Personalized Dosimetry for Liver Cancer Y-90 Radioembolization Using Computational Fluid Dynamics and Monte Carlo Simulation.

Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When… and Y(90)?

Simple SummaryTransarterial radioembolization (TARE) of the liver with Yttrium-90 (Y-90) microspheres is a prominent approach used to treat hepatocellular carcinoma (HCC), the most common primary liver cancer and the third-leading cause of cancer-related deaths worldwide. Recent studies have found that radiation dose estimates based on pretreatment simulations can predict HCC response to Y-90. We hypothesized that (1) Y-90 microspheres deposit heterogeneously due to variabilities in vascular dynamics; and (2) treatment response is better predicted by evaluating dose coverage of HCC in 3-dimensional space using actual Y-90 biodistribution derived from day-of-treatment nuclear imaging. We reviewed a cohort of 50 consecutive HCC patients with TARE Y-90 lobar treatments at a single institution looking for associations between volumetric dose coverage and clinical outcomes. Best treatment response most often occurred at 6 months post-TARE, with a migration toward better response after 3 months, complicating early imaging assessments. Islands of underdosed HCC appeared to compromise outcomes even when the mean or median dose to tumor was high. When prescribed dose increased along with the burden of disease, so did the mean dose to non-tumorous liver, limiting the safety of dose escalation. A multidisciplinary approach promises to accelerate advances in TARE dosimetry leading to improved clinical outcomes.In transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) with Yttrium-90 (Y-90) microspheres, recent studies correlate dosimetry from bremsstrahlung single photon emission tomography (SPECT/CT) with treatment outcomes; however, these studies focus on measures of central tendency rather than volumetric coverage metrics commonly used in radiation oncology. We hypothesized that three-dimensional (3D) isodose coverage of gross tumor volume (GTV) is the driving factor in HCC treatment response to TARE and is best assessed using advanced dosimetry techniques applied to nuclear imaging of actual Y-90 biodistribution. We reviewed 51 lobar TARE Y-90 treatments of 43 HCC patients. Dose prescriptions were 120 Gy for TheraSpheres and 85 Gy for SIR-Spheres. All patients underwent post-TARE Y-90 bremsstrahlung SPECT/CT imaging. Commercial software was used to contour gross tumor volume (GTV) and liver on post-TARE SPECT/CT. Y-90 dose distributions were calculated using the Local Deposition Model based on post-TARE SPECT/CT activity maps. Median gross tumor volume (GTV) dose; GTV receiving less than 100 Gy, 70 Gy and 50 Gy; minimum dose covering the hottest 70%, 95%, and 98% of the GTV (D70, D95, D98); mean dose to nontumorous liver, and disease burden (GTV/liver volume) were obtained. Clinical outcomes were collected for all patients by chart and imaging review. HCC treatment response was assessed according to the modified response criteria in solid tumors (mRECIST) guidelines. Kaplan-Meier (KM) survival estimates and multivariate regression analyses (MVA) were performed using STATA. Median survival was 22.5 months for patients achieving objective response (OR) in targeted lesions (complete response (CR) or partial response (PR) per mRECIST) vs. 7.6 months for non-responders (NR, stable disease or disease progression per mRECIST). On MVA, the volume of underdosed tumor (GTV receiving less than 100 Gy) was the only significant dosimetric predictor for CR (p = 0.0004) and overall survival (OS, p = 0.003). All targets with less than CR (n = 39) had more than 20 cc of underdosed tumor. D70 (p = 0.038) correlated with OR, with mean D70 of 95 Gy for responders and 60 Gy for non-responders (p = 0.042). On MVA, mean dose to nontumorous liver trended toward significant association with grade 3+ toxicity (p = 0.09) and correlated with delivered activity (p < 0.001) and burden of disease (p = 0.05). Dosimetric models supplied area under the curve estimates of > 0.80 predicting CR, OR, and ≥grade 3 acute toxicity. Dosimetric parameters derived from the retrospective analysis of post-TARE Y-90 bremsstrahlung SPECT/CT after lobar treatment of HCC suggest that volumetric coverage of GTV, not a high mean or median dose, is the driving factor in treatment response and that this is best assessed through the analysis of actual Y-90 biodistribution.

