Challenging the challenge: A randomized controlled trial evaluating the inflammatory response and pain perception of healthy volunteers after single-dose LPS administration, as a potential model for inflammatory pain in early-phase drug development.

BACKGROUND AND AIMS: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain. METHODS AND RESULTS: This was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1-3 h post-dose. CONCLUSION: Mild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.

The use of biomarkers in human pharmacology (Phase I) studies.

The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development.

Retinal microcirculation imaging in sickle cell disease patients.

OBJECTIVES: To explore the feasibility of a new quantitative method for microvascular function: non-invasive retinal function imaging (RFI). in sickle cell disease (SCD) patients and healthy controls and have it benchmarked against Laser Speckle Contrast Imaging (LSCI) measurements. METHODS: The variability of Microvascular measurements was assessed in 8 SCD patients and 8 healthy matched controls. Measurements were conducted twice on two different study days. RFI was performed for assessment of arterial and venous retinal blood flow. LSCI measurements included post occlusive reactive hyperemia and IBH challenges. Measured variables included basal flow, flow upon occlusion-reperfusion and flow during an IBH. RESULTS: RFI arterial flow and venous flow and LSCI basal flow and peak flow showed excellent intra subject repeatability between days (CVC of 8.5% 9.5%, 7.6% and 7.7% respectively) and between measurements on one day (CVC of 7.0%, 7.7%, 7.6% and 4.7% respectively). RFI arterial flow (p<0.002), and RFI venous flow (p=0.007) differed significantly between SCD patients and controls in as did LSCI basal flow, maximal flow and delta flow during IBH (p<0.0001). CONCLUSIONS: RFI showed low variability for all readout measures, comparable with most microvascular measures from LSCI. The discriminating power of the RFI between SCD patients and controls demonstrate the feasibility of this device for quantitative assessment of the microcirculation in clinical research.

Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors.

INTRODUCTION: Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. AIM: To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. METHODS: Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 µg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. RESULTS: Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. CONCLUSION: In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 µg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.

MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216.

PURPOSE: Aim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction. METHODS: Data were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO-216, ranging 5-40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216. RESULTS: No inflammatory reaction was observed in HV and sCAD patients following MDCO-216 treatment, judging by body temperature, white cell counts, neutrophil counts, C-reactive protein, circulating cytokines (IL-6, TNF-α), and adverse events. In the ex vivo experiment, the geometric means (SD) of the ratio of MDCO-216 stimulated IL-6 over background levels were 0.8 (1.9), 0.7 (1.5), 1.0 (2.0) for respectively HV, sCAD, aCAD. The corresponding ETC-216 stimulated values were 15.8 (2.9), 9.5 (3.6), 3.8 (4.0). TNF-α results were comparable. Because many ETC-216 stimulated samples had cytokine concentrations >ULOQ, ratios were categorised and marginal homogeneity of the contingency table (MDCO-216 versus ETC-216) was assessed with the Stuart-Maxwell test. P-values were ≤0.0005 for all populations. CONCLUSIONS: MDCO-216 did not induce adverse immunostimulation in HV and sCAD patients, in contrast to ETC-216. Results from the ex vivo stimulation suggests the same holds true for aCAD patients.

Focal salvage therapy for local prostate cancer recurrences after primary radiotherapy: a comprehensive review.

BACKGROUND/AIM: Patients with locally recurrent prostate cancer after primary radiotherapy can be eligible for salvage treatment. Whole-gland salvage techniques carry a high risk of toxicity. A focal salvage approach might reduce the risk of adverse events while maintaining cancer control in carefully selected patients. The aim of this review was to evaluate current literature to assess whether focal salvage leads to a comparable or favourable recurrence rate and less toxicity compared to whole-gland salvage. METHODS: A literature search was performed using PubMed, Embase and the Cochrane Library. A total of 3015 articles were screened and assessed for quality. Eight papers [on focal cryoablation (n = 3), brachytherapy (n = 3) and high-intensity focused ultrasound (n = 2)] were used to report outcomes. RESULTS: One-, 2-, 3- and 5-year biochemical disease-free survival (BDFS) ranges for focal salvage are, respectively, 69-100, 49-100, 50-91 and 46.5-54.5 %. Severe genitourinary, gastrointestinal and sexual function toxicity rates are 0-33.3 %. One study directly compares focal to whole-gland salvage cryotherapy, showing 5-year BDFS of, respectively, 54.4 and 86.5 % with lower toxicity rates for focal salvage patients. CONCLUSION: Provisional data suggest that BDFS rates of focal salvage are in line with those of whole-gland approaches. There is evidence that focal salvage could decrease severe toxicity and preserve erectile function.

