First-in-human study of a novel cell death tracer [99mTc]Tc-Duramycin: safety, biodistribution and radiation dosimetry in healthy volunteers.

BACKGROUND: Imaging of cell death can provide an early indication of treatment response in cancer. [99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [99mTc]Tc-Duramycin in healthy human volunteers. RESULTS: Six healthy volunteers (3 males, 3 females) were injected intravenously with [99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo 99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 µGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85-4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal. CONCLUSION: [99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [99mTc]Tc-Duramycin for clinical treatment response evaluation. TRIAL REGISTRATION: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640 .

Positron emission tomography-magnetic resonance imaging as a research tool in musculoskeletal conditions.

Compared to positron emission tomography/computed tomography (PET/CT), the uptake of PET- magnetic resonance imaging (MRI) has been slow, even more so in clinical practice compared to the (pre-)clinical research setting. However, for applications in musculoskeletal (MSK) research, the combination of PET and MRI into a single modality offers attractive advantages over other imaging modalities. Most importantly, MRI has exquisite soft-tissue detail without the use of contrast agents or ionizing radiation, superior bone marrow visualization, and an extensive spectrum of distinct multiparametric assessment methods. In the preclinical setting, the introduction of PET inserts for small-animal MRI machines has proven to be a successful concept in bringing this technology to the lab. Initial hurdles in quantification have been mainly overcome in this setting. In parallel, a promising range of radiochemistry techniques has been developed to create multimodality probes that offer the possibility of simultaneously querying different metabolic pathways. Not only will these applications help in elucidating disease mechanisms, but they can also facilitate drug development. The clinical applications of PET/MRI in MSK are still limited, but encouraging initial results with novel radiotracers suggest a high potential for use in various MSK conditions, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and inflammation and infection. Further innovations will be required to bring down the cost of PET/MRI to justify a broader clinical implementation, and remaining issues with quality control and standardization also need to be addressed. Nevertheless, PET/MRI is a powerful platform for MSK research with distinct qualities that are not offered by other techniques.

Absolute Quantification in Diagnostic SPECT/CT: The Phantom Premise.

The application of absolute quantification in SPECT/CT has seen increased interest in the context of radionuclide therapies where patient-specific dosimetry is a requirement within the European Union (EU) legislation. However, the translation of this technique to diagnostic nuclear medicine outside this setting is rather slow. Clinical research has, in some examples, already shown an association between imaging metrics and clinical diagnosis, but the applications, in general, lack proper validation because of the absence of a ground truth measurement. Meanwhile, additive manufacturing or 3D printing has seen rapid improvements, increasing its uptake in medical imaging. Three-dimensional printed phantoms have already made a significant impact on quantitative imaging, a trend that is likely to increase in the future. In this review, we summarize the data of recent literature to underpin our premise that the validation of diagnostic applications in nuclear medicine using application-specific phantoms is within reach given the current state-of-the-art in additive manufacturing or 3D printing.

The clinical effectiveness of reconstructing 18F-sodium fluoride PET/CT bone using Bayesian penalized likelihood algorithm for evaluation of metastatic bone disease in obese patients.