18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a functional image technique that can inform clinical decisions related to prognosis. We investigated the predictive role of 18 F-fluorodeoxyglucose PET/CT in patients with hepatocellular carcinoma (HCC) undergoing Yttrium-90 (Y-90) transarterial radioembolization (TARE). Patients with HCC treated with TARE and pre-TARE PET/CT scan were recruited between 2009 and 2013. Maximum standardized uptake value and tumor-to-non-tumorous liver uptake ratio (TLR) were measured. Tumor response was evaluated in accordance with modified RECIST criteria at 3-month intervals after Y-90 TARE. Forty patients were included in the final analysis. The median age was 56.5 years and male predominant. Disease control in treated lesion was achieved in 82.5% (n = 33) of patients. During median 18.3-month follow-up, 27.5% (n = 11) of patients achieved progression-free survival. The cutoff of TLR, which was related to the median value, did not affect disease control rate, progression-free survival, and overall survival in patients with Y-90 TARE. The TLR-based stratification may be a simple method, but our study did not show the usefulness in predicting prognosis in HCC patients with Y-90 TARE. Further studies with large number of patients are needed.

Yttrium-90 Glass Microsphere Transarterial Radioembolization for Patients with Unresectable Liver-Dominant Breast Cancer Metastasis

Hepatoblastoma (HB) is a rare but highly malignant tumor that commonly arises in utero. The mainstay treatment is surgical resection, with adjuvant treatment optionsincluding chemotherapy, hepatic artery chemoembolization, and liver transplantation. Yttrium-90 (Y90) transarterial radioembolization(TARE Y90) is a developing treatment option that utilizes radioactive beads delivered specifically to blood vessels supplying the tumor. This treatment method has previously been utilized in the treatment of adult tumors but has rarely been utilized in the pediatric population. In this report, we discuss the case of a toddler with an unresectable HB who underwent TARE Y90 as an adjuvant treatment to chemotherapy, ending in a successful liver transplantation. This patient was a19-month-old female who presented with an abdominal mass and laboratory findings significant for anemia, thrombocytosis, elevated lactate dehydrogenase (LDH), direct hyperbilirubinemia, and alpha-fetoprotein (AFP) elevation. A computed tomography (CT) scan and magnetic resonance imaging (MRI) displayed a large, multilobular mass involving all lobes of the liver without evidence of metastasis, and biopsy results were consistent with HB. Following four rounds of chemotherapy, an MRI of the abdomen revealed a decrease in tumor size. Due to the continued uptrend of AFP raising concern for lack of control of the tumor, treatment with TARE Y90 microspheres radioembolization as a bridging therapy was initiated. Repeat scans showed an interval increase in the HB size, likely secondary totumor necrosis with edema and hyperemia. Nine months following the diagnosis, the patient underwent an orthotopic liver transplant and a sixth cycle of chemotherapy. This report illustrates the use of TAREY90 in a pediatric patient diagnosed with HB, thereby inducing a direct cytotoxic effect on tumor cells. Adjunctive therapy Y90 radioembolization worked by controlling tumor size and AFP levels, facilitating the crucial aspect of liver transplantation with tumor resection with negative margins. The patient did not suffer any of the known side effects of TARE Y90 therapy, which include, but are not limited to, post-embolization syndrome, biliary complications, stricture, cholangitis, pulmonary complications, and gastrointestinal ulcers. This therapy, along with chemotherapy, has the potential to be anovel approach as a bridge to resection or orthotopic liver transplantin HB patients. Further case reports and a manuscript compiling the use of Y90 radioembolization therapy in pediatric HB patients would be useful in evaluating the efficacy of the treatment in pediatric patients.

Spoilage of agrifood produce is a major issue in the industry. Cooling is an effective technique for extending the shelf life of fresh agrifood produce to minimize spoilage. Due to the practical inability of directly solving the wide spatial and temporal scales in large industrial agrifood cooling systems, the porous medium approach is mostly used. However, improvements of current porous medium models and modeling across much wider scales are needed to better understand the multiscale cooling process and system problems. Recently, as a result of increased computational capacity, multiscale computational fluid dynamics (CFD) modeling approaches have been developed to tackle some of these challenges. The associated problems and applications of CFD in the design and process optimization of cooling processes and systems at different scales are considered. CFD solution and scale bridging techniques relevant for handling multiscale cooling processes and systems problems are discussed. Innovative applications of various CFD modeling techniques at different scales in cooling processes and systems are reviewed. CFD modeling techniques can be used to handle multiscale cooling process and system problems. Lattice Boltzmann method (LBM) is a potentially viable discrete modeling technique for complimentary usages alongside current continuum techniques in future multiscale CFD modeling. The multiscale CFD modeling paradigm can overcome the computational resource limitations associated with the direct modeling approach and enhance model extension across wider spatial and temporal scales. Information from multiscale CFD could be used to improve the accuracy of current porous medium models, and thus the design of more efficient cooling systems.

