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Purpose Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry. Methods Six patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE. Results Administration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend. Conclusion This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization. Registration Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

Since its first suggestion as possible option for liver radioembolization treatment, the therapeutic isotope holmium-166 (166Ho) caught the experts’ attention due to its imaging possibilities. Being not only a beta, but also a gamma emitter and a lanthanide, 166Ho can be imaged using single-photon emission computed tomography and magnetic resonance imaging, respectively. Another advantage of 166Ho is the possibility to perform the scout and treatment procedure with the same particle. This prospect paves the way to an individualized treatment procedure, gaining more control over dosimetry-based patient selection and treatment planning. In this review, an overview on 166Ho liver radioembolization will be presented. The current clinical workflow, together with the most relevant clinical findings and the future prospective will be provided.

Selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-loaded microspheres is increasingly used for the treatment of Intrahepatic Cholangiocarcinoma (ICC). Dosimetry verifications post-treatment are required for a valid assessment of any dose-response relationship. We performed a systematic review of the literature to determine how often clinics conducted post-treatment dosimetry verification to measure the actual radiation doses delivered to the tumor and to the normal liver in patients who underwent SIRT for ICC, and also to explore the corresponding dose-response relationship. We also investigated other factors that potentially affect treatment outcomes, including the type of microspheres used and concomitant chemotherapy. Out of the final 47 studies that entered our study, only four papers included post-treatment dosimetry studies after SIRT to quantitatively assess the radiation doses delivered. No study showed that one microsphere type provided a benefit over another, one study demonstrated better imaging-based response rates associated with the use of glass-based TheraSpheres, and two studies found similar toxicity profiles for different types of microspheres. Gemcitabine and cisplatin were the most common chemotherapeutic drugs for concomitant administration with SIRT. Future studies of SIRT for ICC should include dosimetry to optimize treatment planning and post-treatment radiation dosage measurements in order to reliably predict patient responses and liver toxicity.

Yttrium-86 (

The majority of patients with metastatic colorectal cancer (CRC) to the liver are not amenable to curative-intent surgery or thermal ablation; there is a need for alternative locoregional therapies to control oligometastatic liver disease. Sequential lobar Yttrium-90 (Y90) radioembolization has demonstrated favorable results in the salvage setting for CRC patients with liver only or liver-dominant metastatic disease, but the role of Y90 in earlier-stage disease has not shown to be as promising. Recently, radiation segmentectomy, the super selective delivery of high (ablative) dose Y90 microspheres, has been introduced as a novel approach for patients with unresectable hepatocellular carcinoma. This review provides an overview of the current role of Y90 radioembolization for CRC patients with metastasis to the liver, with specific focus on the evolving application of radiation segmentectomy for patients with limited hepatic metastases from colorectal cancer.

This study aimed to evaluate the prognostic value of metabolic parameters on 18F-FDG PET/CT and tumor dose (TD) on posttreatment 90Y PET/CT in patients with hepatocellular carcinoma (HCC) who underwent 90Y transarterial radioembolization (TARE).Forty-seven HCC patients treated with 90Y TARE were retrospectively enrolled between January 2013 and October 2018. 18F-FDG PET/CT was performed before treatment. Maximum tumor SUV-to-mean normal liver SUV ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for each patient. Voxel dosimetry was performed on 90Y PET/CT images to measure TD. The prognostic significance of metabolic parameters on 18F-FDG PET/CT, TD on 90Y PET/CT, and clinical factors for overall survival (OS) was evaluated. In addition, TD on 90Y PET/CT was analyzed in relation to the administered dose of 90Y-labeled microspheres and metabolic parameters on 18F-FDG PET/CT.The median patient age was 57 years, and 37 patients (78.7%) were men. During the follow-up period, 25 patients (53.2%) died. In univariable analysis, Barcelona Clinic Liver Cancer stage C, Child-Pugh score, TD on 90Y PET/CT, TLR, MTV, and TLG were significant prognostic factors affecting OS (P0.05). In multivariable analysis, Barcelona Clinic Liver Cancer stage C and high TLG on 18F-FDG PET/CT were independent prognostic factors for OS (P0.05). The 1-year OS rates were 72.9% in patients with low TLG and 33.3% in patients with high TLG (P0.05). We also found that TD on 90Y PET/CT was not correlated with the administered dose of 90Y-labeled microspheres, but negatively correlated with TLG on pretreatment 18F-FDG PET/CT (P0.05).TLG, a parameter incorporating both the degree of 18F-FDG uptake and amount of metabolically active tumor volume on pretreatment 18F-FDG PET/CT, is a better prognostic factor than TD on 90Y PET/CT for predicting OS in HCC patients treated with 90Y TARE.

