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Purpose: Portal vein embolization is performed to increase the future liver remnant before liver surgery in patients with liver malignancies. This study assesses the feasibility of a transsinusoidal approach for portal vein embolization (PVE) with the ethylene vinyl alcohol copolymer, Onyx.Methods: Indirect portography through contrast injection in the cranial mesenteric artery was performed in eight healthy pigs. Onyx was slowly injected through a microcatheter from a wedged position in the hepatic vein and advanced through the liver lobules into the portal system. The progression of Onyx was followed under fluoroscopy, and the extent of embolization was monitored by indirect portography. The pigs were euthanized immediately (n = 2), at 7 days (n = 4), or at 21 days postprocedure (n = 2). All pigs underwent necropsy and the ex vivo livers were grossly and histopathologically analyzed.Results: Transsinusoidal PVE was successfully performed in five of eight pigs (63%). In 14 of 21 injections (67%), a segmental portal vein could be filled completely. A mean of 1.6 liver lobes per pig was embolized (range 1-2 lobes). There were no periprocedural adverse events. Focal capsular scarring was visible on the surface of two resected livers, yet the capsules remained intact. Histopathological examination showed no signs of recanalization or abscess formation. Mild inflammatory reaction to Onyx was observed in the perivascular parenchyma.Conclusions: The porcine portal vein can be embolized through injection of Onyx from a wedged position in the hepatic vein. Possible complications of transsinusoidal PVE and the effect on contralateral hypertrophy need further study. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the incidence of extrahepatic deposition of technetium-99m-labeled albumin macroaggregates ((99m)Tc-MAA) after pretreatment angiography, before yttrium-90 radioembolizaton ((90)Y-RE), and to report on technical solutions that can be used to ensure safe delivery of (90)Y-microspheres in patients with initial extrahepatic deposition.Materials and Methods: A retrospective analysis of 26 patients with primary and secondary liver malignancies, who were scheduled for treatment with (90)Y-RE in our institution in 2009, was performed. The angiograms and single-photon emission computed tomography images of all patients were reviewed by an interventional radiologist and a nuclear medicine physician, respectively, to identify and localize extrahepatic deposition of (99m)Tc-MAA when present. Subsequently, the technical solutions were used to successfully perform (90)Y-RE in these patients were evaluated and described.Results: Extrahepatic deposition of (99m)Tc-MAA was observed in 8 of 26 patients (31%). In 7 of 8 patients, a second pretreatment angiography was performed to detect the cause of extrahepatic deposition. The technical solutions to enable safe (90)Y microspheres delivery included more distal placement of the microcatheter in the proper/right hepatic artery in 4 of 7 (57%) patients; (super)selective catheterization of multiple segmental branches in 2 of 7 (29%); and additional coiling of a newly detected branch in the remaining patient (14%). This was confirmed by a second MAA procedure. (90)Y-RE was eventually performed in 25 of 26 (96%) patients. No procedure-related complications (<30 days) were observed.Conclusion: Extrahepatic deposition of (99m)Tc-MAA after pretreatment angiography did occur in 8 of 26 (31%) patients. The technical solutions as presented allowed safe (90)Y-RE delivery in 25 of 26 (96%) patients. [ABSTRACT FROM AUTHOR]

Trauma-Focused mentalization-based treatment (MBT-TF) is an adaptation of mentalization-based treatment (MBT) specifically developed for patients suffering from attachment or complex trauma, with the possibility of co-occurring borderline personality pathology. The creation of MBT-TF was driven by previous research and observations that interventions centered on mentalizing could be significantly improved by directly addressing the impact of trauma. MBT-TF aims to mitigate symptoms that arise post-trauma, such as hyperarousal, hypervigilance, intrusions, flashbacks, avoidance behaviors, dissociative experiences, negative perceptions of self and others, and ensuing relational difficulties. Implemented as a group intervention, MBT-TF typically spans 6-12 months. From a mentalizing perspective, trauma, particularly attachment trauma, leads to a failure in processing the effects of trauma through and with others. Stress and attachment behavioral systems are disrupted, which undermines the capacity for epistemic trust, and impairs mentalizing abilities. This paper offers a concise summary of the reasoning for MBT-TF's creation, its theoretical underpinnings, and its clinical strategy for addressing the adverse impacts of trauma. It further details the treatment phases, their main goals, and their interventions, supplemented by clinical case examples that underscore MBT-TF's distinctive attributes and frequent clinical hurdles., Competing Interests: AB, PF, PL, MS, LN, TN, JV, and LS are involved in the development, training, and/or dissemination of mentalization-based treatments. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Smits, de Vos, Rüfenacht, Nijssens, Shaverin, Nolte, Luyten, Fonagy and Bateman.)