TPS542 Background: In recent years, Yttrium-90 (Y90) trans-arterial radioembolization (TARE) has emerged as a therapeutic option for intermediate stage hepatocellular carcinoma (HCC). Cancer immunotherapy targeting tumour immune evasion has shown remarkable successes in various cancers. Nivolumab, an immune checkpoint inhibitor of programmed death 1 (PD1), has demonstrated encouraging activity in advanced stage HCC. Similarly, chronic hepatitis B virus (HBV) infection, a strong risk factor for HCC, is characterized by immune escape mechanisms. We hypothesize that TARE will stimulate tumor and/or HBV specific T cell responses that can be boosted using nivolumab. We thus propose an open label phase 2 trial investigating the combination of TARE with nivolumab in BCLC intermediate stage HCC. Methods: Eligible patients (pts) have ECOG performance status ≤ 2, Child-Pugh A score, intermediate stage HCC planned for TARE according to institutional practice with adequate organ function. Pts will be treated with TARE followed by nivolumab 240mg, 21 days after TARE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies will be taken. Primary end-point is response rate (RR) of combinational TARE and nivolumab. Key secondary end points are: progression free survival, overall survival, safety and quality of life using FACT-HEP score and EORTC QLQ-C30. Exploratory objectives are to evaluate how tumor PD L-1 expression, HCC mutational burden and blood lymphocyte activation/phenotypic profiles correlate with tumor response. Where possible, serial changes in antigen-specific T cell responses to HBV and/or tumour antigens will also be assessed. This study aims to enroll 40 pts as calculated using the Simon two-stage optimal design with 80% power and one sided significance level of 0.05. This will assess whether the addition of nivolumab improves the RR of TARE at 8 weeks from 21% to 41%. Patient accrual was initiated in December 2016 and as of September 2017, 9 pts have been treated. Clinical trial information: 03033446.

PurposeThe process of converting Yttrium‐90 (Y90) PET/CT images into 3D absorbed dose maps will be explained. The simple methods presented will allow the medical physicst to analyze Y90 PET images following radioembolization and determine the absorbed dose to tumor, normal liver parenchyma and other areas of interest, without application of Monte‐Carlo radiation transport or dose‐point‐kernel (DPK) convolution.MethodsAbsorbed dose can be computed from Y90 PET/CT images based on the premise that radioembolization is a permanent implant with a constant relative activity distribution after infusion. Many Y90 PET/CT publications have used DPK convolution to obtain 3D absorbed dose maps. However, this method requires specialized software limiting clinical utility. The Local Deposition method, an alternative to DPK convolution, can be used to obtain absorbed dose and requires no additional computer processing. Pixel values from regions of interest drawn on Y90 PET/CT images can be converted to absorbed dose (Gy) by multiplication with a scalar constant.ResultsThere is evidence that suggests the Local Deposition method may actually be more accurate than DPK convolution and it has been successfully used in a recent Y90 PET/CT publication. We have analytically compared dose‐volume‐histograms (DVH) for phantom hot‐spheres to determine the difference between the DPK and Local Deposition methods, as a function of PET scanner point‐spread‐function for Y90. We have found that for PET/CT systems with a FWHM greater than 3.0 mm when imaging Y90, the Local Deposition Method provides a more accurate representation of DVH, regardless of target size than DPK convolution.ConclusionUsing the Local Deposition Method, post‐radioembolization Y90 PET/CT images can be transformed into 3D absorbed dose maps of the liver. An interventional radiologist or a Medical Physicist can perform this transformation in a clinical setting, allowing for rapid prediction of treatment efficacy by comparison to published tumoricidal thresholds.

Yttrium-90 (Y-90) transarterial radioembolization (TARE) is widely used for the treatment of primary and metastatic liver tumors and has traditionally been viewed as a purely locoregional radiotherapeutic modality. However, accumulating clinical evidence supports the concept that Y-90 TARE can induce measurable immunologic changes in patients, detectable both systemically and within the tumor microenvironment. Longitudinal analyses of peripheral blood and tumor tissue from patients with hepatocellular carcinoma and liver metastases demonstrate transient immune activation, myeloid remodeling, and adaptive immune perturbations following treatment. Notably, these immune-stimulatory signals may coexist with counter-regulatory mechanisms, including upregulation of immune checkpoint pathways, suggesting a dynamic balance between immune priming and adaptive resistance. In this Perspective, we synthesize available in vivo human evidence supporting the concept that Y-90 TARE functions as an immune modulator rather than a solely cytotoxic intervention. We discuss the pharmacologic implications of these findings, particularly in relation to treatment sequencing, biomarker development, and rational combination strategies with immunotherapies. Recognizing Y-90 TARE as an immunologically active modality may inform the design of future clinical trials and optimize its integration into combination regimens aimed at durable tumor control.