Background: It is estimated that more than 1 million people are diagnosed with liver malignancy each year and one of the treatments is radioembolization with Y-90 and Ho-166. Objective: The aim of this study is to calculate the absorbed doses caused by Y-90 and Ho-166 in tumor and liver parenchyma using a phantom via Monte Carlo method. Methods: A liver model phantom including a tumor imitation of sphere (r =1.5cm) was defined in GATE. The total activity of 40 mCi Y-90 and Ho-166 was prescribed into tumor imitation as source and 2x2x2 mm3 voxel-sized Dose- Actors were identified at 30 locations. The simulation, performed to calculate the absorbed doses left by particles during 1 second for Y-90 and Ho-166, was run for a total of 10 days and 11 days, respectively. Total doses were calculated by taking the doses occurring in 1 second as a reference. Results: The maximum absorbed doses were found to be 2.334E+03±1.576E+01 Gy for Y-90 and 7.006E+02±6.013E- 01 Gy for Ho-166 at the center of tumor imitation. The minimum absorbed doses were found to be 2.133E-03±1.883E- 01 Gy for Y-90 and 1.152E-02±1.036E-03 Gy for Ho-166 at the farthest location from source. The mean absorbed doses in tumor imitation were found to be 1.50E+03±1.36E+00 Gy and 4.58E+02±4.75E-01 Gy for Y-90 and Ho-166, respectively. And, the mean absorbed doses in normal parenchymal tissue were found to be2.07E+01±9.58E-02 Gy and 3.79E+00±2.63E-02 Gy for Y-90 and Ho-166, respectively. Conclusion: Based on the results, Ho-166 is a good alternative to Y-90 according to dosimetric evaluation.

Radioembolization is the selective application of radionuclide-loaded microspheres into liver arteries for the therapy of liver tumours and metastases. In this review, we focused on therapy planning and dosimetry, as well as the main indications of 90Y-glass and resin microspheres and 166Ho-microspheres.Radioembolisation ist die selektive Applikation Radionuklid-beladener Mikrosphären in Leberarterien zur Therapie von Lebertumoren und -metastasen. In diesem Review konzentrierten wir uns auf die Therapieplanung und Dosimetrie sowie auf die Hauptindikationen von 90Y-Glas- und Harz-Mikrosphären und 166Ho-Mikrosphären.

There is significant interest and potential in the treatment of neuroendocrine tumors via peptide receptor radionuclide therapy (PRRT) using one or both of 90Y and 177Lu-labeled peptides. Given the presence of different tumor sizes in patients and differing radionuclide dose delivery properties, the present study aims to use Monte Carlo simulations to estimate S-values to spherical tumors of various sizes with 90Y and 177Lu separately and in combination. The goal is to determine ratios of 90Y to 177Lu that result in the largest absorbed doses per decay of the radionuclides and the most suitable dose profiles to treat tumors of specific sizes.Particle transfer calculations and simulations were performed using the Monte Carlo GATE simulation software. Spherical tumors of different sizes, ranging from 0.5 to 20 mm in radius, were designed. Activities of 177Lu and 90Y, individually and in combination, were homogeneously placed within the total volume of the tumors. We determined the S-values to the tumors, and to the external volume outside of the tumors (cross-dose) which was used to approximate background tissue. The dose profiles were obtained for each of the different tumor sizes, and the uniformity of dose within each tumor was calculated.For all tumor sizes, the self-dose and cross-dose per decay from 90Y were higher than that from 177Lu. We observed that 177Lu had the most uniform dose distribution within tumors with radii less than 5 mm. For tumors greater than 5 mm in radius, a ratio of 25% 90Y to 75% 177Lu resulted in the most uniform doses. When the ratio of 177Lu to 90Y was smaller, the uniformity improved more with increasing tumor size. The cross-dose stayed approximately constant for tumors larger than 15 mm for all ratios of 177Lu to 90Y. Finally, as the size of the tumor increased, differences in the S-values between different ratios of 177Lu to 90Y decreased.Our work showed that to achieve a more uniform dose distribution within the tumor, 177Lu alone is more effective for small tumors. For medium and large tumors, a ratio of 90Y to 177Lu with more or less 177Lu, respectively, is recommended.

Background:: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a β- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. Methods:: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50 fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma. Results:: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. Conclusions:: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for β- radio-guided surgery.

