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Background: Radioembolization with yttrium-90 (Y-90) is utilized to treat primary liver malignancies. The efficacy of this intra-arterial therapy in arterially hypoperfused tumors is not known. Methods: We reviewed data of patients with primary liver tumors treated with Y-90 prescription doses of at least 150 Gy. Baseline patient characteristics, treatment history, imaging-based tumor response assessments, and clinical outcome metrics were recorded. Tumors were classified as arterially hyperperfused versus hypoperfused on post-TARE Y-90 SPECT/CTs or pre-TARE hepatic perfusion SPECT/CTs. Perfusion status was correlated with tumor response assessments and clinical outcomes. Cox proportional hazards models were utilized to compare survival and progression-free survival. Inverse probability weighting was utilized to account for clinical factors and adjusted multivariable proportional hazards analyses to examine the relationship of quantitative perfusion and cancer outcomes. Results: Of 400 Y-90 treatments, 88 patients received a prescribed dose of at least 150 Gy and had pre- or post-treatment SPECT/CT images. 11 and 77 patients had arterially hypoperfused and hyperperfused lesions, respectively. On dedicated liver MRI or CT at 3 months after Y-90, the complete response rates were 5.6% and 16.5% in the hypoperfused and hyperperfused cohort, respectively (P = 0.60). When controlling for various clinical features, including tumor histology, patients with arterially hypoperfused tumors had significantly shorter progression-free survival (HR 1.87, 95% CI - 1.03 - 3.37, P = 0.039) and greater elsewhere liver (HR 3.36, 95% CI = 1.23 - 9.20, P = 0.019) and distant failure (HR 7.64 (2.71 - 21.54, P <0.001). In inverse probability weighted analysis, patients with arterially hypoperfused tumors had worse overall survival (P = 0.032). In the quantitative analysis, lower levels of lesion perfusion were also associated with worse clinical outcomes, again controlling for tumor histology. Conclusion: Compared to arterially hyperperfused tumors, hypoperfused primary liver tumors treated with Y-90 may have worse clinical outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Y-90 Selective Internal Radiotherapy (SIRT) uses injectable radioactive microspheres to treat inoperable liver metastases. It is poorly understood how the effective local control of small-volume metastatic disease with Y-90 SIRT may improve patient survival. Here, we demonstrate that failure to locally control liver metastases with ytrritum-90 (Y-90) SIRT is associated with worse 1-year overall survival for patients with ≤5 metastases, emphasizing the importance of disease control in those with early metastatic disease. Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients. A retrospective, single-institution study identified oligometastatic patients with ≤5 non-intracranial metastases receiving unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. The primary endpoint was OS defined from Y-90 SIRT completion to the date of death or last follow-up. Local failure was classified as a progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. With a median follow-up of 15.7 months, 33 patients were identified who had a total of 79 oligometastatic lesions treated with SIRT, with the majority histology of colorectal adenocarcinoma (n = 22). In total, 94% of patients completed the Y-90 lobectomy. Of the 79 individual lesions treated, 22 (27.8%) failed. Thirteen patients received salvage liver-directed therapy following intrahepatic failure; ten received repeat SIRT. Median OS (mOS) was 20.1 months, and 12-month OS was 68.2%. Intralesional failure was associated with worse 1 y OS (52.3% vs. 86.2%, p = 0.004). These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low-metastatic-burden patients. [ABSTRACT FROM AUTHOR]

BackgroundRadioembolization with yttrium-90 (Y-90) is utilized to treat primary liver malignancies. The efficacy of this intra-arterial therapy in arterially hypoperfused tumors is not known.MethodsWe reviewed data of patients with primary liver tumors treated with Y-90 prescription doses of at least 150 Gy. Baseline patient characteristics, treatment history, imaging-based tumor response assessments, and clinical outcome metrics were recorded. Tumors were classified as arterially hyperperfused versus hypoperfused on post-TARE Y-90 SPECT/CTs or pre-TARE hepatic perfusion SPECT/CTs. Perfusion status was correlated with tumor response assessments and clinical outcomes. Cox proportional hazards models were utilized to compare survival and progression-free survival. Inverse probability weighting was utilized to account for clinical factors and adjusted multivariable proportional hazards analyses to examine the relationship of quantitative perfusion and cancer outcomes.ResultsOf 400 Y-90 treatments, 88 patients received a prescribed dose of at least 150 Gy and had pre- or post-treatment SPECT/CT images. 11 and 77 patients had arterially hypoperfused and hyperperfused lesions, respectively. On dedicated liver MRI or CT at 3 months after Y-90, the complete response rates were 5.6% and 16.5% in the hypoperfused and hyperperfused cohort, respectively (P = 0.60). When controlling for various clinical features, including tumor histology, patients with arterially hypoperfused tumors had significantly shorter progression-free survival (HR 1.87, 95% CI - 1.03 - 3.37, P = 0.039) and greater elsewhere liver (HR 3.36, 95% CI = 1.23 - 9.20, P = 0.019) and distant failure (HR 7.64 (2.71 - 21.54, P < 0.001). In inverse probability weighted analysis, patients with arterially hypoperfused tumors had worse overall survival (P = 0.032). In the quantitative analysis, lower levels of lesion perfusion were also associated with worse clinical outcomes, again controlling for tumor histology.ConclusionCompared to arterially hyperperfused tumors, hypoperfused primary liver tumors treated with Y-90 may have worse clinical outcomes.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body 90Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

