Clinical [18F]FSPG Positron Emission Tomography Imaging Reveals Heterogeneity in Tumor-Associated System xc- Activity.

BACKGROUND: (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography/computed tomography (PET/CT) provides a readout of system xc- transport activity and has been used for cancer detection in clinical studies of different cancer types. As system xc- provides the rate-limiting precursor for glutathione biosynthesis, an abundant antioxidant, [18F]FSPG imaging may additionally provide important prognostic information. Here, we performed an analysis of [18F]FSPG radiotracer distribution between primary tumors, metastases, and normal organs from cancer patients. We further assessed the heterogeneity of [18F]FSPG retention between cancer types, and between and within individuals. METHODS: This retrospective analysis of prospectively collected data compared [18F]FSPG PET/CT in subjects with head and neck squamous cell cancer (HNSCC, n = 5) and non-small-cell lung cancer (NSCLC, n = 10), scanned at different institutions. Using semi-automated regions of interest drawn around tumors and metastases, the maximum standardized uptake value (SUVmax), SUVmean, SUV standard deviation and SUVpeak were measured. [18F]FSPG time-activity curves (TACs) for normal organs, primary tumors and metastases were subsequently compared to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT at 60 min post injection (p.i.). RESULTS: The mean administered activity of [18F]FSPG was 309.3 ± 9.1 MBq in subjects with NSCLC and 285.1 ± 11.3 MBq in those with HNSCC. The biodistribution of [18F]FSPG in both cohorts showed similar TACs in healthy organs from cancer patients. There was no statistically significant overall difference in the average SUVmax of tumor lesions at 60 min p.i. for NSCLC (8.1 ± 7.1) compared to HNSCC (6.0 ± 4.1; p = 0.29) for [18F]FSPG. However, there was heterogeneous retention between and within cancer types; the SUVmax at 60 min p.i. ranged from 1.4 to 23.7 in NSCLC and 3.1-12.1 in HNSCC. CONCLUSION: [18F]FSPG PET/CT imaging from both NSCLC and HNSCC cohorts showed the same normal-tissue biodistribution, but marked tumor heterogeneity across subjects and between lesions. Despite rapid elimination through the urinary tract and low normal-background tissue retention, the diagnostic potential of [18F]FSPG was limited by variability in tumor retention. As [18F]FSPG retention is mediated by the tumor's antioxidant capacity and response to oxidative stress, this heterogeneity may provide important insights into an individual tumor's response or resistance to therapy.

Is System xc- a Suitable Target for Tumour Detection and Response Assessment with Imaging?

System xc- is upregulated in cancer cells and can be imaged using novel radiotracers, most commonly with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid (18F-FSPG). The aim of this review was to summarise the use of 18F-FSPG in humans, explore the benefits and limitations of 18F-FSPG, and assess the potential for further use of 18F-FSPG in cancer patients. To date, ten papers have described the use of 18F-FSPG in human cancers. These studies involved small numbers of patients (range 1-26) and assessed the use of 18F-FSPG as a general oncological diagnostic agent across different cancer types. These clinical trials were contrasting in their findings, limiting the scope of 18F-FSPG PET/CT as a purely diagnostic agent, primarily due to heterogeneity of 18F-FSPG retention both between cancer types and patients. Despite these limitations, a potential further application for 18F-FSPG is in the assessment of early treatment response and prediction of treatment resistance. Animal models of cancer have shown that changes in 18F-FSPG retention following effective therapy precede glycolytic changes, as indicated by 18F-FDG, and changes in tumour volume, as measured by CT. If these results could be replicated in human clinical trials, imaging with 18F-FSPG PET/CT would offer an exciting route towards addressing the currently unmet clinical needs of treatment resistance prediction and early imaging assessment of therapy response.

Advanced Imaging for Detection of Foci of Infection in Staphylococcus aureus Bacteremia- Can a Scan Save Lives?

