Dose-effect relationships in neuroendocrine tumour liver metastases treated with [166Ho]-radioembolization.

PURPOSE: Aim of this study was to investigate a dose-response relationship, dose-toxicity relationship, progression free survival (PFS) and overall survival (OS) in neuroendocrine tumour liver metastases (NELM) treated with holmium-166-microspheres radioembolization ([166Ho]-radioembolization). MATERIALS AND METHODS: Single center, retrospective study included patients with NELM that received [166Ho]-radioembolization with post-treatment SPECT/CT and CECT or MRI imaging for 3 months follow-up. Post-treatment SPECT/CT was used to calculate tumour (Dt) and whole liver healthy tissue (Dh) absorbed dose. Clinical and laboratory toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 5 at baseline and three-months follow-up. Response was determined according to RECIST 1.1. The tumour and healthy doses was correlated to lesion-based objective response and patient-based toxicity. Kaplan Meier analyses were performed for progression free survival (PFS) and overall survival (OS). RESULTS: Twenty-seven treatments in 25 patients were included, with a total of 114 tumours. Median follow-up was 14 months (3 - 82 months). Mean Dt in non-responders was 68 Gy versus 118 Gy in responders, p = 0.01. ROC analysis determined 86 Gy to have the highest sensitivity and specificity, resp. 83% and 81%. Achieving a Dt of ≥ 120 Gy provided the highest likelihood of response (90%) for obtaining response. Sixteen patients had grade 1-2 clinical toxicity and only one patient grade 3. No clear healthy liver dose-toxicity relationship was found. The median PFS was 15 months (95% CI [10.2;19.8]) and median OS was not reached. CONCLUSION: This study confirms the safety and efficacy of [166Ho]-radioembolization in NELM in a real-world setting. A clear dose-response relationship was demonstrated and future studies should aim at a Dt of ≥ 120 Gy, being predictive of response. No dose-toxicity relationship could be established.

Quantitative 166Ho-microspheres SPECT derived from a dual-isotope acquisition with 99mTc-colloid is clinically feasible.

PURPOSE: Accurate dosimetry is essential in radioembolization. To this purpose, an automatic protocol for healthy liver dosimetry based on dual isotope (DI) SPECT imaging, combining holmium-166 (166Ho)-microspheres, and technetium-99 m (99mTc)-colloid was developed: 166Ho-microspheres used as scout and therapeutic particles, and 99mTc-colloid to identify the healthy liver. DI SPECT allows for an automatic and accurate estimation of absorbed doses, introducing true personalized dosimetry. However, photon crosstalk between isotopes can compromise image quality. This study investigates the effect of 99mTc downscatter on 166Ho dosimetry, by comparing 166Ho-SPECT reconstructions of patient scans acquired before (166Ho-only) and after additional administration of 99mTc-colloid (166Ho-DI). METHODS: The 166Ho-only and 166Ho-DI scans were performed in short succession by injecting 99mTc-colloid on the scanner table. To compensate for 99mTc downscatter, its influence was accounted for in the DI image reconstruction using energy window-based scatter correction methods. The qualitative assessment was performed by independent blinded comparison by two nuclear medicine physicians assessing 65 pairs of SPECT/CT. Inter-observer agreement was tested by Cohen's kappa coefficient. For the quantitative analysis, two volumes of interest within the liver, VOITUMOR, and VOIHEALTHY were manually delineated on the 166Ho-only reconstruction and transferred to the co-registered 166Ho-DI reconstruction. Absorbed dose within the resulting VOIs, and in the lungs (VOILUNGS), was calculated based on the administered therapeutic activity. RESULTS: The qualitative assessment showed no distinct clinical preference for either 166Ho-only or 166Ho-DI SPECT (kappa = 0.093). Quantitative analysis indicated that the mean absorbed dose difference between 166Ho-DI and 166Ho-only was - 2.00 ± 2.84 Gy (median 27 Gy; p value < 0.00001), - 5.27 ± 8.99 Gy (median 116 Gy; p value = 0.00035), and 0.80 ± 1.08 Gy (median 3 Gy; p value < 0.00001) for VOIHEALTHY, VOITUMOR, and VOILUNGS, respectively. The corresponding Pearson's correlation coefficient between 166Ho-only and 166Ho-DI for absorbed dose was 0.97, 0.99, and 0.82, respectively. CONCLUSION: The DI protocol enables automatic dosimetry with undiminished image quality and accuracy. CLINICAL TRIALS: The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on 20 February 2014.

Simultaneous 166Ho/99mTc dual-isotope SPECT with Monte Carlo-based downscatter correction for automatic liver dosimetry in radioembolization.