This study examined the impact of clinical severity on treatment outcome in two programs that differ markedly in treatment intensity: day hospital mentalization-based treatment (MBT-DH) and intensive outpatient mentalization-based treatment (MBT-IOP) for borderline personality disorder (BPD). A multicenter randomized controlled trial was conducted. Participants include the full intention-to-treat sample of the original trial of N = 114 randomized BPD patients (MBT-DH n = 70, MBT-IOP n = 44), who were assessed at baseline and subsequently every 6 up to 36 months after start of treatment. Outcomes were general symptom severity, borderline features, and interpersonal functioning. Clinical severity was examined in terms of severity of BPD, general symptom severity, comorbid symptom disorders, comorbid personality disorders, and cluster C personality features. None of the severity measures was related to treatment outcome or differentially predicted treatment outcome in MBT-DH and MBT-IOP, with the exception of a single moderating effect of co morbid symptom disorders on outcome in terms of BPD features, indicating less improvement in MBT-DH for patients with more symptom disorders. Overall, patients with varying levels of clinical severity benefited equally from MBT-DH and MBT-IOP, indicating that clinical severity may not be a useful criterion to differentiate in treatment intensity., (© 2024 John Wiley & Sons Ltd.)

Background: Although clinical guidelines prioritize the treatment of depression and anxiety in young persons, there is accumulating evidence that the presence of symptoms of borderline personality disorder (BPD) is associated with the limited effectiveness of these standard treatments. These findings stress the need for interventions addressing early-stage BPD in young people with presenting symptoms of anxiety and depressive disorders. The aim of this study is to investigate the (cost-)effectiveness of an early intervention programme for BPD (MBT-early) compared to first-choice psychological treatment for depression and anxiety according to Dutch treatment guidelines (CBT), in adolescents with either depression, anxiety, or both, in combination with early-stage BPD., Methods: This study is a multi-centre randomized controlled trial. A total of 132 adolescents, presenting with either depression, anxiety, or both and significant BPD features will be randomized to either MBT-early or CBT. The severity of BPD, symptoms of depression and anxiety, personality, social and academic functioning, and quality of life will be assessed at baseline, end of treatment, and at 12-, 18-, and 24-month follow-up, along with medical costs and costs of productivity losses for cost-effectiveness analyses., Discussion: This study will provide an empirical evaluation of the potential surplus value of early intervention in young people for whom treatment oriented at common mental disorders like anxiety and depression may be insufficient given their underlying personality problems., Trial Registration: Netherlands Trial Register, NL9569. Registered on June 15, 2021., (© 2024. The Author(s).)

Background & Aims: High-dose unilobar radioembolization, or 'radiation lobectomy' (RL), is an induction therapy that achieves contralateral future liver remnant hypertrophy while simultaneously irradiating the tumor. As such, it may prevent further growth, but it is unknown whether RL affects intrahepatic lymphatics, a major route via which liver tumors disseminate., Methods: This was a case-control study conducted at University Medical Center Utrecht. The study compared lymph vessels in livers that had undergone RL (cases) with those in livers that had not undergone RL (controls). Histological samples were acquired from patients diagnosed with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLM) between 2017 and 2022. Lymph vessel morphology was analyzed by two researchers using podoplanin, a protein that is expressed in lymphatic endothelium. In vivo liver lymph drainage of radioembolized livers was assessed using intraoperative liver lymphangiography (ILL): during liver surgery, patent blue dye was injected into the liver parenchyma, followed by inspection for staining of perihepatic lymph structures. ILL results were compared to a previously published cohort., Results: Immunohistochemical analysis on post-RL tumor tissues from ten patients with CRLM and nine patients with HCC revealed aberrant morphology of irradiated liver lymphatics when compared to controls (n = 3 per group). Irradiated lymphatics were tortuous ( p <0.05), thickened ( p <0.05) and discontinuous ( p <0.05). Moreover, post-RL lymphatics had larger lumens (1.5-1.7x, p <0.0001), indicating lymph stasis. ILL revealed diminished lymphatic drainage to perihepatic lymph nodes and vessels in irradiated livers when compared to non-radioembolized controls ( p  = 1.0x10 -4 )., Conclusions: Radioembolization impairs peritumoral lymph vessel function. Further research is needed to evaluate if radioembolization impairs tumor dissemination via this route., Impact and Implications: Unilobar radioembolization can serve as an alternative to portal venous embolization for patients who are considered unresectable due to an insufficient future liver remnant. This research suggests that radioembolization impairs the function of peritumoral liver lymph vessels, potentially hindering dissemination via this route. These findings provide support for considering unilobar radioembolization over standard portal venous embolization., Competing Interests: Marnix Lam is a consultant for Boston Scientific and Terumo. Maarten Smits is consultant for Philips and Terumo/Quierem Medical and has served as speakers for SirTex, BTG, Swedisch Orphan Biovitrum, Terumo and Metronic. The Department of Radiology and Nuclear Medicine of the UMC Utrecht receives royalties from Quirem Medical. No other potential conflict of interest relevant to this article was reported. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Objectives: Although treatments of patients with borderline personality disorder (BPD) were historically associated with relatively high dropout rates, dropout rates in contemporary evidence-based treatments for BPD are typically substantially lower. However, only a few studies have investigated dropout rates in mentalization-based treatment (MBT), and even fewer have investigated predictors of dropout in this type of treatment. In this study, we investigated dropout rates in two types of MBT (day hospital MBT [MBT-DH] and intensive outpatient MBT [MBT-IOP]) using data from a recent multicenter randomized clinical trial. Given the central importance of attachment considerations in MBT, we also investigated the relationship between dropout in these two treatments and attachment dimensions., Design: Within a multicenter randomized clinical trial, 114 BPD patients were randomized to MBT-DH (n = 70) or MBT-IOP (n = 44)., Methods: Dropout in both types of MBT was investigated using descriptive analyses, and its association with attachment anxiety and attachment avoidance, as measured by the Experiences in Close Relationships questionnaire at baseline, was investigated using regression analyses., Results: Dropout rates were relatively low (10.5% across both types of MBT) and did not significantly differ between groups (11.4% in MBT-DH, 9.1% in MBT-IOP). Attachment avoidance and attachment anxiety did not impact dropout, nor did their interaction or the interaction with the type of MBT., Conclusions: Low dropout rates in both types of MBT indicate a high level of engagement of patients in both programmes. Attachment dimensions were not associated with dropout, consistent with the principle that MBT is tailored to each individual's needs. More research is needed, however, to investigate to what extent attachment is a dynamic context-bound adaptive process rather than a static personality feature., (© 2023 The British Psychological Society.)