Bloodstream infection or sepsis is a common cause of mortality globally. Staphylococcus aureus (S. aureus) is of particular concern, through its ability to seed metastatic infections in almost any organ after entering the bloodstream (S. aureus bacteraemia), often without localising signs. A positive blood culture for S. aureus bacteria should lead to immediate and urgent identification of the cause. Failure to detect a precise focus of infection is associated with higher mortality, sometimes despite appropriate antibiotics. This is likely due to the limited ability to effectively target therapy in occult lesions. Early detection of foci of metastatic S. aureus infection is therefore key for optimal diagnosis and subsequent therapeutic management. 18F-FDG-PET/CT and MRI offer us invaluable tools in the localisation of foci of S. aureus infection. Crucially, they may identify unexpected foci at previously unsuspected locations in the body, for example vertebral osteomyelitis in the absence of back pain. S. aureus bloodstream infections are further complicated by their microbiological recurrence; 18F-FDG-PET/CT provide a means of localising, thus enabling source control. More evidence is emerging as to the utility of 18F-FDG-PET/CT in this setting, perhaps even to the point of reducing mortality. 18 F-FDG-PET/MRI may have a similar impact. The available evidence demonstrates a need to investigate the impact of 18F-FDG-PET/CT and MRI scanning in clinical management and outcomes of S. aureus infection further in a randomised prospective clinical trial.

Initial experience in staging primary oesophageal/gastro-oesophageal cancer with 18F-FDG PET/MRI.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) may improve cancer staging by combining sensitive cancer detection with high-contrast resolution and detail. We compared the diagnostic performance of 18F-FDG PET/MRI to 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for staging oesophageal/gastro-oesophageal cancer. Following ethical approval and informed consent, participants with newly diagnosed primary oesophageal/gastro-oesophageal cancer were enrolled. Exclusions included prior/concurrent malignancy. Following 324 ± 28 MBq 18F-FDG administration and 60-min uptake, PET/CT was performed, immediately followed by integrated PET/MRI from skull base to mid-thigh. PET/CT was interpreted by two dual-accredited nuclear medicine physicians and PET/MRI by a dual-accredited nuclear medicine physician/radiologist and cancer radiologist in consensus. Per-participant staging was compared with the tumour board consensus staging using the McNemar test, with statistical significance at 5%. RESULTS: Out of 26 participants, 22 (20 males; mean ± SD age 68.8 ± 8.7 years) completed 18F-FDG PET/CT and PET/MRI. Compared to the tumour board, the primary tumour was staged concordantly in 55% (12/22) with PET/MRI and 36% (8/22) with PET/CT; the nodal stage was concordant in 45% (10/22) with PET/MRI and 50% (11/22) with PET/CT. There was no statistical difference in PET/CT and PET/MRI staging performance (p > 0.05, for T and N staging). The staging of distant metastases was concordant with the tumour board in 95% (21/22) with both PET/MRI and PET/CT. Of participants with distant metastatic disease, PET/MRI detected additional metastases in 30% (3/10). CONCLUSION: In this preliminary study, compared to 18F-FDG PET/CT, 18F-FDG PET/MRI showed non-significant higher concordance with T-staging, but no difference with N or M-staging. Additional metastases detected by 18F-FDG PET/MRI may be of additive clinical value.

Occupational radiation exposure in doctors: an analysis of exposure rates over 25 years.

OBJECTIVES: Healthcare professionals' occupational exposure to ionising radiation may be increasing due to increasing use of imaging and image-guided intervention. This study aims to assess the occupational exposure of doctors over a 25-year period at an NHS teaching hospital. METHODS: Dosemeter measurements were collected prospectively from 1995 to 2019. Two retrospective analyses were performed over time (first including all measurements, second excluding "zero-dose" measurements), and by speciality. Group comparisons were undertaken using multilevel linear regression; a p-value <0.05 was deemed significant. RESULTS: 8,892 measurements (3,983 body, 1,514 collar, 649 eye, 2,846 hand), of which 3,350 were non-zero measurements (1,541 body, 883 collar, 155 eye, 771 hand), were included. Whole dataset analysis found a significant decrease in exposure for radiologists and cardiologists, as measured by body, hand and collar dosemeters over the last 25 years (p < 0.01 for all). The non-zero readings reflect the whole cohort analysis except in the case of eye dosemeters, which showed a significant decrease in exposure for cardiologists (p < 0.01), but a significant increase for radiologists and surgeons/anaesthetists (p < 0.01 for both). CONCLUSIONS: Whilst ionising radiation remains an occupational risk for doctors, the overall decreasing trend in occupational exposure is reassuring. However, a significant rise in eye dose for radiologists, surgeons and anaesthetists is concerning, and close monitoring is required to prevent future issues. ADVANCES IN KNOWLEDGE: This paper is one of few evaluating the occupational radiation exposure to doctors over a 25-year period, showing that although most dosemeter measurements reflect decreasing exposure, the increase in eye exposure warrants caution.