BACKGROUND: Intrahepatic dosimetry is paramount to optimize radioembolization treatment accuracy using radioactive holmium-166 microspheres (166Ho). This requires a practical protocol that combines quantitative imaging of microsphere distribution with automated and robust delineation of the volumes of interest. To this end, we propose a dual isotope single photon emission computed tomography (SPECT) protocol based on 166Ho therapeutic microspheres and technetium-99 m (99mTc) stannous phytate, which accumulates in healthy liver tissue. This protocol may allow accurate and automatic estimation of tumor-absorbed dose and healthy liver-absorbed dose. The current study focuses on a Monte Carlo-based reconstruction framework that inherently corrects for scatter crosstalk between the 166Ho and 99mTc imaging. To demonstrate the feasibility of the method, it is evaluated with realistic phantom experiments and patient data. METHODS: The Utrecht Monte Carlo System (UMCS) was extended to include detailed modeling of crosstalk interactions between 99mTc and 166Ho. First, 99mTc images were reconstructed including energy window-based corrections for 166Ho downscatter. Next, 99mTc downscatter in the 81-keV 166Ho window was Monte Carlo simulated to allow quantitative reconstruction of the 166Ho images. The accuracy of the 99mTc-downscatter modeling was evaluated by comparing measurements with simulations. In addition, the ratio between 99mTc and 166Ho yielding the best 166Ho dose estimates was established and the quantitative accuracy was reported. RESULTS: Given the same level of activity, 99mTc contributes twice as many counts to the 81-keV window than 166Ho, and four times as many counts to the 140-keV window, applying a 166Ho/99mTc ratio of 5:1 yielded a high accuracy in both 166Ho and 99mTc reconstruction. Phantom experiments revealed that the accuracy of quantitative 166Ho activity recovery was reduced by 10% due to the presence of 99mTc. Twenty iterations (8 subsets) of the SPECT/CT reconstructions were considered feasible for clinical practice. Applicability of the proposed protocol was shown in a proof-of-concept case. CONCLUSION: A novel 166Ho/99mTc dual-isotope protocol for automatic dosimetry compensates accurately for downscatter and allows for the addition of 99mTc without compromising 166Ho SPECT image quality.

Characterization of a prototype MR-compatible Delta4 QA system in a 1.5 tesla MR-linac.

To perform patient plan quality assurance (QA) on a newly installed MR-linac (MRL) it is necessary to have an MR-compatible QA device. An MR compatible device (MR-Delta4) has been developed together with Scandidos AB (Uppsala, Sweden). The basic characteristics of the detector response, such as short-term reproducibility, dose linearity, field size dependency, dose rate dependency, dose-per-pulse dependency and angular dependency, were investigated for the clinical Delta4-PT as well as for the MR compatible version. All tests were performed with both devices on a conventional linac and the MR compatible device was tested on the MRL as well. No statistically significant differences were found in the short-term reproducibility (<0.1%), dose linearity (⩽0.5%), field size dependency (<2.0% for field sizes larger than 5 × 5 cm2), dose rate dependency (<1.0%) or angular dependency for any phantom/linac combination. The dose-per-pulse dependency (<0.8%) was found to be significantly different between the two devices. This difference can be explained by the fact that the diodes in the clinical Delta4-PT were irradiated with a much larger dose than the MR-Delta4-PT ones. The absolute difference between the devices (<0.5%) was found to be small, so no clinical impact is expected. For both devices, the results were consistent with the characteristics of the Delta4-PT device reported in the literature (Bedford et al 2009 Phys. Med. Biol. 54 N167-76; Sadagopan et al 2009 J. Appl. Clin. Med. Phys. 10 2928). We found that the characteristics of the MR compatible Delta4 phantom were found to be comparable to the clinically used one. Also, the found characteristics do not differ from the previously reported characteristics of the commercially available non-MR compatible Delta4-PT phantom. Therefore, the MR compatible Delta4 prototype was found to be safe and effective for use in the 1.5 tesla magnetic field of the Elekta MR-linac.

Impact of reconstruction parameters on quantitative I-131 SPECT.

Radioiodine therapy using I-131 is widely used for treatment of thyroid disease or neuroendocrine tumors. Monitoring treatment by accurate dosimetry requires quantitative imaging. The high energy photons however render quantitative SPECT reconstruction challenging, potentially requiring accurate correction for scatter and collimator effects. The goal of this work is to assess the effectiveness of various correction methods on these effects using phantom studies. A SPECT/CT acquisition of the NEMA IEC body phantom was performed. Images were reconstructed using the following parameters: (1) without scatter correction, (2) with triple energy window (TEW) scatter correction and (3) with Monte Carlo-based scatter correction. For modelling the collimator-detector response (CDR), both (a) geometric Gaussian CDRs as well as (b) Monte Carlo simulated CDRs were compared. Quantitative accuracy, contrast to noise ratios and recovery coefficients were calculated, as well as the background variability and the residual count error in the lung insert. The Monte Carlo scatter corrected reconstruction method was shown to be intrinsically quantitative, requiring no experimentally acquired calibration factor. It resulted in a more accurate quantification of the background compartment activity density compared with TEW or no scatter correction. The quantification error relative to a dose calibrator derived measurement was found to be <1%,-26% and 33%, respectively. The adverse effects of partial volume were significantly smaller with the Monte Carlo simulated CDR correction compared with geometric Gaussian or no CDR modelling. Scatter correction showed a small effect on quantification of small volumes. When using a weighting factor, TEW correction was comparable to Monte Carlo reconstruction in all measured parameters, although this approach is clinically impractical since this factor may be patient dependent. Monte Carlo based scatter correction including accurately simulated CDR modelling is the most robust and reliable method to reconstruct accurate quantitative iodine-131 SPECT images.