Mentalization-based treatment (MBT) has demonstrated robust effectiveness in the treatment of borderline personality disorder (BPD) in both day-hospital (MBT-DH) and intensive outpatient MBT (MBT-IOP) programs. Given the large differences in intensity and associated treatment costs, there is a need for studies comparing their cost-effectiveness. A health economic evaluation of MBT-DH versus MBT-IOP was performed alongside a multicenter randomized controlled trial with a 36-month follow-up. In three mental health-care institutions in the Netherlands, 114 patients were randomly allocated to MBT-DH ( n = 70) or MBT-IOP ( n = 44) and assessed every 6 months. Societal costs were compared with quality-adjusted life years (QALYs) gained and the number of months in remission over 36 months. The QALY gains over 36 months were 1.96 ( SD = .58) for MBT-DH and 1.83 ( SD = .56) for MBT-IOP; the respective number of months in remission were 16.0 ( SD = 11.5) and 11.1 ( SD = 10.7). Societal costs were €106,038 for MBT-DH and €91,368 for MBT-IOP. The incremental cost for one additional QALY with MBT-DH compared with MBT-IOP was €107,000. The incremental cost for 1 month in remission was almost €3000. Assuming a willingness-to-pay threshold of €50,000 for a QALY, there was a 33% likelihood that MBT-DH is more cost-effective than MBT-IOP in terms of costs per QALY. Although MBT-DH leads to slightly more QALYs and remission months, it is probably not cost-effective when compared with MBT-IOP for BPD patients, as the small additional health benefits in MBT-DH did not outweigh the substantially higher societal costs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Two types of mentalization-based treatment (MBT), day hospital MBT (MBT-DH) and intensive outpatient MBT (MBT-IOP), have been shown to be effective in treating patients with borderline personality disorder (BPD). This study evaluated trajectories of change in a multi-site trial of MBT-DH and MBT-IOP at 36 months after the start of treatment., Methods: All 114 patients (MBT-DH n = 70, MBT-IOP n = 44) from the original multicentre trial were assessed at 24, 30 and 36 months after the start of treatment. The primary outcome was symptom severity measured with the Brief Symptom Inventory. Secondary outcome measures included borderline symptomatology, personality and interpersonal functioning, quality of life and self-harm. Data were analysed using multilevel modelling and the intention-to-treat principle., Results: Patients in both MBT-DH and MBT-IOP maintained the substantial improvements made during the intensive treatment phase and showed further gains during follow-up. Across both conditions, 83% of patients improved in terms of symptom severity, and 97% improved on borderline symptomatology. No significant differences were found between MBT-DH and MBT-IOP at 36 months after the start of treatment. However, trajectories of change were different. Whereas patients in MBT-DH showed greater improvement during the intensive treatment phase, patients in MBT-IOP showed greater continuing improvement during follow-up., Conclusions: Patients in both conditions showed similar large improvements over the course of 36 months, despite large differences in treatment intensity. MBT-DH and MBT-IOP were associated with different trajectories of change. Cost-effectiveness considerations and predictors of differential treatment outcome may further inform optimal treatment selection.

Objective: Recent meta-analyses suggest that many patients with borderline personality disorder have a history of complex trauma. Although trauma is central in mentalization-based approaches to the understanding of borderline personality disorder, surprisingly little is known about the effects of trauma on outcomes of mentalization-based treatment (MBT). This article investigates the prevalence and impact of childhood trauma among patients with borderline personality disorder participating in a randomized controlled trial (RCT) comparing day hospital MBT (MBT-DH) and intensive outpatient MBT (MBT-IOP)., Methods: All 114 patients from the original multicenter RCT in the Netherlands were included in this study. Childhood trauma was assessed at baseline (with the Childhood Trauma Questionnaire), and its impact on symptom severity, interpersonal functioning, and borderline pathology was investigated through multilevel modeling for 36 months after the start of treatment., Results: Childhood trauma was common among patients with borderline personality disorder referred to MBT, with more than 85% meeting cutoff criteria for substantial childhood trauma. Childhood trauma had little impact on outcomes of either MBT-DH or MBT-IOP in terms of improved borderline personality disorder features or interpersonal functioning. However, patients with substantial childhood trauma seemed to improve more rapidly with MBT-DH, as compared with MBT-IOP, in terms of symptom severity. In addition, patients with a history of emotional neglect showed more rapid changes in symptoms of borderline personality disorder with MBT-DH compared with MBT-IOP., Conclusions: Findings are discussed in the context of a social communicative approach to borderline personality disorder, with a focus on the need to address trauma in MBT.