Radiomicrosphere Therapy (RMT) refers to a liver-directed therapeutic modality based on the intrahepatic arterial administration of radiolabeled microspheres. There is a need for standardization of the terminology of RMT. A descriptive identifier should first name the radioisotope, then the chemical formulation of the microsphere, and lastly add the term RMT that indicates the therapeutic modality. At present, clinically available options include |Y-90| |Resin| |RMT|, |Y-90| |Glass| |RMT| and |Ho-166| |PLLA| |RMT|. The latter is available in Europe and is being considered for clearance by the FDA in the United States. Preclinical studies with |Re-188| |PLLA| |RMT| are underway. Dosimetric considerations are strongly tied to both the type of the radioisotope and the chemical composition of the microsphere type. This review will focus on Y-90 resin and glass RMT, the history, dosimetry, clinical use, and controversies.

Background Data on morbidity and mortality following liver resection after radioembolization (Y90) are limited and controversial. Therefore, the perioperative morbidity and mortality of liver resections after Y90 treatment were investigated with systematic review and meta-analysis. Methods A PubMed search was conducted to identify studies of liver resection after previous Y90 treatment. Systematic review and meta-analysis for perioperative morbidity and mortality were perfomed using the 2009 PRISMA guidelines and STATA 16.1 software. Results A total of 16 studies reporting on 276 patients who underwent liver resection after Y90 met the inclusion criteria and were included in the meta-analysis. Meta-analysis of 30-day mortality rates yielded pooled mortality of 0.5% (95% CI 0.0–3.2%). Six studies (155 patients) reported a pooled 90-day mortality of 3.0% (95% CI 0.3–7.4%). The median time to resection after Y90 ranged from 2 to 12.5 months in various studies. In all studies where the median resection was undertaken eight or more months after Y90, zero 30-day mortality was reported. A meta-analysis of overall grade 3 or higher morbidity noted a rate of 26% (95% CI 16–37%). Conclusions Liver resection after Y90 may be safe in very well selected patients. Delaying resection after Y90 may further decrease mortality.

Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy–hypertrophy complex after SIRT. Three groups of 5–8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy–hypertrophy complex and liver damage without toxicity.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells spread throughout the body, forming the so-called diffuse endocrine system. The gold standard in treating unresectable or disseminated, progressive, and well-differentiated NENs is therapy with radiolabeled somatostatin analogs (peptide receptor radionuclide therapy - PRRT). PRRT is a method based on peptides combined with beta-emitting radionuclides. The study aimed to assess the early and long-term liver complications after administration of Lutetium-177 or Lutetium-177 combined with Yttrium-90. We enrolled 27 patients treated with [177Lu]Lu-DOTATATE with an activity of 7.4 GBq (200 mCi) and 9 patients received the tandem treatment [90Y]Y-DOTATATE + [177Lu]Lu-DOTATATE with an activity of 3.7 GBq (50 mCi + 50 mCi). In the assessment of early as well as long-term complications, no significant effect of the applied treatment on the parameters of liver injury was found. Regarding liver function PRRT was a safe treatment for patients with highly or moderately differentiated, unresectable, or diffuse NENs.

The need to concentrate the anti-tumoral activity ofThis in vivo randomized study was planned to assess the efficacy, safety, and biodistribution of BAT-90 in 46 rabbits implanted with a VX2 tumor. The effects of BAT-90 were compared to those ofBAT-90 localized effectively theBAT-90 can be administered as an adjuvant treatment to clear surgical margins from any potential minimal residual disease, or as an alternative to other loco-regional treatments for non-resectable tumors.

To determine the realized tumor to normal ratios (TNRs) in patients undergoing radiation segmentectomies (RS); determine the relationship between TNRs and particle load in transarterial radioembolization (TARE).In total, 148 patients who underwent 184 TARE procedures for hepatocellular carcinoma were evaluated. Post treatment SPECT CT bremsstrahlung imaging was analyzed utilizing Simplicit90y™ to determine realized TNR. A model which normalized activity across all RS treatments to a level that would achieve 400 Gy by unicompartmental dosing was created to determine the affect realized TNR would have on tumor absorbed dose.The mean TNR in the setting of RS was 2.88 ± 1.60 and was higher for glass as compared to resin microspheres (3.07 ± 1.68 vs 2.24 ± 1.21, p = 0.01). The TNR was significantly greater in the RS as compared to the lobar deliveries (2.88 ± 1.60 vs 2.16 ± 1.12, p 0.01). When normalizing the activity of RS treatments to the level required to achieve 400 Gy by unicompartmental calculations, there was found to be significant differences in the predicted tumor absorbed dose when separated by the median tumor dose (601.2 ± 133.3 vs 1146.9 ± 297.5, p 0.01) or median realized TNR (1119.2 ± 341 Gy vs 635.7 ± 160.2 Gy, p 0.01). Particle load was found to be associated with TNR on univariate (p 0.01) and multivariate (p 0.01) analysis.Significant TNRs are seen in RS and perhaps argue for the use of multi-compartmental dosimetry techniques in this setting and particle load may affect TNR.• Tumor to normal ratios were significantly higher in radiation segmentectomies than lobar deliveries. • Tumor to normal ratios were significantly higher when utilizing glass, as compared to resin microspheres. • When creating a model that prescribed the activity required to reach 400 Gy by MIRD, realized tumor dose varied significantly in radiation segmentectomies.

