally recommended for BCLC B disease, both cTACE and radioembolization are increasingly used for patients with intermediate disease, as well as in select patients with BCLC A and C disease. TAE and DEE are limited in their use currently, due to lack of clear survival benefits or clinical advantages over cTACE. While several studies have demonstrated similar OS between cTACE and radioembolization, radioembolization provides a longer time to progression and fewer toxicities compared to cTACE. This is particularly relevant in the setting of advanced BCLC B and early BCLC C disease, where patients may have limited reserve. Radioembolization also has additional roles as an alternative to ablation, inducing liver hypertrophy, treating patients with PVT, and downstaging lesions to transplant. Ongoing studies will further define the role of locoregional treatment potentially in combination with and in light of developments in systemic therapy.

Neutrophil to lymphocyte ratio predicts disease progression following intra-arterial therapy of hepatocellular carcinoma.

BACKGROUND: Prospectively predicting response to intra-arterial therapy for hepatocellular carcinoma (HCC) is challenging. Neutrophil/lymphocyte ratio (NLR) is a serum biomarker that is associated with survival for multiple malignancies. It was hypothesized that increased NLR would be associated with early disease progression after intra-arterial therapy of HCC. METHODS: The outcomes of 86 treatment-naïve patients who had chemoembolization or radioembolization of HCC between July 2013-July 2014 were reviewed. Pre-treatment laboratory tests and imaging were used to measure NLR, Child-Pugh (CP) score, tumor number and tumor size. High/low NLR groups were defined as >3 and <3 respectively. Follow-up imaging at two months with assessed response using modified response criteria in solid tumors (mRECIST). RESULTS: NLR >3 was seen in 25/86 patients (range 3.0-21.6). NLR >3 patients had a significantly higher baseline CP score. Comorbidities were otherwise similar between groups as was tumor number/size. Disease control was significantly worse (p = 0.014) with NLR >3. Logistic regression for tumor response revealed NLR >3 as the best predictor of early progression (p < 0.0001). DISCUSSION: NLR may be a serologic biomarker of early progressive disease after intra-arterial therapy of HCC. Future research should focus on outcomes by treatment type or potentially combining arterial therapies with ablation and/or targeted biologic agents.

Percutaneous Cryoablation for the Treatment of Primary and Metastatic Lung Tumors: Identification of Risk Factors for Recurrence and Major Complications.

PURPOSE: To identify risk factors for local recurrence and major complications associated with percutaneous cryoablation of lung tumors. MATERIALS AND METHODS: All cases between April 2007 and September 2014 at 1 institution were retrospectively reviewed. Procedures were performed using computed tomography guidance and a double freeze-thaw protocol. Tumor progression was determined via World Health Organization guidelines, and complications were classified using SIR reporting standards. Measures of efficacy were calculated via Kaplan-Meier analysis. Predictors of local progression and major complications were identified by Cox proportional hazards and logistic regression. RESULTS: There were 47 tumors (25 primary, 22 metastatic) treated with median follow-up of 11.1 months. Mean diameter before treatment was 2.4 cm, and an average of 2.1 cryoprobes were used per procedure. Major complications (most commonly, pneumothorax requiring chest tube) occurred in 12 (25%) cases, and minor complications occurred in 13 (27%) cases. Median time to local progression was 14 months (16 mo for primary tumors and 10 mo for metastatic tumors), and median overall survival was 33 months (43 mo for patients with primary tumors and 22 mo for patients with metastatic tumors). On multivariate analysis, tumor diameter > 3 cm was associated with local progression (hazard ratio = 3.2, P = .013), and use of multiple cryoprobes (relative risk [RR] = 7.2, P = .045) and previous local therapy (RR = 15, P = .030) were associated with major complications. CONCLUSIONS: Percutaneous cryoablation of lung tumors is technically feasible with a complication rate comparable to other percutaneous ablation techniques. Percutaneous cryoablation is more efficacious and has fewer complications when offered to patients with small, previously untreated lesions.

Single- versus Triple-Drug Chemoembolization for Hepatocellular Carcinoma: Comparing Outcomes by Toxicity, Imaging Response, and Survival.

PURPOSE: To determine the efficacy of single- versus triple-drug chemoembolization for the treatment of hepatocellular carcinoma, as measured by toxicity, tumor response, time to progression (TTP), and overall survival (OS). MATERIALS AND METHODS: A single-center retrospective review was performed on 337 patients who underwent chemoembolization over a 14-year period; 172 patients underwent triple-drug conventional transarterial chemoembolization, and 165 patients underwent single-agent doxorubicin chemoembolization. Imaging characteristics and clinical follow-up after conventional transarterial chemoembolization were evaluated to determine TTP. Imaging response was determined per World Health Organization and European Association for the Study of Liver criteria. OS from time of first chemoembolization was calculated. RESULTS: Median TTP was similar between groups: 7.9 months (95% confidence interval [CI], 7.1-9.4) and 6.8 months (95% CI, 4.6-8.6) for triple- and single-drug regimens, respectively (P > .05). For single-agent conventional transarterial chemoembolization, median OS varied significantly by Barcelona Clinic for Liver Cancer (BCLC) stage: A, 40.8 months; B, 36.4 months; C, 10.9 months (P < .01). Median OS for triple-drug therapy also varied significantly by BCLC: A, 28.9 months; B, 18.1 months; C, 9.0 months (P < .01). Single-drug conventional transarterial chemoembolization demonstrated longer median OS compared with triple-drug therapy (P < .05) for BCLC A/B patients. CONCLUSIONS: Single-agent chemoembolization with doxorubicin and ethiodized oil demonstrates acceptable efficacy as measured by TTP and OS. Results compare favorably with traditional triple-drug therapy.