The authors present an economic evaluation performed alongside a randomized controlled trial of mentalization-based treatment in a day hospital setting (MBT-DH) versus specialist treatment as usual (S-TAU) for borderline personality disorder (BPD) with a 36-month follow-up period. Ninety-five patients from two Dutch treatment institutes were randomly assigned. Societal costs were compared with the proportion of BPD remissions and quality-adjusted life years (QALYs) measured using the five-dimensional EuroQol instrument. The incremental societal costs for one additional QALY could not be calculated. The costs for one additional BPD remission with MBT-DH are approximately €29,000. There was a 58% likelihood that MBT-DH leads to more remitted patients at additional costs compared with S-TAU, and a 35% likelihood that MBT-DH leads to more remissions at lower costs. MBT-DH is not cost-effective compared with S-TAU with QALYs as the outcome, and slightly more cost-effective than S-TAU at 36 months with BPD symptoms as the outcome.

Background: Two types of mentalisation-based treatment (MBT) have been developed and empirically evaluated for borderline personality disorder (BPD): day hospital MBT (MBT-DH) and intensive out-patient MBT (MBT-IOP). No trial has yet compared their efficacy., Aims: To compare the efficacy of MBT-DH and MBT-IOP 18 months after start of treatment. MBT-DH was hypothesised to be superior to MBT-IOP because of its higher treatment intensity., Method: In a multicentre randomised controlled trial (Nederlands Trial Register: NTR2292) conducted at three sites in the Netherlands, patients with BPD were randomly assigned to MBT-DH (n = 70) or MBT-IOP (n = 44). The primary outcome was symptom severity (Brief Symptom Inventory). Secondary outcome measures included borderline symptomatology, personality functioning, interpersonal functioning, quality of life and self-harm. Patients were assessed every 6 months from baseline to 18 months after start of treatment. Data were analysed using multilevel modelling based on intention-to-treat principles., Results: Significant improvements were found on all outcome measures, with moderate to very large effect sizes for both groups. MBT-DH was not superior to MBT-IOP on the primary outcome measure, but MBT-DH showed a clear tendency towards superiority on secondary outcomes., Conclusions: Although MBT-DH was not superior to MBT-IOP on the primary outcome measure despite its greater treatment intensity, MBT-DH showed a tendency to be more effective on secondary outcomes, particularly in terms of relational functioning. Patients receiving MBT-DH and MBT-IOP, thus, seem to follow different trajectories of change, which may have important implications for clinical decision-making. Longer-term follow-up and cost-effectiveness considerations may ultimately determine the optimal intensity of specialised treatments such as MBT for patients with BPD.

Background: The borderline personality disorder (BPD) population is notably heterogeneous, and this has potentially important implications for intervention. Identifying distinct subtypes of patients may represent a first step in identifying which treatments work best for which individuals., Methods: A cluster-analysis on dimensional personality disorder (PD) features, as assessed with the SCID-II, was performed on a sample of carefully screened BPD patients ( N  = 187) referred for mentalization-based treatment. The optimal cluster solution was determined using multiple indices of fit. The validity of the clusters was explored by investigating their relationship with borderline pathology, symptom severity, interpersonal problems, quality of life, personality functioning, attachment, and trauma history, in addition to demographic and clinical features., Results: A three-cluster solution was retained, which identified three clusters of BPD patients with distinct profiles. The largest cluster ( n  = 145) consisted of patients characterized by "core BPD" features, without marked elevations on other PD dimensions. A second "Extravert/externalizing" cluster of patients ( n  = 27) was characterized by high levels of histrionic, narcissistic, and antisocial features. A third, smaller "Schizotypal/paranoid" cluster ( n  = 15) consisted of patients with marked schizotypal and paranoid features. Patients in these clusters showed theoretically meaningful differences in terms of demographic and clinical features., Conclusions: Three meaningful subtypes of BPD patients were identified with distinct profiles. Differences were small, even when controlling for severity of PD pathology, suggesting a strong common factor underlying BPD. These results may represent a stepping stone toward research with larger samples aimed at replicating the findings and investigating differential trajectories of change, treatment outcomes, and treatment approaches for these subtypes., Trial Registration: The study was retrospectively registered 16 April 2010 in the Nederlands Trial Register , no. NTR2292.

