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 ³S₁ and first excited singlet state 2 ¹S₀), 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 ³He and bosonic ⁴He 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.

Since its first suggestion as possible option for liver radioembolization treatment, the therapeutic isotope holmium-166 (¹⁶⁶Ho) caught the experts’ attention due to its imaging possibilities. Being not only a beta, but also a gamma emitter and a lanthanide, ¹⁶⁶Ho can be imaged using single-photon emission computed tomography and magnetic resonance imaging, respectively. Another advantage of ¹⁶⁶Ho is the possibility to perform the scout and treatment procedure with the same particle. This prospect paves the way to an individualized treatment procedure, gaining more control over dosimetry-based patient selection and treatment planning. In this review, an overview on ¹⁶⁶Ho liver radioembolization will be presented. The current clinical workflow, together with the most relevant clinical findings and the future prospective will be provided.

Purpose: Sentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [^99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs. Methods: A prospective within-patient evaluation study was designed to compare [^99mTc]Tc-tilmanocept with [^99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2–4 h post-injection. Results: The injection site’s remaining radioactivity was significantly lower for [^99mTc]Tc-tilmanocept (29.9%), compared with [^99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [^99mTc]Tc-tilmanocept (1.95%) compared with [^99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [^99mTc]Tc-tilmanocept (0.066) and [^99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [^99mTc]Tc-tilmanocept and [^99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [^99mTc]Tc-tilmanocept (0.57%) and [^99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [^99mTc]Tc-tilmanocept and [^99mTc]Tc-nanocolloid, respectively (p = 0.083). Conclusion: [^99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [^99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [^99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Before ¹⁶⁶Ho radioembolization, a small batch of the same type of microspheres is administered as a scout dose instead of the conventional ^99mTc-macroaggregated albumin (^99mTc-MAA). The ¹⁶⁶Ho scout dose provides a more accurate and precise lung shunt assessment. However, in contrast to ^99mTc-MAA, an unintended extrahepatic deposition of this β-emitting scout dose could inflict radiation damage, the extent of which we aimed to quantify in this study. Methods: All patients eligible for radioembolization in our institute between January 2011 and March 2014 were reviewed. Of the extrahepatic depositions of ^99mTc-MAA on SPECT, the amount and volume were measured. These were used to calculate the theoretic absorbed dose in the case a ¹⁶⁶Ho scout dose had been used. The extrahepatic activity was measured as the sum of all voxels of the deposition. Volumes were measured using a threshold technique including all voxels from the maximum voxel intensity up to a certain percentage. The threshold needed to obtain the true volume was studied in a phantom study. Results: In the phantom study, a threshold of 40% was found to overestimate the volume, with the consequence of underestimating the absorbed dose. Of 160 patients, 32 patients (34 cases) of extrahepatic deposition were identified. The depositions contained a median of 1.3% (range, 0.1%–19.5%) of the administered activity in a median volume of 6.8 mL (range, 1.1–42 mL). The use of a scout dose of 250 MBq of ¹⁶⁶Ho microspheres in these cases would theoretically have resulted in a median absorbed dose of 6.0 Gy (range, 0.9–374 Gy). The dose exceeded a limit of 49 Gy (reported in 2013) in 2 of 34 cases (5.9%; 95% confidence interval, 0.7%–20.1%) or 2 of 160 (1.3%; 95% confidence interval, 0.1%–4.7%) of all patients. In these 2 patients with a large absorbed dose (112 and 374 Gy), the culprit vessel was identified in 1 case. Conclusion: Extrahepatic deposition of a ¹⁶⁶Ho scout dose seems to be theoretically safe in most patients. Its safety in clinical practice is being evaluated in ongoing clinical trials.