Purpose: To calculate the dose distribution using Monte Carlo simulations for a novel high‐dose‐rate Yttrium‐90 (Y‐90) disc source recently developed for episcleral brachytherapy and provide a lookup table for treatment planning. Methods: Monte Carlo simulations were performed to calculate the in‐water dose distribution of the Y‐90 disc source using the "GATE", a software based on the "Geant4" Monte Carlo simulation toolkit developed by the international OpenGATE collaboration. The geometry of this novel beta source, its capsule, and the surrounding water medium were accurately modeled in the simulation input files. The standard Y‐90 element beta spectrum from ICRU 72 was used, and the physics processes for beta and photon interactions with matters were all included. The dose distribution of this Y‐90 disc source was measured in a separate study using Gafchromic EBT‐3 films and the results were reported elsewhere. To match the setup of the experiment, a Gafchromic EBT‐3 film was also included in the simulation geometry. The simulated dose profiles were exported from the 3D dose distribution results and compared with the measured dose profiles. Transverse dose profiles at different distances from the seed surface were also obtained to study the lateral coverage of the source. Results: The measured percent depth dose (PDD) curves along the central axis perpendicular to the surface of the Y‐90 disc were constructed from the experimental and simulated data, and normalized to the reference point at 1 mm from the source capsule. Both PDD curves agreed well up to 4 mm from the source surface (maximum difference ± 10%) but deviated from each other beyond 4 mm. The deviation might be caused by the increased measurement uncertainty in the low‐dose region. The dose rate at the reference point calculated from the Monte Carlo simulation was 1.09 cGy/mCi‐s and agreed very well with the measured dose rate of 1.05 cGy/mCi‐s. If the 80% isodose line is selected as the lateral coverage, the lateral dose coverage is maximal (∼4.5 mm) at the plane next to the source surface, and gradually decreases with the increasing distance, approaching 3.5 mm when the plane is 5 mm from the 6‐mm diameter source surface. Conclusion: Monte Carlo simulations were successfully performed to confirm the measured PDD curve of the novel Y‐90 disc source. This simulation work laid a solid foundation for characterizing the full dosimetry parameters of this source for episcleral brachytherapy applications. [ABSTRACT FROM AUTHOR]

PURPOSETo analyze changes in angiogenesis factors after transarterial radioembolization (TARE) with Yttrium- 90-loaded resin microspheres in hepatocellular carcinoma (HCC) patients.METHODSInterleukin-6, interleukin-8, hepatocyte growth factor, platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor-A (VEGF-A), and angiopoietin-2 levels in 26 patients were measured before TARE and on day 1, 7, 14, and 30 after TARE and evaluated regarding radiological response.RESULTSIn the sixth month of follow-up, 11 (42.30%) patients had a complete or partial response to treatment, while progressive disease was found in 15 (57.69%) patients. The percentage changes in VEGF-A in the non-responders on day 30 (P = 0.034) after TARE were significantly more obvious. Peak formation rates of VEGF-A were higher in non-responders (P = 0.036).CONCLUSIONShort-term changes in angiogenesis factors in HCC patients after TARE with Yttrium-90-loaded resin microspheres fluctuate with different amplitudes at different times. The upregulation of growth factors has a prognostic capacity. Changes in VEGF-A after TARE may be helpful for the early recognition of non-responders.

PURPOSE To analyze changes in angiogenesis factors after transarterial radioembolization (TARE) with Yttri-um-90-loaded resin microspheres in hepatocellular carcinoma (HCC) patients. METHODS Interleukin-6, interleukin-8, hepatocyte growth factor, platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor-A (VEGF-A), and angiopoietin-2 levels in 26 patients were measured before TARE and on day 1, 7, 14, and 30 after TARE and evaluated regarding radiological response. RESULTS In the sixth month of follow-up, 11 (42.30%) patients had a complete or partial response to treatment, while progressive disease was found in 15 (57.69%) patients. The percentage changes in VEGF-A in the non-responders on day 30 (P = 0.034) after TARE were significantly more obvious. Peak formation rates of VEGF-A were higher in non-responders (P = 0.036). CONCLUSION Short-term changes in angiogenesis factors in HCC patients after TARE with Yttrium-90-loaded resin microspheres fluctuate with different amplitudes at different times. The upregulation of growth factors has a prognostic capacity. Changes in VEGF-A after TARE may be helpful for the early recognition of non-responders. [ABSTRACT FROM AUTHOR]

Abstract Background Transarterial radioembolization (TARE) is increasingly used as an alternative to transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). We aimed to perform an overall and individual patient data (IPD) meta‐analysis of studies comparing TACE and TARE. Methods We performed a systematic literature search using pre‐specified keywords with the aid of an informationist for articles from inception to 3/2020. The primary endpoint was overall survival (OS), and the secondary endpoint was time to progression (TTP). Results Seventeen studies met inclusion criteria with 2465 unique patients, with one randomized trial, 4 prospective studies and 12 retrospective studies. Barcelona Clinic Liver Cancer (BCLC) stage B (42.8%) was the most common stage followed by BCLC A (30.3%) and BCLC C (29.0%). There was no difference in OS between the two modalities (−0.55 months, 95% CI −1.95 to 3.05). In three studies with available TTP data, TARE resulted in a longer TTP than TACE (mean TTP 17.5 vs. 9.8 months; mean TTP difference 4.8 months, 95% CI 1.3–8.3 months). IPD‐level meta‐analysis of 311 patients from three studies showed no difference in overall OS between the two modalities including among subgroups stratified by tumor stage and liver function. Limitations of the current literature include inconsistent length of follow‐up, inconsistency in response criteria, and safety reporting. Conclusions Current data suggest TARE provides significantly longer TTP than TACE, although the two treatments do not significantly differ in terms of OS. Given limitations of the current data, there is rationale for prospective studies comparing these modalities.

Skin brachytherapy is a successful practice for treating skin cancer patients. Although a gamma source like an Iridium-192 (Ir-192) is commonly used in the skin brachytherapy, the use of a beta source like Yttrium-90 (Y-90) has also been investigated for this purpose. In the current study, we simulated the dose distribution of a proposed Y-90 applicator and an Ir-192 Leipzig applicator in a skin phantom, and compared the performance of each of the methods in treating three tumors in three hypothetical scenarios. Results of this simulation study showed that because of the sharp dose falloff of beta radiation in tissue, the Y-90 applicator may lead to better protection of the bone and/or cartilage under thin tumors. However, it may lead to excessive skin surface dose if thick skin tumors are treated. To choose between the Ir-192 and Y- 90 applicators, one may need to consider the thickness of the tumor and the thickness of the adipose layer between the tumor and the bone.

