[99mTc]-labelled anti-Programmed Death-Ligand 1 single-domain antibody SPECT/CT: a novel imaging biomarker for myocardial PD-L1 expression.

BACKGROUND: Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT. METHODS: Thoracic [99mTc]NM-01 SPECT/CT was performed in lung cancer patients (n = 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LVmax:BP) and (RVmax:BP) were measured. LVmax was compared to background skeletal muscle (musclemax). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Mean LVmax:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks (p = 0.42). Mean RVmax:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks (p = 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LVmax to musclemax 3.71 ± 0.77 vs 0.98 ± 0.20 (p < 0.001)) and at least twofold for the RV (LVmax to musclemax 2.49 ± 0.63 vs 0.98 ± 0.20 (p < 0.001)). There was excellent intra-rater reliability for LVmax:BP with ICC 0.99 (95% confidence interval 0.94-0.99, p < 0.001), mean bias -0.05 ± 0.14 (95% limits of agreement -0.32 to 0.21). There were no major adverse cardiovascular events or myocarditis during follow-up. CONCLUSION: This study is the first to report PD-L1 expression of the heart that can be quantified non-invasively without invasive myocardial biopsy, with high reliability and specificity. This technique can be applied to investigate myocardial PD-L1 expression in ICI-associated myocarditis and cardiomyopathies. Clinical trial registration PD-L1 Expression in Cancer (PECan) study (NCT04436406). https://clinicaltrials.gov/ct2/show/NCT04436406 June 18th, 2020.

Inter-rater and intra-rater agreement of [99mTc]-labelled NM-01, a single-domain programmed death-ligand 1 (PD-L1) antibody, using quantitative SPECT/CT in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors, including those against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), are routinely used to treat non-small cell lung cancer (NSCLC). PD-L1 is a validated prognostic and predictive immunohistochemical biomarker of anti-PD-1/PD-L1 therapy but displays temporospatial heterogeneity of expression. Non-invasive radiopharmaceutical techniques, including technetium-99m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT, have the potential to improve the predictive value of PD-L1 assessment. This study aims to determine the inter- and intra-rater agreement of the quantitative measurement of [99mTc]NM-01 SPECT/CT in NSCLC. METHODS: Participants (n = 14) with untreated advanced NSCLC underwent [99mTc]NM-01 SPECT/CT at baseline (n = 3) or at baseline plus 9-week follow-up (n = 11). [99mTc]NM-01 uptake (of primary lung, lymph node, thoracic and distant metastases, and healthy reference tissues) was measured using SUVmax and malignant lesion-to-blood pool ratios with Siemens xSPECT Broad Quantification software by three independent raters. Intraclass correlation coefficients (ICC) were calculated and Bland-Altman plot analysis performed to determine inter- and intra-rater agreement. RESULTS: There was excellent inter-rater agreement of manual freehand SUVmax scores of primary lung tumour (T; n = 25; ICC 1.00; 95% CI 0.99-1.00), individual lymph node metastases (LN; n = 56; ICC 0.97; 95% CI 0.95-0.98), thoracic metastases (ThMet; n = 9; ICC 0.94; 95% CI 0.83-0.99) and distant metastases (DisMet; n = 21; ICC 0.91; 95% CI 0.83-0.96). The inter-rater ICCs of tumour-to-blood pool (T:BP), LN:BP, ThMet:BP and DisMet:BP measures of [99mTc]NM-01 uptake also demonstrated good or excellent agreement. Manual freehand scoring of T, LN, ThMet, DisMet and their ratios using [99mTc]NM-01 SPECT/CT following a 28-day interval was consistent for all raters with good or excellent intra-rater agreement demonstrated (ICCs range 0.86-1.00). CONCLUSION: Quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC, using SUVmax of malignant primary or metastatic lesions and their ratios with healthy reference tissues, demonstrated good or excellent inter- and intra-rater agreement in this study. Further validation with ongoing and future larger cohort studies is now warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT04436406 (registered 18th June 2020; available at https://clinicaltrials.gov/ct2/show/NCT04436406 ) and NCT04992715 (registered 5th August 2021; available at https://clinicaltrials.gov/ct2/show/NCT04992715 ).

60 million years of glaciation in the Transantarctic Mountains.