Radioembolization is an established treatment modality that has been subjected to many improvements over the last decade. Developments are occurring at a high pace, affecting patient selection and treatment. The aim of this review is therefore to provide an overview of current practice, with a focus on recent developments in the field of radioembolization. Several practical issues and recommendations in the application of radioembolization will be discussed, ranging from patient selection to treatment response and future applications., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Methods for calculating the activity to be administered during yttrium-90 radioembolization (RE) are largely based on empirical toxicity and efficacy analyses, rather than dosimetry. At the same time, it is recognized that treatment planning based on proper dosimetry is of vital importance for the optimization of the results of RE. The heterogeneous and often clustered intrahepatic biodistribution of millions of point-source radioactive particles poses a challenge for dosimetry. Several studies found a relationship between absorbed doses and treatment outcome, with regard to both toxicity and efficacy. This should ultimately lead to improved patient selection and individualized treatment planning. New calculation methods and imaging techniques and a new generation of microspheres for image-guided RE will all contribute to these improvements. The aim of this review is to give insight into the latest and most important developments in RE dosimetry and to suggest future directions on patient selection, individualized treatment planning, and study designs.

Embolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (±SEM) of the hydrated holmium-lipiodol-alginate microspheres (Ho-lip-ams) was 570±12 μm with a holmium content of 0.38±0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 °C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho-lip-ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolization treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: Failing to identify aberrant hepatic arteries before radioembolization (RE) may compromise its treatment efficacy due to inadequate biodistribution of radioactive microspheres. The purpose of this study was to evaluate how often aberrant hepatic arteries were identified correctly in clinical practice, with computed tomography (CT), and during angiography in patients with liver tumors who received a workup for RE., Methods: The presence and vascularization pattern of aberrant (i.e., accessory and replaced) hepatic arteries was assessed on triphasic liver CT in 110 patients. Subsequently, radiological reports on CT and angiographic procedures were reviewed to determine whether aberrant hepatic arteries were identified correctly in clinical practice. The intrahepatic biodistribution of (99m)Tc-MAA and radioactive microspheres was assessed on SPECT/CT and PET/CT in all patients with unidentified aberrant hepatic arteries., Results: Thirty-seven of 110 patients (34%) had aberrant hepatic arteries. In 18 of 37 (49%) patients, the aberrant hepatic arteries were correctly identified on CT and in 32 of 37 (86%) during angiography. Aberrant right hepatic arteries were identified more frequently than aberrant left hepatic arteries on CT (54 vs. 44%) and during angiography (100 vs. 69%, p = 0.007). In five patients (14%), an aberrant left hepatic artery remained unidentified, resulting in a lack of (99m)Tc-MAA and (90)Y activity in the segmental territory of the unidentified aberrant hepatic arteries., Conclusions: Aberrant left hepatic arteries were the most common unidentified aberrant hepatic arteries, resulting in incomplete radiation coverage. We formulated a practical approach to identify aberrant hepatic arteries correctly before RE.

Purpose: To assess the radiation exposure to individuals coming from patients after treatment with holmium-166 ((166)Ho) microspheres., Materials and Methods: Holmium-166 radioembolization (RE) with escalating whole-liver doses of 20 Gy, 40 Gy, 60 Gy, and 80 Gy was administered to 15 patients. Exposure rates (μSv/h) from patients were measured at 1.0 m distance from a lateral and frontal position at 0, 3, 6, 24, and 48 hours after infusion. The total effective dose equivalent (TEDE) to a maximally exposed contact was calculated in accordance with guidelines of the U.S. Nuclear Regulatory Commission (NRC). Results were extrapolated to a whole-liver dose of 60 Gy used in future treatments., Results: The median exposure rate at discharge, 48 hours after infusion, measured from a lateral position was 26 μSv/h (range, 7-45 μSv/h). Extrapolated to a whole-liver dose of 60 Gy, none of the exposure rates for the NRC contact scenario, at any time, frontal or lateral, would lead to a TEDE > 5 mSv; all patients may be released directly after treatment. Release after 6 hours is possible without contact restrictions for patients who received up to 7 GBq., Conclusions: The TEDE to a contact of patients treated with (166)Ho RE would not exceed the NRC limit of 5 mSv. Contact restrictions 6 hours after treatment are unnecessary for infused activities < 7 GBq., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Borderline personality disorder (BPD) is associated with a high socioeconomic burden. Although a number of evidence-based treatments for BPD are currently available, they are not widely disseminated; furthermore, there is a need for more research concerning their efficacy and cost-effectiveness. Such knowledge promises to lead to more efficient use of resources, which will facilitate the effective dissemination of these costly treatments. This study focuses on the efficacy and cost-effectiveness of Mentalization-Based Treatment (MBT), a manualized treatment for patients with BPD. Studies to date have either investigated MBT in a day hospitalization setting (MBT-DH) or MBT offered in an intensive outpatient setting (MBT-IOP). No trial has compared the efficacy and cost-effectiveness of these MBT programmes. As both interventions differ considerably in terms of intensity of treatment, and thus potentially in terms of efficacy and cost-effectiveness, there is a need for comparative trials. This study therefore sets out to investigate the efficacy and cost-effectiveness of MBT-DH versus MBT-IOP in patients with BPD. A secondary aim is to investigate the association between baseline measures and outcome, which might improve treatment selection and thus optimize efficacy and cost-effectiveness., Methods/design: A multicentre randomized controlled trial comparing MBT-DH versus MBT-IOP in severe BPD patients. Patients are screened for BPD using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and are assessed before randomization, at the start of treatment and 6, 12, 18, 24, 30 and 36 months after the start of treatment. Patients who refuse to participate will be offered care as usual in the same treatment centre. The primary outcome measure is symptom severity as measured by the Brief Symptom Inventory. Secondary outcome measures include parasuicidal behaviour, depression, substance use, social, interpersonal, and personality functioning, attachment, mentalizing capacities, and quality of life. All analyses will be conducted based on the intention-to-treat principle. Cost-effectiveness will be calculated based on costs per quality-adjusted life-year., Discussion: This multisite randomized trial will provide data to refine criteria for treatment selection for severe BPD patients and promises to optimize (cost-)effectiveness of the treatment of BPD patients., Trial Registration: NTR2292 . Registered 16 April 2010.