Characterization of a standardized glucagon challenge test as a pharmacodynamic tool in pharmacological research.

The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone.

Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis.

PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.

[Experiences with MRI-guided brachytherapy for radiorecurrent prostate cancer]. / Ervaringen met MRI-geleide brachytherapie bij prostaatkankerrecidief.

MR-guided brachytherapy offers a focal salvage treatment for the local recurrence in case of isolated locally recurrent prostate cancer in the prostate and/or seminal vesicles after primary radiotherapy. By focusing on only the local recurrence instead of the whole prostate, chances of additional toxicity of the bladder, urethra and rectum can be minimized. In almost all patients, the treatment leads to a good initial treatment response that persists in about half of patients, while others will develop progressive disease later on. For selecting suitable patients, factors such as preexistent urinary- and bowel complaints, localization and size of the recurrence, PSA doubling time and time between primary radiotherapy and development of the recurrence are relevant. MR-guided brachytherapy can provide a suitable salvage strategy, with the aims of deferring androgen deprivation therapy and a chance of cure.

Cardiovascular risk factors: The effects of ageing and smoking on the immune system, an observational clinical study.

Currently immunomodulatory compounds are under investigation for use in patients with cardiovascular disease, caused by atherosclerosis. These trials, using recurrent cardiovascular events as endpoint, require enrollment of large patient groups. We investigated the effect of key risk factors for atherosclerosis development, ageing and smoking, on the immune system, with the objective to identify biomarkers differentiating between human populations, and potentially serving as endpoints for future phase 1B trials with immunomodulatory compounds. Blood was collected from young healthy volunteers (aged 18-25 years, n=30), young smokers (18-25 years, n=20), elderly healthy volunteers (>60 years, n=20), heavy smokers (>45 years, 15 packyears, n=11) and patients with stable coronary artery disease (CAD) (>60 years, n=27). Circulating immune cell subsets were characterized by flow cytometry, and collected plasma was evaluated by proteomics (Olink). Clear ageing effects were observed, mostly illustrated by a lower level in CD8+ and naïve CD4+ and CD8+ T cells, with an increase in CD4+ and CD8+ effector memory T cells in elderly healthy volunteers compared to young healthy volunteers. Heavy smokers showed a more inflammatory cellular phenotype, especially a shift in Th1/Th2 ratio: higher Th1 and lower Th2 percentages compared to young healthy volunteers. A significant decrease in circulating atheroprotective oxLDL-specific IgM was found in patients with CAD compared to young healthy volunteers. Elevated pro-inflammatory and chemotactic proteins TREM1 and CCL11 were observed in elderly volunteers compared to young volunteers. In addition, heavy smokers had an increase in pro-inflammatory cytokine IL-6 and lysosomal protein LAMP3. These data show that ageing and smoking are associated with an inflammatory immunophenotype, and that heavy smokers or aged individuals may serve as potential populations for future clinical trials investigating immunomodulatory drugs targeted for cardiovascular disease.

MR compatibility, safety and accuracy of the redesigned UMC Utrecht single needle implant device.

Purpose. The Utrecht single needle implant device (SNID) was redesigned to increase needle insertion velocity. The purpose of this study is to evaluate the magnetic resonance compatibility, safety and accuracy of the implant device preparing its application in a patient study to investigate the feasibility of inserting a brachytherapy needle into the prostate to a defined tumor target point.Methods. Several experiments were performed to evaluate the mechanical and radiofrequency safety of the needle system, the magnetic field perturbation, the calibration of the implant device in the MR coordinate system, functioning of the implant device during imaging and accuracy of needle insertion.Results. Endurance experiments showed the mechanical safety of the needle system. Magnetic field perturbation was acceptable with induced image distortions smaller than 0.5 mm for clinical MR sequences. Calibration of the implant device in the MR coordinate system was reproducible with average error (mean±standard deviation) of 0.2 ± 0.4 mm, 0.1 ± 0.3 mm and 0.6 ± 0.6 mm in thex,y- andz- direction, respectively. The RF safety measurement showed for clinical MR imaging sequences maximum temperature rises of 0.2 °C at the entry and tip points of the needle. Simultaneous functioning of the implant device and imaging is possible albeit with some intensity band artifacts in the fast field echo images. Finally, phantom measurements showed deviations amounting 2.5-3.6 mm measured as target-to-needle distance at a depth of 12 cm.Conclusions. This preclinical evaluation showed that the MR compatibility, safety and accuracy of the redesigned UMC Utrecht SNID allow its application in a patient study on the feasibility of inserting a brachytherapy needle into the prostate to a defined tumor target point.