Simple Summary: Transarterial 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. [ABSTRACT FROM AUTHOR]

Background: Transarterial radioembolization (TARE) is increasingly used as an alternative to transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). We aimed to perform an overall and individual patient data (IPD) meta‐analysis of studies comparing TACE and TARE. Methods: We performed a systematic literature search using pre‐specified keywords with the aid of an informationist for articles from inception to 3/2020. The primary endpoint was overall survival (OS), and the secondary endpoint was time to progression (TTP). Results: Seventeen studies met inclusion criteria with 2465 unique patients, with one randomized trial, 4 prospective studies and 12 retrospective studies. Barcelona Clinic Liver Cancer (BCLC) stage B (42.8%) was the most common stage followed by BCLC A (30.3%) and BCLC C (29.0%). There was no difference in OS between the two modalities (−0.55 months, 95% CI −1.95 to 3.05). In three studies with available TTP data, TARE resulted in a longer TTP than TACE (mean TTP 17.5 vs. 9.8 months; mean TTP difference 4.8 months, 95% CI 1.3–8.3 months). IPD‐level meta‐analysis of 311 patients from three studies showed no difference in overall OS between the two modalities including among subgroups stratified by tumor stage and liver function. Limitations of the current literature include inconsistent length of follow‐up, inconsistency in response criteria, and safety reporting. Conclusions: Current data suggest TARE provides significantly longer TTP than TACE, although the two treatments do not significantly differ in terms of OS. Given limitations of the current data, there is rationale for prospective studies comparing these modalities. [ABSTRACT FROM AUTHOR]

Several new commercial software packages have become available that can calculate the tumor and normal tissue dose distributions from post-treatment PET-CT scans for Y-90 microsphere treatments of liver lesions. This work seeks to validate the MIM SurePlan Liver Y90 software by comparing its results to a previously developed Monte Carlo derived voxel dose kernel calculation method. We analyzed 10 patients who had treatments for metastatic liver cancer and created contours on post Y-90 treatment PET-CT images. We then performed dose calculations using three methods and compared the results. The first two methods calculated the dose using MIM SurePlan Liver Y90's LDM (Local Deposition Method) and the VSV (Voxel S Value) algorithms. The third method calculated the dose using a publicly available Fluka Monte Carlo-derived dose kernel (MCK) calculation (used as ground truth). We investigated 3D Gamma passing rates and several dosimetric parameters. A total of 3%/3 mm 3D gamma passing rates averaged 99.3% for the VSV and 78.9% for LDM. Compared to the MCK distribution, the differences for combined target GTV V 70Gy and normal liver and/or lobe mean doses were small. Larger differences were seen in GTV mean doses and D 95 , likely due to large dose gradients in the treated regions combined with differences in dose kernel, dose grid and finite volume effects. The MIM SurePlan Liver Y90 VSV algorithm agreed well with the MCK calculation for patients treated with Y-90 microspheres based on the gamma analysis and several dosimetric parameters. Larger dosimetric differences in lesion mean doses and D 95 suggests that these metrics are less robust to changes in calculation grid location and finite volume effects for small lesions. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review describes recent data supporting locoregional ablative radiation in the treatment of oligometastatic colorectal cancer liver metastases. Recent Findings: Stereotactic body radiotherapy (SBRT) demonstrates high rates of local control in colorectal cancer liver metastases when a biologically equivalent dose of > 100 Gy is delivered. Future innovations to improve the efficacy of SBRT include MRI-guided radiotherapy (MRgRT) to enhance target accuracy, systemic immune activation to treat extrahepatic disease, and genomic customization. Selective internal radiotherapy (SIRT) with y-90 is an intra-arterial therapy that delivers high doses to liver metastases internally which has shown to increase liver disease control in phase 3 trials. Advancements in transarterial radioembolization (TARE) dosimetry could improve local control and decrease toxicity. Summary: SBRT and SIRT are both promising options in treating unresectable metastatic colorectal cancer liver metastases. Identification of oligometastatic patients who receive long-term disease control from either therapy is essential. Future advancements focusing on improving radiation design and customization could further improve efficacy and toxicity. [ABSTRACT FROM AUTHOR]

Objective. Contrast-enhanced computed tomography (CECT) is commonly used in the pre-treatment evaluation of liver Y-90 radioembolization feasibility. CECT provides detailed imaging of the liver and surrounding structures, allowing healthcare providers to assess the size, location, and characteristics of liver tumors prior to the treatment. Here we propose a method for translating CECT images to an expected dose distribution for tumor(s) and normal liver tissue. Approach. A pre-procedure CECT is used to obtain an iodine arterial-phase distribution by subtracting the non-contrast CT from the late arterial phase. The liver segments surrounding the targeted tumor are selected using Couinaud's method. The resolution of the resulting images is then degraded to match the resolution of the positron emission tomography (PET) images, which can image the Y-90 activity distribution post-treatment. The resulting images are then used in the same way as PET images to compute doses using the local deposition method. CECT images from three patients were used to test this method retrospectively and were compared with Y-90 PET-based dose distributions through dose volume histograms. Main results. Results show a concordance between predicted and delivered Y-90 dose distributions with less than 10% difference in terms of mean dose, for doses greater than 10% of the 98th percentile (D2%). Significance. CECT-derived predictions of Y-90 radioembolization dose distributions seem promising as a supplementary tool for physicians when assessing treatment feasibility. This dosimetry prediction method could provide a more comprehensive pre-treatment evaluation-offering greater insights than a basic assessment of tumor opacification on CT images., (© 2024 Institute of Physics and Engineering in Medicine.)