Purpose: Radiation pneumonitis is a rare but serious complication of radioembolic therapy of liver tumours. Estimation of the mean absorbed dose to the lungs based on pretreatment diagnostic (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) imaging should prevent this, with administered activities adjusted accordingly. The accuracy of (99m)Tc-MAA-based lung absorbed dose estimates was evaluated and compared to absorbed dose estimates based on pretreatment diagnostic (166)Ho-microsphere imaging and to the actual lung absorbed doses after (166)Ho radioembolization., Methods: This prospective clinical study included 14 patients with chemorefractory, unresectable liver metastases treated with (166)Ho radioembolization. (99m)Tc-MAA-based and (166)Ho-microsphere-based estimation of lung absorbed doses was performed on pretreatment diagnostic planar scintigraphic and SPECT/CT images. The clinical analysis was preceded by an anthropomorphic torso phantom study with simulated lung shunt fractions of 0 to 30 % to determine the accuracy of the image-based lung absorbed dose estimates after (166)Ho radioembolization., Results: In the phantom study, (166)Ho SPECT/CT-based lung absorbed dose estimates were more accurate (absolute error range 0.1 to -4.4 Gy) than (166)Ho planar scintigraphy-based lung absorbed dose estimates (absolute error range 9.5 to 12.1 Gy). Clinically, the actual median lung absorbed dose was 0.02 Gy (range 0.0 to 0.7 Gy) based on posttreatment (166)Ho-microsphere SPECT/CT imaging. Lung absorbed doses estimated on the basis of pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging (median 0.02 Gy, range 0.0 to 0.4 Gy) were significantly better predictors of the actual lung absorbed doses than doses estimated on the basis of (166)Ho-microsphere planar scintigraphy (median 10.4 Gy, range 4.0 to 17.3 Gy; p < 0.001), (99m)Tc-MAA SPECT/CT imaging (median 2.5 Gy, range 1.2 to 12.3 Gy; p < 0.001), and (99m)Tc-MAA planar scintigraphy (median 5.5 Gy, range 2.3 to 18.2 Gy; p < 0.001)., Conclusion: In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic (99m)Tc-MAA imaging. Pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after (166)Ho radioembolization.

Purpose: Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization., Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted., Results: The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT-II infusion., Conclusions: Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization.

Unlabelled: (166)Ho-poly(l-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT- and MR imaging-based dosimetry in the first patients treated with (166)Ho radioembolization., Methods: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with (166)Ho radioembolization according to a dose escalation protocol (20-80 Gy). The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n = 9) or SPECT/CT images (n = 6) and MR imaging-based R2* maps (n = 14). Dosimetry was based on SPECT (n = 15) and MR imaging (n = 9) for all volumes of interest, tumor-to-nontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging- and SPECT-based measurements were evaluated., Results: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio ≥ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R(2) = 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, -11.2 to 18.7)., Conclusion: With the use of (166)Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors.

Unlabelled: Currently, there is no consensus on the use of (90)Y radioembolization for salvage patients with colorectal cancer liver metastases. The purpose of this study was to provide a comprehensive overview of the available data on tumor response and survival after (90)Y radioembolization for this group of patients., Methods: A systematic literature search was conducted in PubMed (Medline), Excerpta Medica (EMBASE), and the Cochrane Library (September 2012) with synonyms for "radioembolization" and "colorectal cancer liver metastases." Results were described separately for patient cohorts treated with (90)Y radioembolization as monotherapy and with (90)Y radioembolization in combination with chemotherapy., Results: The search yielded 13 relevant articles for systematic review on (90)Y radioembolization as monotherapy and 13 relevant articles on (90)Y radioembolization combined with chemotherapy. Disease control rates (i.e., complete response, partial response, and stable disease) ranged from 29% to 90% for (90)Y radioembolization as monotherapy and from 59% to 100% for (90)Y radioembolization combined with chemotherapy. Heterogeneity in the data prohibited pooling of response rates. Survival proportions at 12 mo ranged from 37% to 59% for (90)Y radioembolization as monotherapy and from 43% to 74% for (90)Y radioembolization combined with chemotherapy., Conclusion: In the studies included in this systematic review, approximately 50% of salvage patients with colorectal cancer liver metastases survive more than 12 mo after treatment with (90)Y radioembolization, either as monotherapy or in combination with chemotherapy. Heterogeneity between studies has unfortunately prohibited pooling of data. Future research will discern the precise role of (90)Y radioembolization in general clinical practice in comparison with chemotherapy.