Simulation of the artefact of an iodine seed placed at the needle tip in MRI-guided prostate brachytherapy.

The purpose of this research is to study the influence of different needle materials on the artefact of a prostate brachytherapy iodine seed, placed at the needle tip, in MRI (magnetic resonance imaging)-guided prostate brachytherapy. For this research simulations were performed. The simulations showed that with the currently available MRI compatible titanium needles, determination of the exact seed position is difficult, because of the large artefact at the needle tip. This hampers accurate MRI-guided seed delivery. When a plastic needle is used, the image disturbance is caused by the artefact of the iodine seed alone. When a gradient echo sequence is used, the middle of the seed artefact corresponds well with to middle of the real seed position. With the scan parameters we used this deviation was less than 0.4 mm compared to 1.5 mm when a titanium needle is used.

Sample Aging Profoundly Reduces Monocyte Responses in Human Whole Blood Cultures.

Human whole blood cultures are widely used for the investigation of physiological pathways and drug effects in vitro. Detailed information on the effect of "sample aging" (the time span between blood collection and experimental start) on the experimental outcome is not readily available in the public domain. We studied the effect of sample aging on the ability of immune cells to respond to cell-specific immune triggers (LPS, PMA/ionomycin, and SEB). Sample aging at room temperature profoundly inhibited the LPS-induced monocytic cytokine release in minimally diluted whole blood cultures. The reduction ranged from 20-50% after 30 minutes to 80-100% after 10 hours and differed between cytokines (IL-1ß, IL-2, IL-6, IFNγ, and TNFα). Sample storage at 4°C or 37°C even worsened this. PMA/ionomycin- and SEB-induced cytokine release, both mainly T-cell-driven, were also reduced by sample aging but to a lesser extent (20-50% after 24 hours). Intracellular cytokine staining revealed that the number of LPS-responding cells was not impacted by sample aging and reduced LPS responsivity could also not be explained by apoptosis or downregulated TLR4 expression. Thus, we speculate that sample aging induces an inhibitory pathway downstream from TLR4 in monocytes. These results underline the importance of quick sample handling when investigating innate immune responses in whole blood, especially for monocyte responses.

MR-based source localization for MR-guided HDR brachytherapy.

For the purpose of MR-guided high-dose-rate (HDR) brachytherapy, a method for real-time localization of an HDR brachytherapy source was developed, which requires high spatial and temporal resolutions. MR-based localization of an HDR source serves two main aims. First, it enables real-time treatment verification by determination of the HDR source positions during treatment. Second, when using a dummy source, MR-based source localization provides an automatic detection of the source dwell positions after catheter insertion, allowing elimination of the catheter reconstruction procedure. Localization of the HDR source was conducted by simulation of the MR artifacts, followed by a phase correlation localization algorithm applied to the MR images and the simulated images, to determine the position of the HDR source in the MR images. To increase the temporal resolution of the MR acquisition, the spatial resolution was decreased, and a subpixel localization operation was introduced. Furthermore, parallel imaging (sensitivity encoding) was applied to further decrease the MR scan time. The localization method was validated by a comparison with CT, and the accuracy and precision were investigated. The results demonstrated that the described method could be used to determine the HDR source position with a high accuracy (0.4-0.6 mm) and a high precision (⩽0.1 mm), at high temporal resolutions (0.15-1.2 s per slice). This would enable real-time treatment verification as well as an automatic detection of the source dwell positions.

Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS.

Toll-like receptor-4 (TLR4) pathways are major contributors to pathological inflammatory responses induced by tissue damage. NI-0101 is the first monoclonal antibody (mAb) blocking TLR4 signaling. This activity is independent of the ligand type and concentration, therefore, potentially blocking any TLR4 ligands. A phase I single ascending dose study was conducted in 73 healthy volunteers to evaluate NI-0101 tolerability, preliminary safety, pharmacokinetics (PKs), and pharmacodynamics (PDs), in absence and in presence of a systemic challenge with lipopolysaccharide (LPS), a TLR4 ligand. NI-0101 was well tolerated without safety concern. The PK profile was characterized by a half-life of ∼10 days at high concentrations and by a rapid elimination at low concentrations due to expected target-mediated drug disposition. NI-0101 prevented cytokine release following ex vivo and in vivo LPS administration and prevented the C-reactive protein (CRP) increase and the occurrence of flu-like symptoms expected following the in vivo administration of LPS.

A novel adaptive needle insertion sequencing for robotic, single needle MR-guided high-dose-rate prostate brachytherapy.