Yttrium-90 (Y-90) trans-arterial radioembolization (TARE) is used in the management of unresectable hepatocellular carcinoma (HCC). During the last 5 years, dosimetry software has been developed to allow for a more rigorous approach of dose prescription in Y-90 TARE. We present here a case study of a 77-year-old woman diagnosed with HCC, who underwent a Y-90 TARE as a bridge procedure to liver resection. This clinical scenario represents a unique opportunity to illustrate the predictive value of dosimetric findings correlating dosimetry with pathological findings. In this case, Y-90 TARE dosimetry was predictive of treatment response in which the tumor received a mean dose of 156 Gy and demonstrated a complete pathologic response.

Precision individual dosimetry in Yttrium-90 transarterial radioembolization in the presence of Au nanoparticles

This research explores the application of Contrast-Limited Adaptive Histogram Equalization (CLAHE) as a technique for enhancing the visual quality and diagnostic utility of liver Positron Emission Tomography (PET) images. PET scans are widely used in nuclear medicine to detect metabolic activity, such as tumors, but they often suffer from poor contrast and lack sufficient anatomical detail. By applying CLAHE, we aim to improve local contrast in PET images, making tumor regions more distinguishable without amplifying noise. To validate and precisely localize the tumor boundaries, RTSTRUCT data provided delineated regions of interest (ROIs), which were extracted and overlaid on the corresponding CT slices. This step enabled both validation of the segmentation and clear anatomical localization of the target structure. The study integrates CLAHE-enhanced PET images with these corresponding Computed Tomography (CT) scans to fuse functional and anatomical information. The fusion of PET and CT allows for clearer tumor localization, which is critical for accurate diagnosis and treatment planning, particularly in patients undergoing Yttrium-90 (Y-90) radioembolization therapy for liver cancer “The publicly available Y-90 PET/SPECT/CT dataset used in this study contains four anonymized patients, with no demographic identifiers such as age or gender”. The effectiveness of different CLAHE parameters was evaluated using quantitative metrics such as entropy, Structural Similarity Index Measure (SSIM), and Peak Signal-to-Noise Ratio (PSNR) demonstrating an improvement of 23.7%, 1.1%, and 2.0 dB, respectively, compared to the original PET/CT images. These results indicate that optimized CLAHE effectively enhance image contrast and tumor boundary clarity while preserving structural fidelity, suggesting potential utility in improving PET/CT fusion accuracy for hepatic oncology applications.

No. 31 Comparison of hybrid Angio-CT infused volume and conventional anatomic volume calculation on Y-90 radioembolization dosimetry

Neuroendocrine tumors (NETs) metastatic to the liver are treated with transarterial radioembolization (TARE) using yttrium-90 (Y-90) microspheres or transarterial chemoembolization (TACE). However the criteria for patient selection are not well defined. We sought to determine if Ki67 score could help select patients for one therapy over the other in the management of hepatic neuroendocrine metastases. Single institution analysis of patients treated with Y-90 or TACE between 2001 and 2014. Pathologists blinded to clinical information performed Ki67 staining. Data were analyzed using multivariate association for survival outcomes. Amongst 72 patients (male: 39, female: 33, median age: 57 years) with metastatic NET, the most common site of origin was small bowel (n=35, 49%), while pancreas constituted 32% (n=23). Forty-four patients were treated with Y-90 (61%) and 28 patients received TACE (39%). Ki67 score was available in 28 patients (64%) treated with Y-90 and 16 patients (57%) with TACE. Within Y-90 group, there was greater use of Sandostatin (95% vs. 75%, P=0.02) and less number of total treatments completed (89% vs. 46%, P<0.001). There was no significant difference in overall survival (OS) between Y-90 and TACE when used without selection (median, 69 vs. 82 months, P=0.47). When adjusted for Ki67, patients with Ki67 score ≥3% had better OS with Y-90 compared to TACE (HR, 0.1; CI, 0.01-0.9), however for Ki67 <3%, OS was better when treated with TACE compared to Y-90 (HR, 13.5; CI, 1.22-148.87). There is significant interaction between Ki-67 score and liver-directed treatment benefit in patients with hepatic neuroendocrine metastases. Ki-67 score ≥3% predicts greater benefit with Y-90 and a Ki-67 score <3% predicts greater benefit with TACE.

Impact of Prior Y90 Dosimetry on Toxicity and Outcomes Following SBRT for Hepatocellular Carcinoma