Purpose: Quantitative imaging of the radionuclide distribution is of increasing interest for microsphere radioembolization (RE) of liver malignancies, to aid treatment planning and dosimetry. For this purpose, holmium-166 ((166)Ho) microspheres have been developed, which can be visualized with a gamma camera. The objective of this work is to develop and evaluate a new reconstruction method for quantitative (166)Ho SPECT, including Monte Carlo-based modeling of photon contributions from the full energy spectrum., Methods: A fast Monte Carlo (MC) simulator was developed for simulation of (166)Ho projection images and incorporated in a statistical reconstruction algorithm (SPECT-fMC). Photon scatter and attenuation for all photons sampled from the full (166)Ho energy spectrum were modeled during reconstruction by Monte Carlo simulations. The energy- and distance-dependent collimator-detector response was modeled using precalculated convolution kernels. Phantom experiments were performed to quantitatively evaluate image contrast, image noise, count errors, and activity recovery coefficients (ARCs) of SPECT-fMC in comparison with those of an energy window-based method for correction of down-scattered high-energy photons (SPECT-DSW) and a previously presented hybrid method that combines MC simulation of photopeak scatter with energy window-based estimation of down-scattered high-energy contributions (SPECT-ppMC+DSW). Additionally, the impact of SPECT-fMC on whole-body recovered activities (A(est)) and estimated radiation absorbed doses was evaluated using clinical SPECT data of six (166)Ho RE patients., Results: At the same noise level, SPECT-fMC images showed substantially higher contrast than SPECT-DSW and SPECT-ppMC+DSW in spheres ≥ 17 mm in diameter. The count error was reduced from 29% (SPECT-DSW) and 25% (SPECT-ppMC+DSW) to 12% (SPECT-fMC). ARCs in five spherical volumes of 1.96-106.21 ml were improved from 32%-63% (SPECT-DSW) and 50%-80% (SPECT-ppMC+DSW) to 76%-103% (SPECT-fMC). Furthermore, SPECT-fMC recovered whole-body activities were most accurate (A(est) = 1.06 × A - 5.90 MBq, R(2) = 0.97) and SPECT-fMC tumor absorbed doses were significantly higher than with SPECT-DSW (p = 0.031) and SPECT-ppMC+DSW (p = 0.031)., Conclusions: The quantitative accuracy of (166)Ho SPECT is improved by Monte Carlo-based modeling of the image degrading factors. Consequently, the proposed reconstruction method enables accurate estimation of the radiation absorbed dose in clinical practice.

Aim: To assess the technical feasibility and clinical outcome of percutaneous transluminal angioplasty (PTA) with and without stent placement for treatment of buttock claudication caused by internal iliac artery (IIA) stenosis., Methods: Between September 2001 and July 2011, thirty-four patients with buttock claudication underwent endovascular treatment. After angiographic lesion evaluation PTA with or without stent placement was performed. Technical success was recorded. Clinical outcome post-treatment was assessed at three months post-intervention and was classified as: 1) complete relief of symptoms, 2) partial relief, or 3) no relief of symptoms. Complications during follow-up were recorded., Results: Forty-four lesions in 34 symptomatic patients were treated with PTA. Eight lesions were treated with additional stent placement. Technical success was achieved in 40/44 lesions (91%). Three procedure-related minor complications occurred, i.e. asymptomatic conservatively treated intimal dissections. After a median of 2.9 months, patients experienced no relief of symptoms in 7/34 cases (21%), partial relief in 14/34 cases (41%), and complete relief in 13/34 cases (38%). Six patients required a reintervention during follow-up., Conclusion: Endovascular treatment of IIA stenosis has a high technical success rate and a low complication rate. Complete or partial relief of symptoms is achieved in the majority (79%) of patients.