The Antarctic continent reached its current polar location ~83 Ma and became shrouded by ice sheets ~34 Ma, coincident with dramatic global cooling at the Eocene-Oligocene boundary. However, it is not known whether the first Antarctic glaciers formed immediately prior to this or were present significantly earlier. Here we show that mountain glaciers were likely present in the Transantarctic Mountains during the Late Palaeocene (~60-56 Ma) and middle Eocene (~48-40 Ma). Temperate (warm-based) glaciers were prevalent during the Late Eocene (~40-34 Ma) and, in reduced numbers, during the Oligocene (~34-23 Ma), before larger, likely cold-based, ice masses (including ice sheets) dominated. Some temperate mountain glaciers were present during the Miocene Climatic Optimum (~15 Ma), before a widespread switch to cold-based glaciation. Our findings highlight the longevity of glaciation in Antarctica and suggest that glaciers were present even during the Early-Cenozoic greenhouse world.

Guidance on medical physics expert support for nuclear medicine.

The Ionising Radiation (Medical Exposure) Regulations require employers to appoint suitable medical physics experts (MPE) for nuclear medicine services, and they also define the areas where MPEs are required to provide advice and specify matters that they must contribute towards. Applications for employer licences under IR(ME)R require employers to specify the level of MPE support available and if this is provided by onsite MPEs or remotely. Assessment of these applications by the Administration of Radioactive Substances Advisory Committee (ARSAC) has highlighted variability in the levels of MPE support being provided for similar services across the UK. A working party including representatives from IPEM, ARSAC, BIR and BNMS was formed and has produced these recommendations on MPE support. Nuclear medicine services were divided into seven broad categories and MPE support for each category has been considered. However, some services that differ from the scenarios provided in this guidance may require different levels of MPE support. Positron emission tomography (PET)/CT and gamma camera imaging have been considered separately here, although it is recognised that both PET/CT and gamma cameras are often sited within the same department in many centres. The separation has been done for pragmatic purposes, as there are felt to be sufficient differences in the MPE role requirements. This guidance sets out recommendations for MPE support, and broader physics support, to run a safe nuclear medicine service and defines the responsibilities of these staff for a range of clinical nuclear medicine services. The recommendations on MPE support made are advice, but will assist employers in meeting regulatory requirements.

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia.

Cilia are evolutionarily highly conserved organelles with important functions in many organs. The extracellular component of the cilium protruding from the plasma membrane comprises an axoneme composed of microtubule doublets, arranged in a 9 + 0 conformation in primary cilia or 9 + 2 in motile cilia. These microtubules facilitate transport of intraflagellar cargoes along the axoneme. They also provide structural stability to the cilium, which may play an important role in sensory cilia, where signals are received from the movement of extracellular fluid. Post-translational modification of microtubules in cilia is a well-studied phenomenon, and acetylation on lysine 40 (K40) of alpha tubulin is prominent in cilia. It is believed that this modification contributes to the stabilization of cilia. Two classes of enzymes, histone acetyltransferases and histone deacetylases, mediate regulation of tubulin acetylation. Here we use a genetic approach, immunocytochemistry and behavioral tests to investigate the function of tubulin deacetylases in cilia in a zebrafish model. By mutating three histone deacetylase genes (Sirt2, Hdac6, and Hdac10), we identify an unforeseen role for Hdac6 and Sirt2 in cilia. As expected, mutation of these genes leads to increased acetylation of cytoplasmic tubulin, however, surprisingly it caused decreased tubulin acetylation in cilia in the developing eye, ear, brain and kidney. Cilia in the ear and eye showed elevated levels of mono-glycylated tubulin suggesting a compensatory mechanism. These changes did not affect the length or morphology of cilia, however, functional defects in balance was observed, suggesting that the level of tubulin acetylation may affect function of the cilium.

Use of zebrafish models to investigate rare human disease.

Rare diseases are collectively common and often extremely debilitating. Following the emergence of next-generation sequencing (NGS) technologies, the variants underpinning rare genetic disorders are being unearthed at an accelerating rate. However, many rare conditions lack effective treatments due to their poorly understood pathophysiology. There is therefore a growing demand for the development of novel experimental models of rare genetic diseases, so that potentially causative variants can be validated, pathogenic mechanisms can be investigated and therapeutic targets can be identified. Animal models of rare diseases need to be genetically and physiologically similar to humans, and well-suited to large-scale experimental manipulation, considering the vast number of novel variants that are being identified through NGS. The zebrafish has emerged as a popular model system for investigating these variants, combining conserved vertebrate characteristics with a capacity for large-scale phenotypic and therapeutic screening. In this review, we aim to highlight the unique advantages of the zebrafish over other in vivo model systems for the large-scale study of rare genetic variants. We will also consider the generation of zebrafish disease models from a practical standpoint, by discussing how genome editing technologies, particularly the recently developed clustered regularly interspaced repeat (CRISPR)/CRISPR-associated protein 9 system, can be used to model rare pathogenic variants in zebrafish. Finally, we will review examples in the literature where zebrafish models have played a pivotal role in confirming variant causality and revealing the underlying mechanisms of rare diseases, often with wider implications for our understanding of human biology.