PURPOSE To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). METHODS In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status. RESULTS Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity. CONCLUSION The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.

The surgical treatment for large hepatocellular carcinoma (HCC) remains controversial because of a high risk of recurrence after resection. This study aimed to compare long-term outcomes of transarterial radioembolization (TARE) with resection for patients with large HCC.

High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.

Objective To evaluate the long-term outcomes of Class II treatment with the Jasper Jumper appliance and comprehensive orthodontic treatment concerning inclination of the mandibular incisors and gingival recession. Methods Sixteen patients with Class II malocclusion at a mean age of 12.54y (SD = 1.17) were treated with the Jasper Jumper appliance and comprehensive orthodontic treatment. The mean treatment time was 2.05y (SD = 0.21). Dental records were taken before (T1), after treatment (T2) and 11.90y (SD = 0.48) after debonding (T3). The frequency of gingival recession, clinical crown height and mandibular incisor position were evaluated using intraoral photographs, digital models and lateral cephalograms. Interphase changes were evaluated using dependent t and McNemar’s tests. Correlation between clinical crown height and final position of the mandibular incisors was evaluated using Pearson correlation test (P . Results The frequency of gingival recessions increased over time and was observed in 6 (9.4%), 12 (18.8%) and 24 (37.5%) of the mandibular incisors at T1, T2 and T3, respectively. A significant increase in labial inclination and protrusion of the mandibular incisors was observed between T1 and T2 interval. The clinical crown height significantly increased in the follow-up period (T3–T2) and in the complete observation time (T3–T1). There was no correlation between the amount of labial inclination and protrusion of the mandibular incisors and clinical crown height for all time intervals. Conclusion No significant correlation between the amount of labial movement of the mandibular incisor and clinical crown height increase was found.

Summary Background Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. Methods Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov , NCT03033446 and has been completed. Findings 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4–48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3–4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). Interpretation Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. Funding National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.

Key Points Megadose radioimmunotherapy with 90Y-ibritumomab tiuxetan treats relapsed/refractory aggressive BCLs safely and successfully.Radioimmunotherapy conditioning regimens warrant further exploration for curative-intent treatment in relapsed/refractory lymphomas., Visual Abstract, Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced-intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens.

The present review describes the methodological aspects and prospects of the production of Positron Emission Tomography (PET) radiometals in a liquid target using low-medium energy medical cyclotrons. The main objective of this review is to delineate and discuss the critical factors involved in the liquid target production of radiometals, including type of salt solution, solution composition, beam energy, beam current, the effect of irradiation duration (length of irradiation) and challenges posed by in-target chemistry in relation with irradiation parameters. We also summarize the optimal parameters for the production of various radiometals in liquid targets. : Additionally, we discuss the future prospects of PET radiometals production in the liquid targets for academic research and clinical applications. Significant emphasis has been given to the production of 68Ga using liquid targets due to the growing demand for 68Ga labeled PSMA vectors, [68Ga]- Ga-DOTATATE, [68Ga]Ga-DOTANOC and some upcoming 68Ga labeled radiopharmaceuticals. Other PET radiometals included in the discussion are 86Y, 63Zn and 89Zr.