MR-guided high-dose-rate (HDR) brachytherapy has gained increasing interest as a treatment for patients with localized prostate cancer because of the superior value of MRI for tumor and surrounding tissues localization. To enable needle insertion into the prostate with the patient in the MR bore, a single needle MR-compatible robotic system involving needle-by-needle dose delivery has been developed at our institution. Throughout the intervention, dose delivery may be impaired by: (1) sub-optimal needle positioning caused by e.g. needle bending, (2) intra-operative internal organ motion such as prostate rotations or swelling, or intra-procedural rectum or bladder filling. This may result in failure to reach clinical constraints. To assess the first aforementioned challenge, a recent study from our research group demonstrated that the deposited dose may be greatly improved by real-time adaptive planning with feedback on the actual needle positioning. However, the needle insertion sequence is left to the doctor and therefore, this may result in sub-optimal dose delivery. In this manuscript, a new method is proposed to determine and update automatically the needle insertion sequence. This strategy is based on the determination of the most sensitive needle track. The sensitivity of a needle track is defined as its impact on the dose distribution in case of sub-optimal positioning. A stochastic criterion is thus presented to determine each needle track sensitivity based on needle insertion simulations. To assess the proposed sequencing strategy, HDR prostate brachytherapy was simulated on 11 patients with varying number of needle insertions. Sub-optimal needle positioning was simulated at each insertion (modeled by typical random angulation errors). In 91% of the scenarios, the dose distribution improved when the needle was inserted into the most compared to the least sensitive needle track. The computation time for sequencing was less than 6 s per needle track. The proposed needle insertion sequencing can therefore assist in delivering an optimal dose in HDR prostate brachytherapy.

[MRI-guided brachytherapy in prostate cancer]. / MRI-geleide brachytherapie bij prostaatkankerrecidief.

The number of patients treated for prostate cancer by radiotherapy treatment has increased substantially over recent decades. However, after both external radiotherapy and brachytherapy, a subset of patients still develops recurrent disease during follow-up. In many patients these recurrences are often limited to one localisation in the prostate. In the past, on diagnosis of a recurrence, palliative hormonal treatment was started. Medical imaging by means of a CT scan was not adequate for delineating the recurrent lesion or for excluding metastases. In case where radiotherapy was considered the best treatment for the recurrence, this often resulted in serious adverse effects. Due to improvements in both imaging and radiotherapy techniques, it is now possible to target the local recurrent lesion only. In recurring prostate cancer this technique is known as focal salvage.

Adaptive cone-beam CT planning improves long-term biochemical disease-free survival for 125I prostate brachytherapy.

PURPOSE: Determining the independent effect of additional intraoperative adaptive C-arm cone-beam CT (CBCT) planning vs. transrectal ultrasound (TRUS)-guided interactive planning alone in 125I brachytherapy for prostate cancer (PCa) on biochemical disease-free survival (BDFS). METHODS AND MATERIALS: T1/T2-stage PCa patients receiving TRUS-guided brachytherapy from 2000 to 2014 were analyzed. From October 2006, patients received additional intraoperative adaptive CBCT planning for dosimetric evaluation and subsequent remedial seed placement in underdosed areas. Patients were stratified according to the National Comprehensive Cancer Network (NCCN) risk classification. Kaplan-Meier analysis was used to estimate BDFS (primary outcome), overall survival, and PCa-specific survival (secondary outcomes). Cox regression was used to assess the relation between CBCT use and biochemical failure (BF) and overall mortality. RESULTS: In all, 1623 patients were included. Median followup was 99 months (interquartile range 70-115) for TRUS patients (n = 613) and 51 months (interquartile range 29-70) for CBCT patients (n = 1010). BF occurred 203 times and 206 patients died, 26 from PCa. For TRUS and CBCT patients, 7-year BDFS was 87.2% vs. 93.5% (log rank: p = 0.04) for low, 75.9% vs. 88.5% (p < 0.001) for intermediate, and 57.1% vs. 85.0% for high-risk patients (p < 0.001). For TRUS and CBCT patients, 7-year PCa-specific survival was 96.0% vs. 100% (p < 0.0001). After Cox regression, CBCT patients had lower hazard of BF: hazard ratio (HR) 0.25 (95% confidence interval [CI]: 0.18-0.33; p < 0.0001). Corrected for confounders, CBCT remained a predictor of BF: HR 0.51 (95% CI: 0.31-0.86; p = 0.01) but not for overall mortality: HR 0.66 (95% CI: 0.40-1.07; p = 0.09). CONCLUSIONS: Additional intraoperative adaptive CBCT planning in 125I prostate brachytherapy leads to a significant increase in BDFS in all NCCN risk groups.

First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment.

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.