Transarterial radioembolization using yttrium-90 (Y-90) microspheres is an important therapy in the management of unresectable primary liver tumors or hepatic metastases. While radioembolization is generally well-tolerated, it is not free from adverse events, and familiarity with the prevention and treatment of radioembolization-specific complications is an important component of patient care. This article aims to review radioembolization-specific toxicities stratified by hepatic, extrahepatic, and systemic effects, with a focus on preventing and mitigating radioembolization-induced morbidity. [ABSTRACT FROM AUTHOR]

• The resolution conversion method allowed comparison of 99mTc and 90Y imaging. • 99mTc pre-therapy imaging was predictive of the 90Y absorbed dose to normal liver. • 99mTc pre-therapy imaging had poor predictability for tumours smaller than 100 cm3. The aims of this study were to develop and apply a method to correct for the differences in partial volume effects of pre-therapy Technetium-99 m (99mTc)-MAA SPECT and post-therapy Yttrium-90 (90Y) bremsstrahlung SPECT imaging in selective internal radiation therapy, and to use this method to improve quantitative comparison of predicted and delivered 90Y absorbed doses. The spatial resolution of 99mTc SPECT data was converted to that of 90Y SPECT data using a function calculated from 99mTc and 90Y point spread functions. This resolution conversion method (RCM) was first applied to 99mTc and 90Y SPECT phantom data to validate the method, and then to clinical data to assess the power of 99mTc SPECT imaging to predict the therapeutic absorbed dose. The maximum difference between absorbed doses to phantom spheres was 178%. This was reduced to 27% after the RCM was applied. The clinical data demonstrated differences within 38% for mean absorbed doses delivered to the normal liver, which were reduced to 20% after application of the RCM. Analysis of clinical data showed that therapeutic absorbed doses delivered to tumours greater than 100 cm3 were predicted to within 52%, although there were differences of up to 210% for smaller tumours, even after the RCM was applied. The RCM was successfully verified using phantom data. Analysis of the clinical data established that the 99mTc pre-therapy imaging was predictive of the 90Y absorbed dose to the normal liver to within 20%, but had poor predictability for tumours smaller than 100 cm3. [ABSTRACT FROM AUTHOR]

Introduction: In yttrium-90 imaging, image quality is highly dependent on the selection of energy window and collimator design becausetheY-90 bremsstrahlung photons have a continuous and broad energy distribution. The current study aimed to optimize the bremsstrahlung energy window setting and collimator for the improvement of both resolution and sensitivity. Material and Methods: In the present study, simulation of medical imaging nuclear detectors (SIMIND) Monte Carlo program was used to simulate Siemens Medical System Symbia. The SIMIND was utilized to generate the Y-90 bremsstrahlung single-photon emission computed tomography (SPECT) projection of the point source. Six energy windows settings and two collimators denoting medium energy and high energy were used in order to assess the effect of the energy window on the resolution. Results: The experimental measurements and simulation results showed a similar pattern in the point spread functions with the energy window. The simulation data indicated that the geometric component reached 73%for the energy window within the range of51-120keVusingthe high-energy (HE) collimator. In addition, the obtained results showed that the full width at half maximum (FWHM) and full width at tenth maximum (FWTM)(FWHM=7mm and FWTM=35mm)were higher in this window in comparison to those reported for other windows. Conclusion: According to the obtained results of the present study, the optimal energy window for Y-90 bremsstrahlung SPECT imaging was within the range of 51-120 keV. The obtained optimal energy window and optimal HE collimator had the potential to improve the image resolution and sensitivity of Y-90 SPECT images. [ABSTRACT FROM AUTHOR]

Although hybrid angiography-CT (Angio-CT) has a long history of use for interventional oncology procedures, its applications for transarterial radioembolization (TARE) are not as well described in the literature. This pictorial essay demonstrates a single-institution experience with the utilization of an Angio-CT system for TARE treatment of hepatocellular carcinoma. Procedural images and clinical data for twenty-four patients who underwent initial angiographic mapping with hepatopulmonary shunt fraction assessment and or administration of Yttrium-90 (Y-90) microspheres using the Angio-CT system to date were reviewed. Cases were reviewed for examples that highlight the specific utility of Angio-CT. Three representative TARE cases were selected which illustrate unique advantages and applications of the Angio-CT system when performing TARE. These include the ability to optimally delineate hepatic vascular anatomy, accurately calculate liver volumes for dosimetry, and improve the detection and characterization of equivocal lesions. Angio-CT has unique advantages which can be applied to TARE treatment of patients with HCC. The technology has potential to be an especially effective tool for those who aim to be at the cutting edge of the rapidly growing field of interventional oncology. [ABSTRACT FROM AUTHOR]

The safety and efficacy of Yttrium-90 (Y-90) radio-embolization therapy is partly dependent on the lung shunt fraction (LSF). There may be a notable disparity between LSF when calculated using 2D planar imaging vs 3D single photon emission CT (SPECT); this can affect the total allowable Y-90 dose delivered and therefore change the effectiveness of the procedure. The case presented demonstrates an 81% decrease in LSF when calculated by SPECT as compared to 2D planar imaging. This case highlights the importance of considering the imaging technique and the potential discrepancies that can arise between planar and SPECT imaging in LSF assessment., Competing Interests: None declared., (Published by Oxford University Press on behalf of the British Institute of Radiology 2024.)

Image reconstruction in low-count PET is particularly challenging because gammas from natural radioactivity in Lu-based crystals cause high random fractions that lower the measurement signal-to-noise-ratio (SNR). In model-based image reconstruction (MBIR), using more iterations of an unregularized method may increase the noise, so incorporating regularization into the image reconstruction is desirable to control the noise. New regularization methods based on learned convolutional operators are emerging in MBIR. We modify the architecture of an iterative neural network, BCD-Net, for PET MBIR, and demonstrate the efficacy of the trained BCD-Net using XCAT phantom data that simulates the low true coincidence count-rates with high random fractions typical for Y-90 PET patient imaging after Y-90 microsphere radioembolization. Numerical results show that the proposed BCD-Net significantly improves CNR and RMSE of the reconstructed images compared to MBIR methods using non-trained regularizers, total variation (TV) and non-local means (NLM). Moreover, BCD-Net successfully generalizes to test data that differs from the training data. Improvements were also demonstrated for the clinically relevant phantom measurement data where we used training and testing datasets having very different activity distributions and count-levels. [ABSTRACT FROM AUTHOR]