MR imaging enables measurement of therapeutic nanoparticle uptake in rat N1-S1 liver tumors after nanoablation.

PURPOSE: To test the hypothesis that magnetic resonance (MR) imaging can quantify intratumoral superparamagnetic iron oxide (SPIO) nanoparticle uptake after nanoablation. MATERIALS AND METHODS: SPIO nanoparticles functionalized with doxorubicin were synthesized. N1-S1 hepatomas were successfully induced in 17 Sprague-Dawley rats distributed into three dosage groups. Baseline tumor R2* values (the reciprocal of T2*) were determined using 7-tesla (T) MR imaging. After intravenous injection of SPIO nanoparticles, reversible electroporation (1,300 V/cm, 8 pulses, 100-µs pulse duration) was applied. Imaging of rats was performed to determine tumor R2* values after the procedure, and change in R2* (ΔR2*) was calculated. Inductively coupled plasma mass spectrometry was used to determine intratumoral iron (Fe) concentration after the procedure, which served as a proxy for SPIO nanoparticle uptake. Mean tumor Fe concentration [Fe] and ΔR2* for each subject were assessed for correlation with linear regression, and mean [Fe] for each dosage group was compared with analysis of variance. RESULTS: ΔR2* significantly correlated with tumor SPIO nanoparticle uptake after nanoablation (r = 0.50, P = .039). On average, each 0.1-ms(-1) increase in R2* corresponded to a 0.1394-mM increase in [Fe]. There was no significant difference in mean SPIO nanoparticle uptake among dosage groups (P = .57). CONCLUSIONS: Intratumoral SPIO nanoparticle uptake after nanoablation can be successfully quantified noninvasively with 7-T MR imaging. Imaging can be used as a method to estimate localized drug delivery after nanoablation.

Preclinical Development and Validation of Translational Temperature Sensitive Iodized Oil Emulsion Mediated Transcatheter Arterial Chemo-Immuno-Embolization for the Treatment of Hepatocellular Carcinoma.

Herein a practical strategy for augmenting immune activation in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) is presented. Pluronic F127 (PF127) is incorporated with Lipiodol (LPD) to achieve safe and effective delivery of therapeutic agents during transcatheter intra-arterial (IA) local delivery. Enhanced emulsion stability, IA infusion, embolic effect, safety, pharmacokinetics, and tumor response of Doxorubicin loaded PF127-LPD (Dox-PF127-LPD) for TACE in both in vitro and in vivo preclinical VX2 liver cancer rabbit model and N1S1 HCC rat model are demonstrated. Then, transcatheter arterial chemo-immuno-embolization (TACIE) combining TACE and local delivery of immune adjuvant (TLR9 agonist CpG oligodeoxynucleotide) is successfully performed using CpG-loaded Dox-PF127-LPD. Concurrent and safe local delivery of CpG and TACE during TACIE demonstrate leveraged TACE-induced immunogenic tumor microenvironment and augment systemic anti-tumor immunity in syngeneic N1S1 HCC rat model. Finally, the broad utility and enhanced therapeutic efficacy of TACIE are validated in the diethylnitrosamine-induced rat HCC model. TACIE using clinically established protocols and materials shall be a convenient and powerful therapeutic approach that can be translated to patients with HCC. The robust anti-cancer immunity and tumor regression of TACIE, along with its favorable safety profile, indicate its potential as a novel localized combination immunotherapy for HCC treatment.

Role of interventional oncology in hepatocellular carcinoma: Future best practice beyond current guidelines.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Liver transplant remains the goal of curative treatment, but limited supply of organs decreases accessibility and prolongs waiting time to transplantation. Therefore, interventional oncology therapies have been used to treat the majority of HCC patients, including those awaiting transplant. The Barcelona Clinic Liver Cancer (BCLC) classification is the most widely used staging system in management of HCC that helps allocate treatments. Since its inception in 1999, it was updated for the fifth time in November 2021 and for the first time shaped by expert opinions outside the core BCLC group. The most recent version includes additional options for early-stage disease, substratifies intermediate disease into three groups, and lists alternates to Sorafenib that can double the expected survival of advanced-stage disease. The group also proposed a new BCLC staging schema for disease progression, and endorsed treatment stage migration (TSM) directly into the main staging and treatment algorithm. This article reviews the recent developments underlying the current BCLC guidelines and highlights ongoing research, particularly involving radioembolization, that will shape future best practice.