Optical Interrogation of Sympathetic Neuronal Effects on Macroscopic Cardiomyocyte Network Dynamics.

Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. We present approaches to study neuron-cardiomyocyte interactions involving optogenetic selective probing and all-optical electrophysiology to measure activity in an automated fashion. Here we demonstrate the utility of optical interrogation of sympathetic neurons and their effects on macroscopic cardiomyocyte network dynamics to address research targets such as the effects of adrenergic stimulation via the release of neurotransmitters, the effect of neuronal numbers on cardiac behavior, and the applicability of optogenetics in mechanistic in vitro studies. As arrhythmias are emergent behaviors that involve the coordinated activity of millions of cells, we image at macroscopic scales to capture complex dynamics. We show that neurons can both decrease and increase wave stability and re-entrant activity in culture depending on their induced activity-a finding that may help us understand the often conflicting results seen in experimental and clinical studies.

Measuring Limb Volume: Accuracy and Reliability of Tape Measurement Versus Perometer Measurement.

BACKGROUND: Accurate limb volume measurement is key in the assessment of outcomes in lymphedema microsurgery. There are two commonly used methods as follows: manual circumferential measurement (tape) or Perometer measurement. There are no data on the intra- and interclass correlation of either method, making it difficult to establish a gold standard of limb volume measurement. We aim to assess the intra- and interclass correlation of each method to establish the most appropriate method for clinical practice and future research studies, aiming to compare the accuracy and reliability of tape measurement as assessed against Perometer measurement. METHODS AND RESULTS: Student volunteers and experts (lymphedema practitioners) were each asked to perform repeat tape and Perometer measurements on the upper or lower limb of one healthy volunteer. Perometer measurements were globally more accurate than tape (average SE [Perometer]: 23.23 vs. 77.21 [tape]). For intraobserver reliability, experts outperformed students in all domains tested, with little difference in intraobserver reliability using tape or Perometer (average Cronbach's alpha 0.9597 [expert)] vs. 0.6033 [student]). CONCLUSIONS: We recommend that, for increased interobserver reliability, the Perometer provides a more reliable standard of limb volume measurement.

Do surgical interventions for limb lymphoedema reduce cellulitis attack frequency?

INTRODUCTION: Recurrent cellulitis is a frequent and challenging complication of lymphoedema. British Lymphology Society cellulitis guidelines state that decongestive lymphatic therapy reduces the frequency of cellulitis attacks, but do not mention the effect of surgical interventions. This systematic review aims to assess whether surgical interventions for lymphoedema reduce the frequency of attacks of cellulitis. MATERIALS AND METHODS: Embase, Medline, and the Cochrane database were searched for relevant articles from database inception to January 2016. Four hundred and thirty-six abstracts were retrieved. Studies were included which contained quantitative data on cellulitis incidence before and after a surgical intervention. Two independent reviewers applied selection criteria, selecting 27 papers for full text review. Two were unavailable in the UK from any source. RESULTS: A variety of surgical techniques were utilized in the 25 papers included: lymphaticovenous anastomosis, superficial-to-deep lymphaticolymphatic anastomosis, lymph node transfer, Charles procedure, muscle flap transfer, Homan's procedure, and subcutaneous tissue excision below skin flaps. Five studies combined techniques. One study compared the intervention to a control group (physical therapy). Cellulitis incidence was decreased following surgical intervention in 24/25 studies included. Eight had quantifiable reductions in cellulitis over a set follow-up period; in the other 16 preoperative incidence was not precisely defined. CONCLUSION: Surgery appears effective at reducing cellulitis incidence in lymphoedema. However, high quality evidence from randomized controlled trials is lacking. Future research should concentrate on comparison with control groups, for example compression alone versus compression with surgical intervention, in patients with lymphoedema and greater than two attacks of cellulitis per year.