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Purpose 90 Y selective internal radiation therapy (SIRT) has become a safe and effective treatment option for liver cancer. However, segmentation of target and organ-at-risks is labor-intensive and time-consuming in 90 Y SIRT planning. In this study, we developed a convolutional neural network (CNN) -based method for automated lungs, liver, and tumor segmentation on 99m Tc-MAA SPECT/CT images for 90 Y SIRT planning. Methods 99m Tc-MAA SPECT/CT images and corresponding clinical segmentations were retrospectively collected from 56 patients who underwent 90 Y SIRT. The collected data were used to train three CNN-based segmentation algorithms for lungs, liver, and tumor segmentation. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), surface DSC, and average symmetric surface distance (ASSD). Dosimetric parameters (volume, counts, and lung shunt fraction) were measured from the segmentation results and were compared with clinical reference segmentations. Results The evaluation results show that the method can accurately segment lungs, liver, and tumor with median [interquartile range] DSCs of 0.98 [0.97-0.98], 0.91 [0.83-0.93], and 0.85 [0.71-0.88]; surface DSCs of 0.99 [0.97-0.99], 0.86 [0.77-0.93], and 0.85 [0.62-0.93], and ASSDs of 0.91 [0.69-1.5], 4.8 [2.6-8.4], and 4.7 [3.5-9.2] mm, respectively. Dosimetric parameters from the three segmentation networks show linear relationship with those from the reference segmentations. The overall segmentation took about 1 min per patient on an NVIDIA RTX-2080Ti GPU. Conclusion This work presents CNN-based algorithms to segment lungs, liver, and tumor from 99m Tc-MAA SPECT/CT images. The results demonstrated the potential of the proposed CNN-based segmentation method for assisting 90 Y SIRT planning while drastically reducing operator time. This article is protected by copyright. All rights reserved.

Background Selective internal radiation therapy (SIRT) is applied to hepatocellular carcinoma (HCC), a disease with increased incidence in the elderly. However, SIRT has rarely been specifically studied in elderly population. The aim of this study was to investigate efficacy and safety of SIRT in elderly HCC patients. Methods We studied retrospectively data from patients treated with SIRT for HCC. Clinical and laboratory data were retrieved. We used 70-years old as threshold between younger and elderly populations, to compare outcomes. Results A total of 222 patients treated with SIRT for HCC were studied, of which 134 patients were younger and 88 older. Median overall survival (OS) was not significantly different between younger and elderly group: 15.6 months (95% CI, 11.7-19.5) and 14.8 months (95% CI, 9.4-20.3) (P = 0.86). Age was not associated with OS in multivariable analysis, with a Hazard ratio of 1.09 (95% CI, 0.82-1.45, P = 0.55). Results of progression-free survival and responses were also similar in both groups. Toxicities were similar between the two groups, including the occurrence of radioembolization-induced liver disease (11.5 vs. 11.4%, P = 0.97). Conclusion SIRT appears to be a well-tolerated treatment with the same efficacy in elderly compared to younger patients in HCC. Our study is the first to study its impact with glass microspheres. This warrants confirmation in large prospective studies.

This study explored factors that can predict effectiveness outcomes after transarterial radioembolization in colorectal liver metastases in the liver. In a cohort of 237 patients, among other factors, we found that an Aspartate transaminase to Platelet Ratio Index (APRI) value of > 0.40 was a particularly strong independent predictor of worse overall survival, progression-free survival and hepatic progression-free survival outcomes. Background: Transarterial radioembolisation (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with metastatic colorectal cancer in the liver (mCRC). A better understanding of the prognostic factors and treat-ment application can improve survival outcomes. Methods: We analysed the safety and effectiveness of 237 mCRC patients included in the prospective observational study CIRSE Registry for SIR-Spheres Therapy (CIRT) for indepen-dent prognostic factors for overall survival (OS), progression-free survival (PFS) and hepatic progression-free survival (hPFS) using the Cox proportional-hazard model. Results: The median OS was 9.8 months, median PFS was 3.4 months and median hPFS was 4.2 months. Independent prognostic factors for an improved overall survival were the absence of extra-hepatic disease ( P = .0391), prior locoregional procedures ( P = .0037), an Aspartate transaminase to Platelet Ratio Index (APRI) value of 0.40 ( P = .0416) and prior ablation ( P = .0323), and for hPFS these were 2 to 5 tumor nodules ( P = .0148), Albumin-bilirubin (ALBI) grade 3 ( P = .0075) and APRI > 0.40 ( P = .0207). During the study, 95 of 237 (40.1%) patients experienced 197 adverse events, with 28 of 237 (11.8%) patients having a grade 3 or higher adverse events. Conclusion: Including easy-to-acquire laboratory markers INR, APRI, ALBI and using partition model dosimetry can identify mCRC patients that may benefit from TARE.

In some patients undergoing radioembolization, lung toxicity is a limiting factor when calculating their dose. At the same time, it is known that the lung shunt fraction (LSF) is overestimated by the mapping exam. Furthermore, there are multiple methods to measure LSF. Planar measurement is both the most commonly utilized and easiest to perform, however new dosimetry software provides the ability to use more advanced 3D techniques. This paper reviews the different LSF calculation methods and elucidates the available data comparing the techniques, clinical relevance, and dose calculation.