OBJECTIVE: A new Bayesian penalized likelihood reconstruction algorithm for positron emission tomography (PET) (Q.Clear) is now in clinical use for fludeoxyglucose (FDG) PET/CT. However, experience with non-FDG tracers and in special patient populations is limited. This pilot study aims to compare Q.Clear to standard PET reconstructions for 18F sodium fluoride (18F-NaF) PET in obese patients. METHODS: 30 whole body 18F-NaF PET/CT scans (10 patients with BMI 30-40 Kg/m2 and 20 patients with BMI >40 Kg/m2) and a NEMA image quality phantom scans were analyzed using ordered subset expectation maximization (OSEM) and Q.Clear reconstructions methods with B400, 600, 800 and 1000. The images were assessed for overall image quality (IQ), noise level, background soft tissue, and lesion detectability, contrast recovery (CR), background variability (BV) and contrast-to-noise ratio (CNR) for both algorithms. RESULTS: CNR for clinical cases was higher for Q.Clear than OSEM (p < 0.05). Mean CNR for OSEM was (21.62 ± 8.9), and for Q.Clear B400 (31.82 ± 14.6), B600 (35.54 ± 14.9), B800 (39.81 ± 16.1), and B1000 (40.9 ± 17.8). As the ß value increased the CNR increased in all clinical cases. B600 was the preferred ß value for reconstruction in obese patients. The phantom study showed Q.Clear reconstructions gave lower CR and lower BV than OSEM. The CNR for all spheres was significantly higher for Q.Clear (independent of ß) than OSEM (p < 0.05), suggesting superiority of Q.Clear. CONCLUSION: This pilot clinical study shows that Q.Clear reconstruction algorithm improves overall IQ of 18F-NaF PET in obese patients. Our clinical and phantom measurement results demonstrate improved CNR and reduced BV when using Q.Clear. A ß value of 600 is preferred for reconstructing 18F-NaF PET/CT with Q.Clear in obese patients. ADVANCES IN KNOWLEDGE: 18F-NaF PET/CT is less susceptible to artifacts induced by body habitus. Bayesian penalized likelihood reconstruction with18F-NaF PET improves overall IQ in obese patients.

Quality Assessment in FDG-PET/CT Imaging of Head-and-Neck Cancer: One Home Run Is Better Than Two Doubles.

2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is indicated in head-and-neck cancer for the initial workup when clinically indicated (e. g., large tumors, clinically positive neck, cervical adenopathy from an unknown primary, etc.), for the assessment of treatment response 12 weeks after completion of (chemo)radiotherapy, and during follow-up when there is suspicion of relapse. The successful implementation of FDG-PET/CT in routine clinical practice requires an in-depth understanding of the recent advances in physics and engineering that have significantly improved the imaging capabilities of PET/CT scanners (e.g., digital silicon photomultipliers, point-spread function modeling, and time-of-flight, and Bayesian penalized likelihood reconstruction). Moreover, a coordinated harmonization effort from professional societies (e.g., EANM) and international bodies (e.g., IAEA) has resulted in the creation of quality assurance frameworks (e.g., QUANUM, EARL, GMP) and guidelines that collectively cover the entire spectrum from tracer production, hardware calibration, patient preparation, and scan acquisition, to image interpretation (e.g., PERCIST, Hopkins criteria). The ultimate goal is to standardize the PET/CT technique and to guarantee accurate and reproducible imaging results for every patient. This review summarizes the recent technical breakthroughs in PET/CT scan design and describes the existing quality assessment frameworks with a focus on applications in head-and-neck cancer. Strict adherence to these harmonization efforts will enable leveraging the full potential of PET/CT and translate the proven benefits of this technique into tangible improvements in outcome for patients with head-and-neck cancer in routine clinical care.

SPECT/CT: Standing on the Shoulders of Giants, It Is Time to Reach for the Sky!

Twenty years ago, SPECT/CT became commercially available, combining the strengths of both techniques: the diagnostic sensitivity of SPECT and the anatomic detail of CT. Other benefits initially included attenuation correction of SPECT reconstructions, ultimately evolving to correction techniques that would enable absolute tracer uptake quantification. Recent developments in SPECT hardware include solid-state digital systems with higher sensitivity and resolution, using novel collimator designs based on tungsten. Similar advances in CT technology have been introduced in hybrid SPECT/CT systems, replacing low-end x-ray tubes with high-end multislice CT scanners equipped with iterative reconstruction, metal artifact reduction algorithms, and dual-energy capabilities. More recently, the design of whole-body SPECT/CT systems has taken another major leap with the introduction of a ring-shaped gantry equipped with multiple movable detectors surrounding the patient. These exciting developments have fueled efforts to develop novel SPECT radiopharmaceuticals, creating new chelators and prosthetic groups for radiolabeling. Innovative SPECT radionuclide pairs have now become available for radiolabeling with the potential for use as theranostic agents. The growth of precision medicine and the associated need for accurate radionuclide treatment dosimetry will likely drive the use of SPECT/CT in the near future. In addition, expanding clinical applications of SPECT/CT in other areas such as orthopedics offer exciting opportunities. Although it is true that the SPECT/CT ecosystem has seen several challenges during its development over the past 2 decades, it is now a feature-rich and mature tool ready for clinical prime time.