Background: Brachytherapy of thin skin tumors using beta particles can protect underlying sensitive structures such as the bone because of the rapid dose falloff of this type of radiation in tissue. The current work describes a skin brachytherapy applicator, based on beta radiation, that can provide the needed cell‐killing radiation dose matched to the shape of individual skin tumors. Materials and methods: The applicator and its template were fabricated using 3D printing technology. Any clinically approved beta‐emitting isotope in the form of a radioactive gel could theoretically be used in this applicator. Monte Carlo simulations were employed to study the capability of the applicator in conforming dose distribution based on the shape of the tumor. Dose profile in the shallow depth, transverse dose profiles at different depths, and the percent depth dose from this applicator were calculated. The radioisotope of choice for our calculations was Yttrium‐90 (Y‐90). Results: Using the proposed applicator, it is possible to create a desired dose profile matching the tumor surface shape. Conclusion: The short‐range of the beta radiation, together with the dose conforming capability of the applicator, may lead to minimal interactions with the healthy tissue around the skin lesion. [ABSTRACT FROM AUTHOR]

Quantitative yttrium-90 (Y-90) SPECT imaging is challenging due to the nature of Y-90, an almost pure beta emitter that is associated with a continuous spectrum of bremsstrahlung photons that have a relatively low yield. This paper proposes joint spectral reconstruction (JSR), a novel bremsstrahlung SPECT reconstruction method that uses multiple narrow acquisition windows with accurate multi-band forward modeling to cover a wide range of the energy spectrum. Theoretical analyses using Fisher information and Monte-Carlo (MC) simulation with a digital phantom show that the proposed JSR model with multiple acquisition windows has better performance in terms of covariance (precision) than previous methods using multi-band forward modeling with a single acquisition window, or using a single-band forward modeling with a single acquisition window. We also propose an energy-window subset (ES) algorithm for JSR to achieve fast empirical convergence and maximum-likelihood based initialization for all reconstruction methods to improve quantification accuracy in early iterations. For both MC simulation with a digital phantom and experimental study with a physical multi-sphere phantom, our proposed JSR-ES, a fast algorithm for JSR with ES, yielded higher recovery coefficients (RCs) on hot spheres over all iterations and sphere sizes than all the other evaluated methods, due to fast empirical convergence. In experimental study, for the smallest hot sphere (diameter 1.6cm), at the 20th iteration the increase in RCs with JSR-ES was 66 and 31% compared with single wide and narrow band forward models, respectively. JSR-ES also yielded lower residual count error (RCE) on a cold sphere over all iterations than other methods for MC simulation with known scatter, but led to greater RCE compared with single narrow band forward model at higher iterations for experimental study when using estimated scatter. [ABSTRACT FROM AUTHOR]

Purpose: The aims of the study were: 1) to compare two phases of dual-phase cone beam computed tomography (DPCBCT) achieved before and after Yttrium-90 (90Y) administration and to evaluate additional benefits during radioembolisation (RE) procedures; and 2) to compare DP-CBCT with pre-procedure contrast enhanced cross-sectional images in terms of tumour detection. Material and methods: Twenty-three hepatocellular carcinoma patients undergoing RE treatment were scanned with DPCBCT consisting of early arterial (EA) and late arterial (LA) phases before and after 90Y administration. The CT-like datasets were compared according to embolisation effect, enhancement patterns, lesion detectability, image quality, and artifacts by two interventional radiologists blinded to each other. The compatibility of the two radiologists was evaluated with kappa statistical analysis, and the difference between EA and LA phases was evaluated with marginal homogeneity test. Also, DP-CBCT images were compared with preprocedural cross-sectional images (CT/MRI). Results: For 23 patients 92 data were acquired. Thirteen patients showed a decrease on post-embolisation images both visually and on Hounsfield unit (HU) measurements. No statistical difference was found for tumour detection between EA and LA phases (p = 1.0). Tumour enhancement was visually superior at LA phases whereas EA phases were better for arterial mapping for selective catheterisation. DP-CBCT images were not inferior to preprocedural cross-sectional imaging findings. Conclusions: DP-CBCT is a promising tool for predicting tumour response to therapy and is not inferior to preprocedural cross-sectional imaging in terms of tumour detection. It allows better assessment during RE procedures because early phases provide good mapping for superselective catheterisation whereas late phases are better for visualisation of tumour enhancement. [ABSTRACT FROM AUTHOR]

The frequency of transradial access in interventional radiology has been steadily increasing, including for yttrium-90 (Y-90) selective internal radiation therapy to treat hepatic malignancies. The aim of this article is to detail an optimized approach to transradial Y-90 (TRY-90), showing it to be a safe and feasible first-line approach to hepatic selective internal radiation therapy. Salient preprocedural considerations to enable appropriate patient selection for TRY-90 are discussed and a detailed equipment list is provided. The article will describe our approach to TRY-90 in addition to a discussion around technical pearls and pitfalls. [ABSTRACT FROM AUTHOR]

Purpose: Yttrium‐90 (90Y) microsphere radioembolization enables selective internal radiotherapy for hepatic malignancies. Currently, there is no standard postdelivery imaging and dosimetry of the microsphere distribution to verify treatment. Recent studies have reported utilizing the small positron yield of 90Y (32 ppm) with positron emission tomography (PET) to perform treatment verification and dosimetry analysis. In this study, we validated a commercial dosimetry software, MIM SurePlan™ LiverY90 (MIM Software Inc., Cleveland, OH), for clinical use. Methods: A MATLAB‐based algorithm for 90Y PET‐based dosimetry was developed in‐house and validated for the purpose of commissioning the commercial software. The algorithm is based on voxel S values and dosimetry formalism reported in MIRD Pamphlet 17. We validated the in‐house algorithm to establish it as the ground truth by comparing results from a digital point phantom and a digital uniform cylinder to manual calculations. Once we validated our in‐house MATLAB‐based algorithm, we used it to perform acceptance testing and commissioning of the commercial dosimetry software, MIM SurePlan, which uses the same dosimetry formalism. A 0.4 cm/5% gamma test was performed on PET‐derived dose maps from each algorithm of uniform digital and nonuniform physical phantoms filled with 90Y chloride solution. Average dose (Davg) and minimum dose to 70% (D70) of a given volume of interest (VOI) were compared for the digital phantom, the physical phantom, and five patient cases (27 tumor VOIs), representing different clinical scenarios. Results: The gamma‐pass rates were 97.26% and 97.66% for the digital and physical phantoms, respectively. The differences between Davg and D70 were 0.076% and 0.10% for the digital phantom, respectively, and <5.2% for various VOIs in the physical phantom. In the clinical cases, 96.3% of the VOIs had a difference <5% for Davg, and 88.9% of the VOIs had a difference <5% for D70. Conclusions: Dose calculation results from MIM SurePlan were found to be in good agreement with our in‐house algorithm. This indicates that MIM SurePlan performs as it should and, hence, can be deemed accepted and commissioned for clinical use for post‐implant PET‐based dosimetry of 90Y radioembolization. [ABSTRACT FROM AUTHOR]