Frequency metrology in quantum degenerate helium: direct measurement of the 2 3S1 --> 2 1S0 transition.

Precision spectroscopy of simple atomic systems has refined our understanding of the fundamental laws of quantum physics. In particular, helium spectroscopy has played a crucial role in describing two-electron interactions, determining the fine-structure constant and extracting the size of the helium nucleus. Here we present a measurement of the doubly forbidden 1557-nanometer transition connecting the two metastable states of helium (the lowest energy triplet state 2 (3)S(1) and first excited singlet state 2 (1)S(0)), for which quantum electrodynamic and nuclear size effects are very strong. This transition is weaker by 14 orders of magnitude than the most predominantly measured transition in helium. Ultracold, submicrokelvin, fermionic (3)He and bosonic (4)He atoms are used to obtain a precision of 8 × 10(-12), providing a stringent test of two-electron quantum electrodynamic theory and of nuclear few-body theory.

Enhanced heat flow in the hydrodynamic collisionless regime.

We study the heat conduction of a cold, thermal cloud in a highly asymmetric trap. The cloud is axially hydrodynamic, but due to the asymmetric trap radially collisionless. By locally heating the cloud we excite a thermal dipole mode and measure its oscillation frequency and damping rate. We find an unexpectedly large heat conduction compared to the homogeneous case. The enhanced heat conduction in this regime is partially caused by atoms with a high angular momentum spiraling in trajectories around the core of the cloud. Since atoms in these trajectories are almost collisionless they strongly contribute to the heat transfer. We observe a second, oscillating hydrodynamic mode, which we identify as a standing wave sound mode.

Diagnosis and treatment of pustular disorders in the neonate.

The diagnosis of a pustular dermatosis occurring during the first months of life is usually based on clinical findings. However, some cases may require simple investigations including microscopic examination of pustular content, cultures, and skin biopsies. The main benign transient neonatal types of pustulosis include erythema toxicum neonatorum, infantile acropustulosis, transient neonatal pustular melanosis, and neonatal acne. The most common causes of infectious pustular skin lesions include bacterial infections, which may be initially localized (Staphylococcus aureus) or septicemic (with Listeria monocytogenes as the leading causitive agent); viral infections (herpes simplex, varicella-zoster, and cytomegalovirus infections); fungal infections (candidiasis); or parasitic disorders (scabies). The main objective of this article is to propose a systematic approach to pustular eruptions in the neonate. The need for investigating every neonate with pustules for an infectious disease is emphasized. The Tzanck smear, the Gram's stain, and a potassium hydroxide preparation are the most important quick diagnostic tests. The Tzanck smear is a very easy, rapid, and sensitive test for detection of a herpetic infection (multinucleated giant cells) as well as noninfectious pustular eruptions (eosinophils, neutrophils). Therefore the Tzanck smear should be the first test performed. Moreover, a Gram's stain and potassium hydroxide preparation should be performed in cases of neonatal pustular disorders to detect bacterial and fungal infections. The goal of this diagnostic approach is to spare a healthy neonate with a benign transient condition an invasive evaluation for sepsis, potentially harmful antibiotic therapy, and prolonged hospitalization, with its own inherent morbidity.

Airway responsiveness after a single dose of salmeterol and during four months of treatment in children with asthma.

BACKGROUND: Inhalation of a single dose of the long-acting beta 2-adrenoceptor agonist salmeterol protects against methacholine-induced airway obstruction and other bronchoconstricting stimuli for at least 12 hours. Hypothetically, twice daily dosing of salmeterol may result in continuous protection. OBJECTIVE: This study was designed to investigate the protective effect of a single dose of salmeterol and of continuous twice daily treatment on airway responsiveness to methacholine. METHODS: In a double- blind, parallel study, salmeterol 50 micrograms twice daily was compared with salbutamol 200 micrograms twice daily. Thirty children with mild asthma, who had little or no bronchial obstruction and were hyperresponsive to methacholine (PD20 < or = 150 micro g) were allocated to receive either salmeterol or salbutamol. Airway responsiveness was measured before study entry, 12 hours after a single dose of drug was given, and monthly during 4 months of daily treatment. Measurements were always performed at the same time of the day, 12 hours after the last dose of medication was administered. RESULTS: No significant differences in FEV 1 were found between treatments at any time point. PD20 significantly increased after the first dose of salmeterol was given (geometric mean, 100 micro g). Geometric mean PD20 values were significantly better during salmeterol treatment than during salbutamol treatment, 52 and 25 micro g, respectively (p = 0.005). CONCLUSION: The protection provided by salmeterol during maintenance treatment was less than that provided after the first dose (p <0.001). However, protection did not diminish during the 4-month treatment period and remained significant compared with baseline (p = 0.003).