Cryptic speciation in Protoceratium reticulatum (Dinophyceae): Evidence from morphological, molecular and ecophysiological data.

The cosmopolitan, potentially toxic dinoflagellate Protoceratium reticulatum possesses a fossilizable cyst stage which is an important paleoenvironmental indicator. Slight differences in the internal transcribed spacer ribosomal DNA (ITS rDNA) sequences of P. reticulatum have been reported, and both the motile stage and cyst morphology of P. reticulatum display phenotypic plasticity, but how these morpho-molecular variations are related with ecophysiological preferences is unknown. Here, 55 single cysts or cells were isolated from localities in the Northern (Arctic to subtropics) and Southern Hemispheres (Chile and New Zealand), and in total 34 strains were established. Cysts and/or cells were examined with light microscopy and/or scanning electron microscopy. Large subunit ribosomal DNA (LSU rDNA) and/or ITS rDNA sequences were obtained for all strains/isolates. All strains/isolates of P. reticulatum shared identical LSU sequences except for one strain from the Mediterranean Sea that differs in one position, however ITS rDNA sequences displayed differences at eight positions. Molecular phylogeny was inferred using maximum likelihood and Bayesian inference based on ITS rDNA sequences. The results showed that P. reticulatum comprises at least three ribotypes (designated as A, B, and C). Ribotype A included strains from the Arctic and temperate areas, ribotype B included strains from temperate regions only, and ribotype C included strains from the subtropical and temperate areas. The average ratios of process length to cyst diameter of P. reticulatum ranged from 15% in ribotype A, 22% in ribotype B and 17% in ribotype C but cyst size could overlap. Theca morphology was indistinguishable among ribotypes. The ITS-2 secondary structures of ribotype A displayed one CBC (compensatory change on two sides of a helix pairing) compared to ribotypes B and C. Growth response of one strain from each ribotype to various temperatures was examined. The strains of ribotypes A, B and C exhibited optimum growth at 15 °C, 20 °C and 20-25 °C, respectively, thus corresponding to cold, moderate and warm ecotypes. The profiles of yessotoxins (YTXs) were examined for 25 strains using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The parent compound yessotoxin (YTX) was produced by strains of ribotypes A and B, but not by ribotype C strains, which only produced the structural variant homoyessotoxin (homoYTX). Our results support the notion that there is significant intra-specific variability in Protoceratium reticulatum and the biogeography of the different ribotypes is consistent with specific ecological preferences.

Quantitative radionuclide imaging of bone metastases.

By improving the localization of foci of pathological tracer uptake and offering information on their computed tomography (CT) morphology, single photon emission computed tomography (SPECT)/CT hybrid imaging has considerably improved the diagnostic accuracy of skeletal scintigraphy. SPECT/CT also has the potential to measure tracer uptake in vivo in absolute units. The present article reviews the methodology for and the potential clinical impact of quantitative skeletal scintigraphy.

The potential of sedimentary ancient DNA for reconstructing past sea ice evolution.

Sea ice is a crucial component of the Arctic climate system, yet the tools to document the evolution of sea ice conditions on historical and geological time scales are few and have limitations. Such records are essential for documenting and understanding the natural variations in Arctic sea ice extent. Here we explore sedimentary ancient DNA (aDNA), as a novel tool that unlocks and exploits the genetic (eukaryote) biodiversity preserved in marine sediments specifically for past sea ice reconstructions. Although use of sedimentary aDNA in paleoceanographic and paleoclimatic studies is still in its infancy, we use here metabarcoding and single-species quantitative DNA detection methods to document the sea ice conditions in a Greenland Sea marine sediment core. Metabarcoding has allowed identifying biodiversity changes in the geological record back to almost ~100,000 years ago that were related to changing sea ice conditions. Detailed bioinformatic analyses on the metabarcoding data revealed several sea-ice-associated taxa, most of which previously unknown from the fossil record. Finally, we quantitatively traced one known sea ice dinoflagellate in the sediment core. We show that aDNA can be recovered from deep-ocean sediments with generally oxic bottom waters and that past sea ice conditions can be documented beyond instrumental time scales. Our results corroborate sea ice reconstructions made by traditional tools, and thus demonstrate the potential of sedimentary aDNA, focusing primarily on microbial eukaryotes, as a new tool to better understand sea ice evolution in the climate system.