A derivation of the Bateman equation combined with successive liquid scintillation counting measurements was used to rapidly determine accurate individual activities of 90Sr and 90Y in samples containing both isotopes regardless of the sample age. This method does not require chemical separation of Sr from Y or waiting for secular equilibrium to take place. Accurate data can be obtained within 3 half-lives of 90Y ingrowth (i.e. within 5 days), associated uncertainties with this method are comparable to those obtained with traditional techniques that include separations. This novel technique allows for decreased sample processing cost and time, without reducing data quality. [ABSTRACT FROM AUTHOR]

Background: Targeted radiotherapy is one of the important methods of radiotherapy that involves the use of beta-emitting radionuclides to deliver a dose of radiation to tumor cells. An important feature of this method is the tumor size and the finite range of beta particles emitted as a result of radionuclide disintegration those have significant effects for the curability of tumors. Material and Methods: Monte Carlo simulations and mathematical models have been used to investigate the relationship of curability to tumors size for tumors treated with targeted 131I and 90Y. The model assumed that radionuclides are distributed uniformly throughout tumors. Results: The results show that there is an optimal tumor size for cure. For any given cumulated activity, cure probability is greatest for tumors whose diameter is close to the optimum value. There is a maximum value of curability that occurs at a diameter of approximately 3.5 mm for 131I. For 90Y maximum curability occurs at a tumor diameter of approximately 3.5 cm. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a significant proportion of the disintegration energy escapes and is deposited outside the tumor volume. Tumors larger than the optimal size are less curable because of greater clonogenic cell number. Conclusion: With single radionuclide targeted radiotherapy, there is an optimal tumor size for tumor cure. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated disease when multiple tumors of differing size may be present. The use of several radionuclides concurrently would be more effective than reliance on single radionuclide. This approach of using combination of radionuclides with complementary properties could hopefully prepare new measures and improve the efficiency of tumor therapy.

Nivolumab has recently received approval by the Food and Drug Administration for treatment of advanced hepatocellular carcinoma (HCC) in patients previously treated with sorafenib. Nivolumabs' overall response rate of 20% (El-Khoueiry et al. in Lancet 389:2492-2502, 2017) is a step forward for these patients, but there is significant room for improvement. We describe a case of combining Y-90 radioembolization with nivolumab for treatment of angioinvasive HCC, which successfully bridged patient to partial hepatectomy. Surgical pathology showed negative margins with complete pathological response. With the introduction of immunotherapy for HCC, combining Y-90 radioembolization with immunotherapy may enhance the anti-tumoral immune response of checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of ≤14.67 ± 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min.

Objective . 90 Y selective internal radiation therapy (SIRT) treatment of hepatocellular carcinoma (HCC) can potentially underdose lesions, as identified on post-therapy PET/CT imaging. This study introduces a methodology and explores the feasibility for selectively treating SIRT-underdosed HCC lesions, or lesion subvolumes, with stereotactic body radiation therapy (SBRT) following post-SIRT dosimetry. Approach . We retrospectively analyzed post-treatment PET/CT images of 20 HCC patients after 90 Y SIRT. Predicted tumor response from SIRT was quantified based on personalized post-therapy dosimetry and corresponding response models. Predicted non-responding tumor regions were then targeted with a hypothetical SBRT boost plan using a framework for selecting eligible tumors and tumor subregions. SBRT boost plans were compared to SBRT plans targeting all tumors irrespective of SIRT dose with the same prescription and organ-at-risk (OAR) objectives. The potential benefit of SIRT followed by a SBRT was evaluated based on OAR dose and predicted toxicity compared to the independent SBRT treatment. Main results . Following SIRT, 14/20 patients had at least one predicted non-responding tumor considered eligible for a SBRT boost. When comparing SBRT plans, 10/14 (71%) SBRT boost and 12/20 (60%) SBRT alone plans were within OAR dose constraints. For three patients, SBRT boost plans were within OAR constraints while SBRT alone plans were not. Across the 14 eligible patients, SBRT boost plans had significantly less dose to the healthy liver (decrease in mean dose was on average ± standard deviation, 2.09 Gy ± 1.99 Gy, ) and reduced the overall targeted PTV volume (39% ± 21%) compared with SBRT alone . Significance . A clinical methodology for treating HCC using a synergized SIRT and SBRT approach is presented, demonstrating that it could reduce normal tissue toxicity risk in a majority of our retrospectively evaluated cases. Selectively targeting SIRT underdosed HCC lesions, or lesion subvolumes, with SBRT could improve tumor control and patient outcomes post-SIRT and allow SIRT to function as a target debulking tool for cases when SBRT is not independently feasible., (Creative Commons Attribution license.)

Nowadays, the bone-seeking radiopharmaceuticals play an important role in the treatment of the bone-related pathologies. Whereas various phosphonate ligands have already been identified, a DOTA-based bisphosphonate, 4-{[(bis(phosphonomethyl))carbamoyl]methyl}- 7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec- 1-yl (BPAMD) with better characteristics has recently been synthesized. In this study, 90Y-BPAMD was developed with radiochemical purity >98% and the specific activity of 3.52 TBq/mmol in the optimized conditions as a new bone-seeking therapeutic agent. The complex demonstrated significant stability at room temperature and in human serum even after 48 h. At even low amount of hydroxyapatite (5 mg), more than 90% binding to hydroxyapatite was observed. Biodistribution studies after injection of the complex into the Syrian rats showed major accumulation of the labelled compound in the bone tissue and an insignificant uptake in the other organs all the times after injection. Generally, 90Y-BPAMD demonstrated interesting characteristics compared to the other 90Y bone-seeking agents and even 166Ho-BPAMD, and can be considered as a new bone-seeking candidate for therapeutic applications. [ABSTRACT FROM AUTHOR]