Unlabelled: In hepatic (90)Y radioembolization, pretreatment (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) nuclear imaging is used for lung shunt analysis, evaluation of extrahepatic deposition, and sometimes for treatment planning, using a partition model. A high level of agreement between pretreatment (99m)Tc-MAA distribution and final (90)Y-microsphere distribution is assumed. The aim of this study was to investigate the value of pretreatment (99m)Tc-MAA SPECT to predict intrahepatic posttreatment (90)Y-microsphere distribution., Methods: Volumes of interest (VOIs) were delineated on pretreatment contrast-enhanced CT or MR images according to Couinaud liver segmentation. All VOIs were registered to the (99m)Tc-MAA SPECT and (90)Y SPECT images. The (99m)Tc-MAA SPECT and (90)Y SPECT activity counts were normalized to the total administered activity of (90)Y. For each VOI, this practice resulted in a predictive amount of (90)Y (MBq/cm(3)) based on (99m)Tc-MAA SPECT in comparison with an actual amount of (90)Y based on (90)Y SPECT. Bland-Altman analysis was used to investigate the agreement of the activity distribution between (99m)Tc-MAA SPECT and (90)Y SPECT., Results: A total of 39 procedures (225 VOIs) in 31 patients were included for analysis. The overall mean difference between pretreatment and posttreatment distribution of activity concentration for all segments was -0.022 MBq/cm(3) with 95% limits of agreement of -0.581 to 0.537 MBq/cm(3) (-28.9 to 26.7 Gy absorbed dose). A difference of >10%, >20%, and >30% of the mean activity per milliliter was found in, respectively, 153 (68%), 97 (43%), and 72 (32%) of the 225 segments. In every (99m)Tc-MAA procedure, at least 1 segment showed an under- or overestimation of >10%. The position of the catheter tip during administrations, as well as the tumor load of the liver segments, significantly influenced the disagreement., Conclusion: In current clinical practice, (99m)Tc-MAA distribution does not accurately predict final (90)Y activity distribution. Awareness of the importance of catheter positioning and adherence to specific recommendations may lead to optimization of individualized treatment planning based on pretreatment imaging.

Objective: To investigate clinical and laboratory toxicity in patients with unresectable liver metastases, treated with yttrium-90 radioembolization ((90)Y-RE)., Methods: Patients with liver metastases treated with (90)Y-RE, between February 1(st) 2009 and March 31(st) 2012, were included in this study. Clinical toxicity assessment was based on the reporting in patient's charts. Laboratory investigations at baseline and during a four-month follow-up were used to assess laboratory toxicity according to the Common Terminology Criteria for Adverse Events version 4.02. The occurrence of grade 3-4 laboratory toxicity was stratified according to treatment strategy (whole liver treatment in one session versus sequential sessions). Response assessment was performed at the level of target lesions, whole liver and overall response in accordance with RECIST 1.1 at 3- and 6 months post-treatment. Median time to progression (TTP) and overall survival were calculated by Kaplan-Meier analysis., Results: A total of 59 patients, with liver metastases from colorectal cancer (n = 30), neuroendocrine tumors (NET) (n = 6) and other primary tumors (n = 23) were included. Clinical toxicity after (90)Y-RE treatment was confined to grade 1-2 events, predominantly post-embolization symptoms. No grade 3-4 clinical toxicity was observed, whereas laboratory toxicity grade 3-4 was observed in 38% of patients. Whole liver treatment in one session was not associated with increased laboratory toxicity. Three-months disease control rates for target lesions, whole liver and overall response were 35%, 21% and 19% respectively. Median TTP was 6.2 months for target lesions, 3.3 months for the whole liver and 3.0 months for overall response. Median overall survival was 8.9 months., Conclusion: The risk of severe complications or grade 3-4 clinical toxicity in patients with liver metastases of various primary tumors undergoing (90)Y-RE is low. In contrast, laboratory toxicity grade 3-4 can be expected to occur in more than one-third of patients without any clinical signs of radiation induced liver disease.

Radioembolization using yttrium-90 microspheres (⁹⁰Y-RE) is an emerging treatment option for breast cancer liver metastases (BCLM) patients if other locoregional and systemic treatment options fail. The purpose of this study was to provide a systematic overview of the current literature concerning ⁹⁰Y-RE for BCLM patients. A systematic search for relevant articles was performed in MEDLINE, EMBASE, and The Cochrane Library (January 2012) by combining an extensive list of synonyms for the determinants 'radioembolization', 'yttrium-90' and 'microsphere' with synonyms for the domain 'liver'. Data on tumor response, survival and toxicity were extracted and collected from all relevant articles. The search yielded 4078 studies, of which six were finally included for analysis, concerning a total of 198 patients. Tumor response was scored in five studies using either RECIST (n=3) or WHO criteria (n=2). Overall disease control rates (complete response, partial response and stable disease) at 2-4 months post treatment ranged from 78% to 96%. Median survival, available in four studies, ranged from 10.8 to 20.9 months. In total, gastric ulceration was reported in ten patients (5%) and treatment related mortality in three patients (2%). The results from the analyzed studies consistently show that ⁹⁰Y-RE is a safe and effective treatment option for BCLM patients. Comparative studies, especially combining ⁹⁰Y-RE with systemic therapy are strongly encouraged., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose., Methods: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose., Results: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001)., Conclusion: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

Background: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases., Methods: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784., Findings: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity., Interpretation: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Patients with malignant tumors originating from the biliary tree have a poor prognosis, since only a minority of tumors can be resected and most palliative regimens have shown only limited success. We present two patients with unresectable tumors, who were treated with trans-arterial (90)yttrium radioembolization: a patient with an infiltrating gallbladder carcinoma and a patient with an extensive intrahepatic cholangiocarcinoma. In both cases the treatment was technically feasible, effective in controlling tumor growth, and without significant side effects. In conclusion, the presented cases demonstrate the potential of (90)yttrium radioembolization as a palliative treatment option for malignant tumors of the biliary tree.

Background: Intra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-RE in patients with liver metastases., Methods: The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution., Discussion: This will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.