On the causes of Arctic sea ice in the warm Early Pliocene.

Scattered and indirect evidence suggests that sea ice occurred as far south as the Iceland Sea during the Early Pliocene, when the global climate was warmer than present. However, conclusive evidence as well as potential mechanisms governing sea ice occurrence outside the Arctic Ocean during a time with elevated greenhouse gas concentrations are still elusive. Here we present a suite of organic biomarkers and palynological records from the Iceland Sea and Yermak Plateau. We show that sea ice appeared as early as ~4.5 Ma in the Iceland Sea. The sea ice either occurred seasonally or was transported southward with the East Greenland Current. The Yermak Plateau mostly remained free of sea ice and was influenced dominantly by Atlantic water. From ~4.0 Ma, occurrence of extended sea ice conditions at both the Yermak Plateau and Iceland Sea document a substantial expansion of sea ice in the Arctic. The expansion occurred contemporaneous with increased northward heat and moisture transport in the North Atlantic region, which likely led to a fresher Arctic Ocean that favors sea ice formation. This extensive sea ice cover along the pathway of the East Greenland Current gradually isolated Greenland from warmer Atlantic water in the Late Pliocene, providing a positive feedback for ice sheet expansion in Greenland.

Early Pliocene onset of modern Nordic Seas circulation related to ocean gateway changes.

The globally warm climate of the early Pliocene gradually cooled from 4 million years ago, synchronous with decreasing atmospheric CO2 concentrations. In contrast, palaeoceanographic records indicate that the Nordic Seas cooled during the earliest Pliocene, before global cooling. However, a lack of knowledge regarding the precise timing of Nordic Seas cooling has limited our understanding of the governing mechanisms. Here, using marine palynology, we show that cooling in the Nordic Seas was coincident with the first trans-Arctic migration of cool-water Pacific mollusks around 4.5 million years ago, and followed by the development of a modern-like Nordic Seas surface circulation. Nordic Seas cooling precedes global cooling by 500,000 years; as such, we propose that reconfiguration of the Bering Strait and Central American Seaway triggered the development of a modern circulation in the Nordic Seas, which is essential for North Atlantic Deep Water formation and a precursor for more widespread Greenland glaciation in the late Pliocene.

Northern hemisphere glaciation during the globally warm early Late Pliocene.

The early Late Pliocene (3.6 to ∼3.0 million years ago) is the last extended interval in Earth's history when atmospheric CO2 concentrations were comparable to today's and global climate was warmer. Yet a severe global glaciation during marine isotope stage (MIS) M2 interrupted this phase of global warmth ∼3.30 million years ago, and is seen as a premature attempt of the climate system to establish an ice-age world. Here we propose a conceptual model for the glaciation and deglaciation of MIS M2 based on geochemical and palynological records from five marine sediment cores along a Caribbean to eastern North Atlantic transect. Our records show that increased Pacific-to-Atlantic flow via the Central American Seaway weakened the North Atlantic Current and attendant northward heat transport prior to MIS M2. The consequent cooling of the northern high latitude oceans permitted expansion of the continental ice sheets during MIS M2, despite near-modern atmospheric CO2 concentrations. Sea level drop during this glaciation halted the inflow of Pacific water to the Atlantic via the Central American Seaway, allowing the build-up of a Caribbean Warm Pool. Once this warm pool was large enough, the Gulf Stream-North Atlantic Current system was reinvigorated, leading to significant northward heat transport that terminated the glaciation. Before and after MIS M2, heat transport via the North Atlantic Current was crucial in maintaining warm climates comparable to those predicted for the end of this century.