Yittrium-90 (Y-90) is a radioisotope having half-life 64 hour and emitting strong energy beta radiation at 2.28 MeV. It is one of the radionuclides suitable to the applications in targeted therapy. Y-90 can be generated from radioactive decay of strontium-90 (Sr-90), which is one of the fission products of uranium fuel in the nuclear reactor. Y-90 must be highly pure and free form Sr-90 and other metal ions to get high efficient uses. In this study, process for separation of Y from Sr in 4-7 M HNO 3 with extraction chromatography technique has been investigated using column of Sr resin, column of RE resin and combined columns of both resins. Most feed solutions used in the study contained Y and Sr at the concentration ratio of Y: Sr around 0.18: 756 to simulate the equilibrium composition ratio of their radionuclides, Y-90 and Sr-90. It was found that a series of 3 columns packed with 0.35 g Sr resin each was required to adsorb Sr up to 4 mg from 4 mL feed in 4 M HNO 3 and Y was barely adsorbed by Sr resin. A column packed with 0.25 g of RE resin could be used to continuously purify Y in effluent from Sr column by selectively adsorb Sr. The adsorbed species could be eluted with dilute nitric acid, 0.05-0.1 M. Feed solution spiked with trace of Sr-90/Y-90 was also used to determine the purity of the obtained Y product and it was found that the activity ratio of Sr-90 to Y-90 was in the order of 10 -4 . This process was found to be simple to operate continuously and the recovery of Y-90 was higher than 80%. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study is to evaluate the correlation between pretreatment planning technetium-99m (Tc) macroaggregated albumin (MAA) SPECT images and posttreatment transarterial radioembolization (TARE) yttirum-90 (Y) PET/CT images by comparing the ratios of tumor-to-normal liver counts. Methods: Fifty-two patients with advanced hepatic malignancy who underwent Y microsphere radioembolization from January 2010 to December 2012 were retrospectively reviewed. Patients had undergone Tc MAA intraarterial injection SPECT for a pretreatment evaluation of microsphere distribution and therapy planning. After the administration of Y microspheres, the patients underwent posttreatment Y PET/CT within 24 h. For semiquantitative analysis, the tumor-to-normal uptake ratios in Y PET/CT (TNR-yp) and Tc MAA SPECT (TNR-ms) as well as the tumor volumes measured in angiographic CT were obtained and analyzed. The relationship of TNR-yp and TNR-ms was evaluated by Spearman's rank correlation and Wilcoxon's matched pairs test. Results: In a total of 79 lesions of 52 patients, the distribution of microspheres was well demonstrated in both the SPECT and PET/CT images. A good correlation was observed of between TNR-ms and TNR-yp (rho value = 0.648, p < 0.001). The TNR-yp (median 2.78, interquartile range 2.43) tend to show significantly higher values than TNR-ms (median 2.49, interquartile range of 1.55) ( p = 0.012). The TNR-yp showed weak correlation with tumor volume (rho = 0.230, p = 0.041). Conclusions: The Tc MAA SPECT showed a good correlation with Y PET/CT in TNR values, suggesting that Tc MAA can be used as an adequate pretreatment evaluation method. However, the Tc MAA SPECT image consistently shows lower TNR values compared to Y PET/CT, which means the possibility of underestimation of tumorous uptake in the partition dosimetry model using Tc MAA SPECT. Considering that Tc MAA is the only clinically available surrogate marker for distribution of microsphere, we recommend measurement of tumorous uptake using Y PET/CT should be included routinely in the posttherapeutic evaluation. [ABSTRACT FROM AUTHOR]

Background: Targeted radiotherapy is one of the important methods of radiotherapy that involves the use of beta-emitting radionuclides to deliver a dose of radiation to tumor cells. An important feature of this method is the tumor size and the finite range of beta particles emitted as a result of radionuclide disintegration those have significant effects for the curability of tumors. Material and Methods: Monte Carlo simulations and mathematical models have been used to investigate the relationship of curability to tumors size for tumors treated with targeted 131I and 90Y. The model assumed that radionuclides are distributed uniformly throughout tumors. Results: The results show that there is an optimal tumor size for cure. For any given cumulated activity, cure probability is greatest for tumors whose diameter is close to the optimum value. There is a maximum value of curability that occurs at a diameter of approximately 3.5 mm for 131I. For 90Y maximum curability occurs at a tumor diameter of approximately 3.5 cm. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a significant proportion of the disintegration energy escapes and is deposited outside the tumor volume. Tumors larger than the optimal size are less curable because of greater clonogenic cell number. Conclusion: With single radionuclide targeted radiotherapy, there is an optimal tumor size for tumor cure. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated disease when multiple tumors of differing size may be present. The use of several radionuclides concurrently would be more effective than reliance on single radionuclide. This approach of using combination of radionuclides with complementary properties could hopefully prepare new measures and improve the efficiency of tumor therapy. [ABSTRACT FROM AUTHOR]

Introduction Therapeutic potential of β-emitting cytotoxic radionuclides 90 Y and 177 Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy 90 Y and 177 Lu. A new bifunctional chelate 5p- C -NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p- C -NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin α v β 3 protein overexpressed on various cancers. 5p- C -NETA was conjugated to c (RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of 90 Y and 177 Lu. Methods 5p- C -NETA conjugated with c (RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p- C -NETA- c (RGDyK) was compared to that of 3p- C -NETA- c (RGDyK). 177 Lu-5p- C -NETA- c (RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice. Result The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, 90 Y or 177 Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (> 99%, RT, < 1 min). 90 Y- and 177 Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with 90 Y or 177 Lu. 177 Lu-radiolabeled 5p- C -NETA- c (RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile. Conclusion The results of in vitro and in vivo evaluation suggest that 5p- C -NETA is an effective bifunctional chelate of 90 Y and 177 Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ( 90 Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin’s lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p- C -DE4TA and 3p- C -NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p- C -DE4TA and 3p- C -NE3TA along with the known bimodal ligands 3p- C -NETA and 3p- C -DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides 90 Y and 177 Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with 90 Y and 177 Lu, and the corresponding 90 Y or 177 Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding 90 Y and 177 Lu, and the corresponding 90 Y- and 177 Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p- C -DE4TA and 3p- C -NE3TA are promising bifunctional ligands for targeted radiotherapy applications of 90 Y and 177 Lu. [ABSTRACT FROM AUTHOR]