Radiation pneumonitis is a rare but possibly fatal side effect of Yttrium-90 (⁹⁰Y) radioembolization. It may occur 1 to 6 months after therapy, in case a significant part of the ⁹⁰Y microspheres shunt to the lungs. In current clinical practice, a predicted value of lung dose greater than 30Gy is considered a criterion to exclude patients from treatment. However, contrasting findings regarding the occurrence of radiation pneumonitis and lung dose were previously reported in literature. In this study, the relationship between the lung dose value and the eventual occurrence of radiation pneumonitis after ⁹⁰Y radioembolization was investigated. Methods: A total of 317 ⁹⁰Y liver radioembolization procedures performed during an 8-years period (Feb.2012–Sep.2020) were retrospectively analyzed. Predicted lung mean dose using ^99mTc-MAA planar scintigraphy (LMD_MAA) acquired during the planning phase and left lung mean dose (LMD_Y-90) using the ⁹⁰Y PET/CT acquired after the treatment were calculated. For the lung dose computation, it was chosen to use the left lung as representative lung volume, to compensate for the scatter from the liver moving in the cranial-caudal direction due to breathing and mainly affecting the right lung. Results: Two hundred and seventy-two patients underwent ⁹⁰Y procedures, of which 63% performed with glass microspheres and 37% with resin microspheres. Median injected activity was 1974MBq (range: 242-9538MBq). Median LMD_MAA was 3.5Gy (range: 0.2–89.0Gy). For 14 procedures LMD_MAA was >30Gy. Median LMD_Y-90 was 1Gy (range: 0.0–22.1Gy). No patients had a LMD_Y-90 >30Gy. Of the three patients with a LMD_Y-90 >12Gy, two patients (LMD_Y-90 = 22.1Gy, LMD_MAA = 89Gy and LMD_Y-90 = 17.7Gy, LMD_MAA = 34.1Gy, respectively) developed radiation pneumonitis and consequently died. A third patient with a LMD_Y-90 equal to 18.4Gy (LMD_MAA = 29.1Gy) died 2 months after treatment, before imaging evaluation, due to progressive disease. Conclusion: The occurrence of radiation pneumonitis as a consequence of lung shunt following ⁹⁰Y radioembolization is rare (<1 %). No radiation pneumonitis developed in cases with a measured LMD_Y-90 lower than 12Gy.

Background: High activities of holmium-166 (¹⁶⁶Ho)–labeled microspheres are used for therapeutic radioembolization, ideally directly followed by SPECT imaging for dosimetry purposes. The resulting high-count rate potentially impacts dead time, affecting the image quality and dosimetric accuracy. This study assesses gamma camera performance and SPECT image quality at high ¹⁶⁶Ho activities of several GBq. To this purpose, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with ¹⁶⁶Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10:1. Multiple SPECT/CT scans were acquired over a range of activities up to 2.7 GBq. Images were reconstructed using a commercially available protocol incorporating attenuation and scatter correction. Dead time effects were assessed from the observed count rate in the photopeak (81 keV, 15% width) and upper scatter (118 keV, 12% width) window. Post reconstruction, each image was scaled with an individual conversion factor to match the known total activity in the phantom at scanning time. The resulting activity concentration was measured in the tumors and non-tumorous liver. The image quality as a function of activity was assessed by a visual check of the absence of artifacts by a nuclear medicine physician. The apparent lung shunt fraction (nonzero due to scatter) was estimated on planar and SPECT images. Results: A 20% count loss due to dead time was observed around 0.7 GBq in the photopeak window. Independent of the count losses, the measured activity concentration was up to 100% of the real value for non-tumorous liver, when reconstructions were normalized to the known activity at scanning time. However, for tumor spheres, activity concentration recovery was ~80% at the lowest activity, decreasing with increasing activity in the phantom. Measured lung shunt fractions were relatively constant over the considered activity range. Conclusions: At high ¹⁶⁶Ho count rate, all images, visually assessed, presented no artifacts, even at considerable dead time losses. A quantitative evaluation revealed the possibility of reliable dosimetry within the healthy liver, as long as a post-reconstruction scaling to scanning activity is applied. Reliable tumor dosimetry, instead, remained hampered by the dead time.