Liver radioembolization (RE) is an emerging treatment against liver primary and secondary tumours. The whole procedure of RE involves different health care specialists with different expertise. During the fractionation and infusion phases, the personnel manipulates high activities of 90Y. In our centre, the number of RE treatments per year is increasing; the aim of this study is to monitor the dose to the operators and to estimate the radiological risk for the operators involved in the RE. At present, two medical devices are approved: Sir-Sphere® and Therasphere™, both loaded with 90Y. The dosimeters used were TLD placed over the fingertips, for a total of four dosimeters for each phase; the selected dose descriptor was Hp0.07. The study concerned 17 patients affected by malignant hepatic lesions, treated from September 2017 to March 2018. We performed 27 procedures: 10 fractionations (with Sir-Sphere®) and 17 infusions to the patients (10 with Sir-Spheres®, seven with Theraspheres™). For fractionation phase, the average activity of each preparation was 3.34 GBq, the average value of Hp0.07 was 0.50 mSv. For infusion phase, the average activity was 1.51 GBq for Sir-Sphere® and 2.10 GBq for Theraspheres™, the average value of Hp0.07 was 0.10 mSv. No significant differences were found between senior (Hp0.07 = 0.08 mSv) and young operators (Hp0.07 = 0.09 mSv), respectively. Similarly, no significant differences were found between the right and left hand, with the same average value of Hp0.07 (0.01 mSv). In conclusion, the results are encouraging, since fingertips reported doses very low. The handling of 90Y microspheres and the RE procedure can be carried out under safe conditions.

Conventional cross-sectional imaging done shortly after radioembolization of hepatocellular carcinoma (HCC) does not reliably predict long-term response to treatment. This study evaluated whether quantitative contrast-enhanced ultrasound (CEUS) can predict the long-term response of HCC to yttrium-90 (Y-90) treatment. Fifteen patients underwent CEUS at three time points: immediately following treatment and 1 and 2 wk post-treatment. Response 3–6 mo after treatment was categorized on contrast-enhanced magnetic resonance imaging by two experienced radiologists using the Modified Response Evaluation Criteria in Solid Tumors. CEUS data were analyzed by quantifying tumor perfusion and residual fractional vascularity using time–intensity curves. Patients with stable disease on magnetic resonance imaging had significantly greater fractional vascularity 2 wk post-treatment (65.15%) than those with partial or complete response (13.8 ± 9.9%, p = 0.007, and 14.9 ± 15.4%, p = 0.009, respectively). Complete responders had lower tumor vascularity at 2 wk than at post-operative examination (–38.3 ± 15.4%, p = 0.045). Thus, this pilot study suggests CEUS may provide an earlier indication of Y-90 treatment response than cross-sectional imaging.

AIM: The manufacturers' recommended methods to calculate delivered activities in liver radioembolization are simplistic and only slightly personalized. Activity planning could also be based on a 99mTc-macroaggregated albumin SPECT/CT (MAA) using the partition model but its accuracy is controversial. This study evaluates the dose parameters in the normal liver and in the tumor compartments using MAA SPECT/CT (pre-therapeutic imaging) and 90Y TOF-PET/CT (post-therapy imaging). Finally, we propose a prescription of the activity as a function of the normal liver MAA distribution. METHOD: 66 procedures of RE (with resin microspheres) corresponding to 171 lesions were analyzed. Tumor to normal targeted liver uptake (T/NTL), tumor absorbed dose (TD) and whole normal liver absorbed (WNLD) were assessed with MAA and 90Y imaging. Secondly, activities were recalculated using the MAA distribution in the normal liver compartment to reach the maximal tolerable liver dose. These Activities were compared to activities defined with the BSA method. RESULTS: Compared to 90Y imaging, our study demonstrated an accurate estimation of the WNLD using MAA imaging (Pearson's R = 0.97, p < 0.001). On the contrary, significant variations were found for TD (R = 0.65, p < 0.001). The MAA T/NTL ratio has a 85% positive predictive value in identifying patients who will get a 90Y T/NTL ratio above 1.5. Moreover, activities calculated using the MAA distribution in the normal liver compartment were significantly higher to activities defined with the BSA method. CONCLUSION: Whole normal liver absorbed doses are accurately predicted with MAA imaging and could be used to optimize the activity planning.