Current standard methods to calculate the dose of radiation emitted during medical applications by beta-minus emitting microspheres rely on an over-simplistic formalism. This formalism is a function of the average activity of the radioisotope used and the physiological dimensions of the patient only. It neglects the variation in energy of the emitted beta particle due to self-attenuation, or self-absorption, effects related to the finite size of the sphere. Here it is assumed the sphere is comprised of a pure radioisotope with beta particles being emitted isotropically throughout the material. The full initial possible kinetic energy distribution of a beta particle is taken into account as well as the energy losses due to scattering by other atoms in the microsphere and bremsstrahlung radiation. By combining Longmire’s theory of the mean forward range of charged particles and the Rayleigh distribution to take into account the statistical nature of scattering and energy straggling, the linear attenuation, or self-absorption, coefficient for beta-emitting radioisotopes has been deduced. By analogy with gamma radiation transport in spheres, this result was used to calculate the rate of energy emitted by a beta-emitting microsphere and its efficiency. Comparisons to standard point dose kernel formulations generated using Monte Carlo data show the efficacy of the proposed method. Yttrium-90 is used as a specific example throughout, as a medically significant radioisotope, frequently used in radiation therapy for treating cancer. [ABSTRACT FROM AUTHOR]

Different methods to calculate 90 Y resin microspheres activity for Selective Internal Radiation Therapy (SIRT) were compared. Such comparison is not yet available and is needed in clinical practice to optimize patient specific treatment planning. 32 99m Tc-macroagregates (MAA) evaluations were performed, followed by 26 treatments. Four methods to calculate 90 Y-activity were applied retrospectively: three based on Body Surface Area and one based on MIRD formalism, partition model (PM). Relationships between calculated activities, lung breakthrough (LB), the activity concentration ratio between lesions and healthy liver (T/N) and tumour involvement were investigated, where lobar and whole liver treatments were analysed separately. Without attenuation correction, overestimation of LB was 65%. In any case, the estimated lungs' doses remained below 30 Gy. Thus, the maximal injectable activity (MIA) is not limited by lungs' irradiation. Moreover, LB was not significantly related to T/N, neither to tumour involvement nor radiochemical purity (RP). Differences in calculated activity with the four methods were extremely large, in particular they were greater between BSA-based and PM activities for lobar treatments (from −85% to 417%) compared to whole liver treatments (from −49% to 61%). Two values of T/N ratio were identified as thresholds: for BSA-based methods, healthy liver doses are much higher than 30 Gy when T/N < 3; for PM, tumour doses are higher than 120 Gy when T/N > 4. As PM accounts for uptake ratio between normal and tumour liver, this method should be employed over BSA-based methods. [ABSTRACT FROM AUTHOR]

Purpose: To investigate early diffusion-weighted imaging (DWI) at 30-days post-yttrium-90 (Y-90) radioembolization as a predictor of treatment response and survival in unresectable infiltrative hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Materials and methods: In a prospective study, 18 consecutive patients with unresectable infiltrative HCC and PVT underwent Y-90 therapy. MR imaging was obtained pre Y-90, and at 1 and 3 months post-therapy with DWI fat-suppressed tri-directional diffusion gradient ( b = 50, 400, 800 s/mm). Response was evaluated using target mRECIST and EASL. Relative change in apparent diffusion coefficient (ADC) value of tumors was evaluated. Statistical analysis using receiver operator characteristic curves was performed. Paired t test and Pearson correlation coefficient ( r) were used to assess intra- and inter-observer variability. Survival analysis was performed using Kaplan-Meier estimation and log-rank test. Results: Mean ADC values of all HCC's at baseline and at 30-days post-Y90 therapy was 0.86 × 10 and 1.17×10 mm/s, respectively ( p < 0.001). Tumors with objective response by mRECIST had significantly increased ADC value when compared to 'non-responders' (1.27 vs. 1.05×10 mm/s, p = 0.002). A >30% increase in ADC value at 30-days was found to be at least 90% sensitive in predicting response at 90 days. A >30% increase in ADC value at 30-days predicted significantly prolonged survival. Conclusion: A 30% increase in ADC value at 30-days measured post Y90 is a reproducible early imaging response biomarker predicting tumor response and prolonged survival following Y-90 therapy in infiltrative HCC with PVT. [ABSTRACT FROM AUTHOR]

Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of ≤14.67 ± 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min. [ABSTRACT FROM AUTHOR]

Targeting epidermal growth factor receptor (EGFR)-overexpressing tumors with radiolabeled anti-EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [90Y]Y-CHX-A″-DTPA-C225 (Y-90-C225) in a 3-D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control dose 50% (SCD50, external irradiation dose inducing 50% loss of spheroid regrowth). Spheroids were cultured using a standardized platform. Therapy response after treatment with C225, CHX-A″-DTPA-C225 (DTPA-C225), [90Y]Y-CHX-A″-DTPA (Y-90-DTPA) and Y-90-C225 alone or in combination with X-ray was evaluated by long-term monitoring (60 days) of spheroid integrity and volume growth. Penetration kinetics into spheroids and EGFR binding capacities on spheroid cells were identical for unconjugated C225 and Y-90-C225. Spheroid-associated radioactivity upon exposure to the antibody-free control conjugate Y-90-DTPA was negligible. Determination of the SCD50 demonstrated higher intrinsic radiosensitivity of FaDu as compared with SAS spheroids. Treatment with unconjugated C225 alone did not affect spheroid growth and cell viability. Also, C225 treatment after external irradiation showed no additive effect. However, the combination of external irradiation with Y-90-C225 (1 µg/ml, 24 hr) resulted in a considerable benefit as reflected by a pronounced reduction of the SCD50 from 16 Gy to 9 Gy for SAS spheroids and a complete loss of regrowth for FaDu spheroids due to the pronounced accumulation of internal dose caused by the continuous exposure to cell-bound radionuclide upon Y-90-C225-EGFR interaction. [ABSTRACT FROM AUTHOR]