Paradoxical cold conditions during the medieval climate anomaly in the Western Arctic.

In the Northern Hemisphere, most mountain glaciers experienced their largest extent in the last millennium during the Little Ice Age (1450 to 1850 CE, LIA), a period marked by colder hemispheric temperatures than the Medieval Climate Anomaly (950 to 1250 CE, MCA), a period which coincided with glacier retreat. Here, we present a new moraine chronology based on (36)Cl surface exposure dating from Lyngmarksbræen glacier, West Greenland. Consistent with other glaciers in the western Arctic, Lyngmarksbræen glacier experienced several advances during the last millennium, the first one at the end of the MCA, in ~1200 CE, was of similar amplitude to two other advances during the LIA. In the absence of any significant changes in accumulation records from South Greenland ice cores, we attribute this expansion to multi-decadal summer cooling likely driven by volcanic and/or solar forcing, and associated regional sea-ice feedbacks. Such regional multi-decadal cold conditions at the end of the MCA are neither resolved in temperature reconstructions from other parts of the Northern Hemisphere, nor captured in last millennium climate simulations.

Patterns, variants, artifacts, and pitfalls in conventional radionuclide bone imaging and SPECT/CT.

Bone scintigraphy is one of the most common investigations performed in nuclear medicine and is used routinely in the evaluation of patients with cancer for suspected bone metastases and in various benign musculoskeletal conditions. Innovations in equipment design and other advances, such as single-photon emission computed tomography (SPECT), positron emission tomography, positron emission tomography/computed tomography (CT), and SPECT/CT have been incorporated into the investigation of various musculoskeletal diseases. Bone scans frequently show high sensitivity but specificity, which is variable or limited. Some of the limited specificity can be partially addressed by a thorough knowledge and experience of normal variants and common patterns to avoid misinterpretation. In this review, we discuss the common patterns, variants, artifacts, and pitfalls in conventional radionuclide planar, SPECT, and hybrid bone (SPECT/CT) imaging.

Multislice SPECT/CT in benign and malignant bone disease: when the ordinary turns into the extraordinary.

Nuclear medicine has entered a new era of multimodality imaging. Dedicated multislice single-photon emission computed tomography/computed tomography (SPECT/CT) cameras are relatively new additions to the diagnostic armamentarium in nuclear medicine. The integration of SPECT and CT provides precise anatomical localization and may enable characterization of abnormalities identified on planar or SPECT imaging by providing structural information by CT. The evidence in support of SPECT/CT is rapidly amounting but still relatively limited. To date, studies have suggested improved diagnostic confidence and specificity in the diagnosis of bone pathology. The combination of functional information and anatomical localization has the potential to influence medical practice with newer imaging algorithms. This review presents the current evidence and potential indications of SPECT/CT bone imaging in the assessment of benign and malignant conditions.

A randomized double-blind study to assess the effects of silicic acid compared to placebo in patients with mild to moderate acne.

OBJECTIVE: To establish the efficacy and safety of silicic acid in comparison to placebo in patients with mild to moderate acne vulgaris. PATIENTS AND METHODS: Forty adult patients with facial acne vulgaris were randomized to silicic acid or placebo applied twice daily for 8 weeks. Efficacy was assessed by number of acne lesions, acne grade and sebum excretion rate (SER). Clinical safety and tolerance were also assessed and global assessments and psychological profile questionnaires were completed. RESULTS: There were no significant differences between silicic acid and placebo in the number of inflamed lesions (the primary efficacy variable). In contrast, silicic acid significantly reduced the number of non-inflamed lesions, total acne lesions and the acne grade after 8 weeks and SER over 4 weeks when compared with placebo. There were no significant differences between silicic acid and placebo in the responses to the questionnaires or the global assessments after 8 weeks. Silicic acid was well tolerated with few adverse events. CONCLUSIONS: Silicic acid may have a positive treatment effect on the non-inflammatory component of mild to moderate facial acne. These preliminary findings now need to be confirmed by similar studies.

Nuclear medicine: from photons to physiology.

Nuclear Medicine involves studying the time course of radioactive tracers and the physiological response of the body in vivo using external imaging devices. These devices are quantitative and can be used to assay tracer concentrations. This chapter briefly discusses the historical milieu, current state-of-the-art in terms of both single photon and positron tomography (SPECT and PET), and shows a semi-quantitative example of monitoring response to anti-cancer treatment with readily available instrumentation (a gamma camera) and radiopharmaceutical ([(18)F]-FDG). Nuclear Medicine is being increasingly utilised in drug discovery and development, and its role looks set to increase even further in the future.