Wouter Bult

Holmium-166 radioembolization for the treatment of patients with liver metastases : design of the phase I HEPAR trial

BackgroundIntra-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.MethodsThe 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.DiscussionThis 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.Trial registrationClinicalTrials.gov NCT01031784

Microspheres with ultrahigh holmium content for radioablation of malignancies

PurposeThe aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter.MethodsMicrospheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT).ResultsMicrospheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT.ConclusionsHoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Intratumoral administration of Holmium-166 Acetylacetonate Microspheres: antitumor efficacy and feasibility of multimodality imaging in renal cancer

Purpose The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres (166HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI. Methods 166HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry. Results 166HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in 166HoAcAcMS treated mice (0.10±0.01 cm3 vs. 4.15±0.3 cm3 for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of 166HoAcAcMS in the kidney. Conclusions Intratumorally administered 166HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.

Microbrachytherapy using holmium-166 acetylacetonate microspheres: a pilot study in a spontaneous cancer animal model

PURPOSE Holmium-166 acetylacetonate microspheres ((166)Ho-AcAc-MS) are proposed as an intratumoral radioablation device. This article presents a pilot study in housecats with unresectable liver cancer. Feasibility and tolerability of intratumoral administrations of (166)Ho-AcAc-MS was investigated. METHODS AND MATERIALS Three cats with unresectable liver tumors of different histotype were included. One cat had hepatocellular carcinoma (HCC), one had cholangiocarcinoma (CC), and one had a malignant epithelial liver tumor (MELT) of unspecified histotype. (166)Ho-AcAc-MS were injected percutaneously under ultrasound guidance into the tumors. Followup consisted of physical examinations and hematologic and biochemical analyses. RESULTS (166)Ho-AcAc-MS were administered to three liver tumor-bearing cats. The treatment was well tolerated and the clinical condition, that is body weight, alertness, mobility, and coat condition of the animals improved markedly. Most biochemical and hematologic parameters normalized shortly after treatment. Life of all cats was extended and associated with a good quality of life. The HCC cat that received 33-Gy tumor-absorbed dose was euthanized 6 months after the first administration owing to disease progression. The MELT cat received 99-Gy tumor dose and was euthanized 3 months posttreatment owing to bacterial meningitis. The CC cat received 333Gy and succumbed 4 months after the first treatment owing to the formation of a pulmonary embolism. CONCLUSIONS Percutaneous intratumoral injection of radioactive (166)Ho-AcAc-MS is feasible in liver tumor-bearing cats. The findings of this pilot study indicate that (166)Ho-AcAc-MS may constitute safe brachytherapeutic microspheres and warrant studies to confirm the clinical utility of this novel brachytherapy device.

Improved usability of a multi-infusion setup using a centralized control interface: A task-based usability test

The objective of this study was to assess the usability benefits of adding a bedside central control interface that controls all intravenous (IV) infusion pumps compared to the conventional individual control of multiple infusion pumps. Eighteen dedicated ICU nurses volunteered in a between-subjects task-based usability test. A newly developed central control interface was compared to conventional control of multiple infusion pumps in a simulated ICU setting. Task execution time, clicks, errors and questionnaire responses were evaluated. Overall the central control interface outperformed the conventional control in terms of fewer user actions (40±3 vs. 73±20 clicks, p<0.001) and fewer user errors (1±1 vs. 3±2 errors, p<0.05), with no difference in task execution times (421±108 vs. 406±119 seconds, not significant). Questionnaires indicated a significant preference for the central control interface. Despite being novice users of the central control interface, ICU nurses displayed improved performance with the central control interface compared to the conventional interface they were familiar with. We conclude that the new user interface has an overall better usability than the conventional interface.

Improved usability of a multi-infusion setup using a central control display

Citation for published version (APA): Rasmussen, B. S., Maltesen, R., Hanifa, M., Pedersen, S., Kristensen, S. R., & Wimmer, R. (2016). Metabonomics identifies early molecular changes associated with progression into postoperative hypoxemia in cardiac surgery patient: a human model that can provide new insights into the pathophysiology of acute lung injury and potentially identify specific biomarkers of lung tissue injury. Intensive Care Medicine Experimental, 4(Suppl. 1), 13. [A22]. https://doi.org/10.1186/s40635-016-0098-x

Parenteral versus enteral potassium suppletion in icu patients: does it make a difference?

Hypokalemia is a common electrolyte disturbance in the ICU, which makes potassiumchloride (KCl) suppletion a frequent necessity. Parenteral KCl suppletion is mostly used in critically ill patients, but it is associated with safety risks, such as overcorrection and line-infections. Enteral KCl suppletion could be a safe and effective alternative in many instances. However, it is not known whether bioavailability of enterally administered KCl is sufficient in critically ill patients. Renal potassium excretion (RPE) was used as a measure of absorbed KCl.

effect of 5-aminolaevulenic acid on postoperative lactate levels in patients undergoing surgery for malignant brain tumours

5-aminolaevulinic acid (5-ALA) is a natural precursor of haemoglobin. Exogenously administered 5-ALA can lead to intracellular accumulation of fluorescent porphyrins in malignant tissues, such as glioblastoma. 5-ALA is increasingly used to improve tumour visualisation and enable more optimal resection of malignant gliomas. In vitro, 5-ALA can cause oxidative damage to rat liver mitochondria. In vivo, rats exposed to 5-ALA developed increased lactate levels; possibly because inhibition of oxidative metabolism [1]. Univariate data also suggested an effect of 5-ALA in neurosurgical patients [2]. Since lactate levels are widely used to monitor patients, we performed multivariate analysis on the impact of 5-ALA on lactate levels.

Holmium-166 acetylacetonate microspheres as an intratumoral radioablation device

Opportunistic pathogens are ubiquitous and lead to life threatening infection making it a common place for mankind. Localizing occult infection noninvasively, has continued to be as challenging as treating the infection. Pathogenesis of infection is associated with activation of a large number of parameters. Over the past 35 years, a variety of these parameters have been targeted for a development of a most suitable radiopharmaceutical that will image abscesses conveniently and with high sensitivity and specificity. These parameters include polymorphonuclear neutrophil (PMNs), cytokines, bacteria and glycosis to name a few. However, challenges for specificity still arise, not from the lack of availability of agents that will image infection, but from the lack of their versality. The good old Ga‐67‐citrate takes too long to image abscesses before abscesses can be localized after its administration. In‐111‐Oxine, although considered the best, suffers from ex vivo labeling of blood cells, cost and long half life of In‐111. Tc‐99m‐HMPAO elutes off the labeled White blood cells, cytokines specific agents can present toxicity, PMN specific antibodies do not label PMNs with high avidity and bacterial agents do not target bacteria specifically. Radioactive agents that harbor into infection foci nonspecifically through increased capillary permeability are plentiful but of course are nonspecific and the current popular agent F‐18‐FDG does not localize only infection and renders itself nonspecific. Despite the far from ideal circumstances, NM physicians have done a remarkable job, and have continued to provide excellent care for those patients who suffer from bacterial infection or inflammation. Scientists and physician scientists on the other hand have continued to seek new and improved agents that may address some of the present challenges. This presentation will summarize today’s challenges and attempt to present tomorrow’s prospects. OP203 SPECT-CT in the diagnosis of inflammation and infection