Yttrium-90 (Y-90) radioembolization for the treatment of hepatocellular carcinoma can present safety challenges when transplanting recently treated Y-90 patients. To reduce surgeons' contact with radioactive tissue and remain within occupational dose limits, current guidelines recommend delaying transplants at least 14 days, if possible. We wanted to determine the level of radiation exposure to the transplant surgeon when explanting an irradiated liver before the recommended decay period. Anex-vivoradiation exposure analysis was conducted on the explanted liver of a patient who received Y-90 therapy 46 h prior to orthotopic liver transplant. To estimate exposure to the surgeon's hands, radiation dosimeter rings were placed inside three different surgical glove configurations and exposed to the explanted liver. Estimated radiation doses corrected for Y-90 decay were calculated. Radiation safety gloves performed best, with an average radiation exposure rate of 5.36 mSV h-1in the static hand position, an 83% reduction in exposure over controls with no glove (31.31 mSv h-1). Interestingly, non-radiation safety gloves also demonstrated reduced exposure rates, well below occupational regulation limits. Handling of Y-90 radiated organs within the immediate post-treatment period can be done safely and does not exceed federal occupational dose limits if appropriate gloves and necessary precautions are exercised.

Many laboratories around the world work on the issue of protection against ionising radiation. It is a very broad topic, covering both the protection of members of the public and workers exposed to ionising radiation, based on personal or environmental monitoring. Thermoluminescence detectors are commonly used for this purpose, which is accepted in most countries. The entire process of dose evaluation with such dosimeters can be divided into several steps. Undoubtedly, one of the most important steps is the calibration procedure. The calibration should be performed in conditions as similar as possible to those experienced during the exposure. Moreover, the calibration is performed using only the Cs-137 source. This article presents results of Panasonic UD-802 irradiation dosimeters in different radiation fields generated by Cs-137, Kr-85, Sr-90/Y-90 and an x-ray tube, series N, and at different angles such as 0°, 30°, 60°, 90°. On the basis of the obtained results, the calibration coefficients and correction factors were determined in relation to calibration based on Cs-137 or Sr-90/Y-90 irradiated at 0°.

The incidence of hepatocellular carcinoma (HCC) has been rising, and 80% of HCCs are unresectable at the time of presentation. In recent years, Yttrium-90 (Y90) radioembolization has arisen as a potential tool to treat the primary HCC tumor while also inducing contralateral liver hypertrophy to increase future liver remnant volumes. The goal of this multidisciplinary review is to summarize the contemporary evidence on the safety, efficacy, and utility of Y90 as a bridge to liver resection and transplant in patients with HCC. A narrative review was conducted of the recent literature regarding the utilization of Y90 as a therapy prior to liver resection or transplant in patients with HCC. A specific emphasis was placed on articles published in the last 10 years. Y90 radioembolization has demonstrated a high safety profile and increasing utility in bridging and downstaging patients with HCC who subsequently undergo liver resection or transplant. The continuous advancements in treatment strategies and radiation dosimetry have paved the way for the incorporation of Y90 in all stages of HCC with different intents, including downstaging and bridging. Y90 radioembolization can be safely used in the HCC population to bridge patients to resection or transplantation, induce future liver remnant growth, and select for less aggressive tumor biology prior to surgery.

A 54-year-old man with hepatocellular carcinoma from alcohol-induced cirrhosis presented with hepatic encephalopathy and refractory ascites related to decompensated liver disease. MRI confirmed disease progression adjacent the site of prior radiofrequency ablation, performed 2 years prior, with associated right hepatic vein tumor thrombus. 99mTc-labeled macroaggregated albumin lung shunt imaging performed before 90Y radioembolization identified a left lower lobe wedge-shaped defect, confirmed as pulmonary embolism on CT pulmonary angiography and MRI.

Background and aims Locoregional therapies, including yttrium-90 radioembolization, play an important role in the treatment of unresectable HCC. The aim of the LEGACY (Local radioEmbolization using Glass Microspheres for the Assessment of Tumor Control with Y-90) study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with yttrium-90 glass microspheres. Approach and results LEGACY is a multicenter, single-arm, retrospective study conducted at three sites that included all eligible, consecutive patients with HCC treated with radioembolization between 2014 and 2017. Eligibility criteria included solitary HCC ≤ 8 cm, Child-Pugh A cirrhosis, and Eastern Cooperative Oncology Group performance status 0-1. Primary endpoints were ORR and DoR based on modified Response Evaluation Criteria in Solid Tumors in the treated area (localized), as evaluated by blinded, independent, central review. Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival was evaluated using Kaplan-Meier and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were Eastern Cooperative Oncology Group 0, and the median tumor size was 2.7 cm (range: 1-8) according to blinded, independent, central review. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse Kaplan-Meier. ORR (best response) was 88.3% (CI: 82.4-92.4), with 62.2% (CI: 54.1-69.8) exhibiting a DoR ≥ 6 months. Three-year overall survival was 86.6% for all patients and 92.8% for those neoadjuvant patients with resected or transplanted liver. Conclusions In this multicenter study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤ 8 cm.

To evaluate the impact of virtual tumor absorbed dose (vTAD) on tumor response in patients with hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization.The institutional review board approved this retrospective single center study, which comprised 100 patients with nodular HCC who underwent yttrium-90 radioembolization between November 2015 and December 2019. The vTAD was calculated assuming that all infused microspheres were distributed only in the tumor. The ability of mean absorbed dose (mAD) and vTAD in predicting complete response were evaluated by receiver operating characteristic (ROC) curve analyses.The mAD was 263.9 Gy ± 125.8, and the mean vTAD was 2005.8 Gy ± 2348.9. In terms of tumor response, 63 patients had complete response, 25 partial response, and 12 stable disease. For predicting complete response, ROC curve analyses revealed that the area under the curve (AUC) value of the vTAD was significantly higher (p0.001) than that of the mAD. Multivariate analysis revealed that Child-Pugh class A5, unilobar disease, and vTAD (952 Gy) were significant factors in predicting complete response.High vTAD (952 Gy) plays a significant role in complete response in patients with nodular HCC.

PURPOSE To quantify the relationship of the tumor-to-normal ratio (TNR) attained from the technetium-99m macroaggregated albumin (MAA) and posttreatment yttrium-90 bremsstrahlung (Y90-Brem) single-photon emission computerized tomography (SPECT)/computer tomography (CT) studies in patients with hepatocellular carcinoma (HCC) treated with glass microspheres. MATERIALS AND METHODS Retrospectively, a total of 190 consecutive patients with HCC who underwent 204 MAA and Y90-Brem SPECT/CT for glass microsphere Y90 radiation segmentectomy (Y90-RS) or lobar treatment (Y90-RLT) between 2013 and 2018 were included. Semi-automated regions-of-interests were drawn around the targeted tumor and nontumoral liver tissue on the SPECT/CT studies. TNR values from MAA and Y90-Brem SPECT/CT were compared using paired t-tests, Pearson correlation, and median with interquartile ranges (IQR). RESULTS The mean TNR for MAA and Y90-Brem SPECT/CT was 2.96 ± 1.86 (median, 2.64; IQR, 2.50) and 2.29 ± 1.10 (median, 2.06; IQR, 1.05), respectively (P < .0001). The mean Y90-RLT TNR was 2.88 ± 1.67 (median, 2.59; IQR, 0.83) and 2.17 ± 0.89 (median, 1.98; IQR, 0.81) for MAA and Y90-Brem SPECT/CT, respectively (P < .0001). The mean Y90-RS TNR was 3.02 ± 2.01 (median, 2.87; IQR, 3.01) and 2.39 ± 1.25 (median, 2.11; IQR, 1.28) for MAA and Y90-Brem SPECT/CT, respectively (P = .0003). TNR attained from MAA and Y90 SPECT/CT studies showed a moderate correlation in a positive linear fashion for the overall (r = 0.54; P < .001), Y90-RLT (r = 0.66, P < .001), and Y90-RS cohorts (r = 0.48, P < .001). CONCLUSIONS The TNR attained from Y90-Brem SPECT/CT is often underestimated, positively correlated, and less variable than that attained from MAA SPECT/CT.

PURPOSE: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 ((90)Y) (scout(90)Y) microspheres with those of technetium-99m macroaggregated albumin (MAA) in predicting the therapeutic (90)Y (Rx(90)Y) dose for patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout(90)Y. Rx(90)Y activity was administered 3 days after mapping. Using paired t test and Pearson correlation, the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), predicted mean tumor dose (TD), and nontumoral liver dose (NTLD) by MAA and scout(90)Y were compared with those by Rx(90)Y. Bland-Altman plots compared the level of agreement between the TNR and LSF of scout(90)Y and MAA with that of Rx(90)Y. The safety of scout(90)Y was evaluated by examining the discrepancy in extrahepatic activity between MAA and scout(90)Y. RESULTS: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx(90)Y. Scout(90)Y had a moderate LSF, strong TNR, strong TD, and very strong NTLD in correlation with those of Rx(90)Y. Furthermore, the TNR and LSF of scout(90)Y had a stronger agreement with those of Rx(90)Y than with those of MAA. In the nonsegmental subgroup, MAA had no significant correlation with the TD and NTLD of Rx(90)Y, whereas scout(90)Y had a very strong correlation with both of these factors. In the segmental subgroup, both MAA and scout(90)Y had a strong linear correlation with the TD and NTLD of Rx(90)Y. CONCLUSIONS: Compared with MAA, scout(90)Y is a more accurate surrogate for Rx(90)Y biodistribution for nonsegmental therapies.