Fever of unknown origin in pediatrics: role of nuclear medicine.

Fever of unknown origin (FUO) is a debated issue in numerous scientific studies in adult patients with a not jet-defined workflow in a clinical and diagnostic setting. Few works are published about pediatric patients even if FUO represents a challenging, not infrequent scenario in hospital and outpatient recovery. The fever might be the onset symptom of a transient mild infection or the beginning of a more difficult-to-diagnose and serious pathological condition. In the adult workflow 18FDG PET-CT is nowadays playing a relevant role, considering the limited spread of conventional 99mTc-HMPAO-White Blood Cells scintigraphy. It represents a robust tool for diagnosing the eventual site of infection, but it is limited by procedural complexity and long duration, up to 24 hours. The WBC-scintigraphy is also not suitable for children, only for young adults or adolescents, considering the relevant blood sample entity and the procedural risk for sensitive subjects. The most assessed clinical and diagnostic know-how on Pediatric FUO are summarized and a synthetic flow-chard is presented to support the clinical management and to choose the best diagnostic pathway.

Clinical Evaluation of Deep Learning for Tumor Delineation on 18F-FDG PET/CT of Head and Neck Cancer.

Artificial intelligence (AI) may decrease 18F-FDG PET/CT-based gross tumor volume (GTV) delineation variability and automate tumor-volume-derived image biomarker extraction. Hence, we aimed to identify and evaluate promising state-of-the-art deep learning methods for head and neck cancer (HNC) PET GTV delineation. Methods: We trained and evaluated deep learning methods using retrospectively included scans of HNC patients referred for radiotherapy between January 2014 and December 2019 (ISRCTN16907234). We used 3 test datasets: an internal set to compare methods, another internal set to compare AI-to-expert variability and expert interobserver variability (IOV), and an external set to compare internal and external AI-to-expert variability. Expert PET GTVs were used as the reference standard. Our benchmark IOV was measured using the PET GTV of 6 experts. The primary outcome was the Dice similarity coefficient (DSC). ANOVA was used to compare methods, a paired t test was used to compare AI-to-expert variability and expert IOV, an unpaired t test was used to compare internal and external AI-to-expert variability, and post hoc Bland-Altman analysis was used to evaluate biomarker agreement. Results: In total, 1,220 18F-FDG PET/CT scans of 1,190 patients (mean age ± SD, 63 ± 10 y; 858 men) were included, and 5 deep learning methods were trained using 5-fold cross-validation (n = 805). The nnU-Net method achieved the highest similarity (DSC, 0.80 [95% CI, 0.77-0.86]; n = 196). We found no evidence of a difference between expert IOV and AI-to-expert variability (DSC, 0.78 for AI vs. 0.82 for experts; mean difference of 0.04 [95% CI, -0.01 to 0.09]; P = 0.12; n = 64). We found no evidence of a difference between the internal and external AI-to-expert variability (DSC, 0.80 internally vs. 0.81 externally; mean difference of 0.004 [95% CI, -0.05 to 0.04]; P = 0.87; n = 125). PET GTV-derived biomarkers of AI were in good agreement with experts. Conclusion: Deep learning can be used to automate 18F-FDG PET/CT tumor-volume-derived imaging biomarkers, and the deep-learning-based volumes have the potential to assist clinical tumor volume delineation in radiation oncology.

Potential Clinical Impact of LAFOV PET/CT: A Systematic Evaluation of Image Quality and Lesion Detection.

We performed a systematic evaluation of the diagnostic performance of LAFOV PET/CT with increasing acquisition time. The first 100 oncologic adult patients referred for 3 MBq/kg 2-[18F]fluoro-2-deoxy-D-glucose PET/CT on the Siemens Biograph Vision Quadra were included. A standard imaging protocol of 10 min was used and scans were reconstructed at 30 s, 60 s, 90 s, 180 s, 300 s, and 600 s. Paired comparisons of quantitative image noise, qualitative image quality, lesion detection, and lesion classification were performed. Image noise (n = 50, 34 women) was acceptable according to the current standard of care (coefficient-of-varianceref < 0.15) after 90 s and improved significantly with increasing acquisition time (PB < 0.001). The same was seen in observer rankings (PB < 0.001). Lesion detection (n = 100, 74 women) improved significantly from 30 s to 90 s (PB < 0.001), 90 s to 180 s (PB = 0.001), and 90 s to 300 s (PB = 0.002), while lesion classification improved from 90 s to 180 s (PB < 0.001), 180 s to 300 s (PB = 0.021), and 90 s to 300 s (PB < 0.001). We observed improved image quality, lesion detection, and lesion classification with increasing acquisition time while maintaining a total scan time of less than 5 min, which demonstrates a potential clinical benefit. Based on these results we recommend a standard imaging acquisition protocol for LAFOV PET/CT of minimum 180 s to maximum 300 s after injection of 3 MBq/kg 2-[18F]fluoro-2-deoxy-D-glucose.

Long-Term Follow-Up of Thyroid Incidentalomas Visualized with 18F-Fluorodeoxyglucose Positron Emission Tomography-Impact of Thyroid Scintigraphy in the Diagnostic Work-Up.

Our objective was to evaluate the frequency of malignancy in incidental thyroidal uptake on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a cohort of Danish patients, and furthermore to evaluate the impact of thyroid scinti-graphy in the diagnostic work-up. All whole-body PET/CT reports from 1 January 2010 to 31 December 2013 were retrospectively reviewed and further analyzed if visually increased thyroidal FDG uptake was reported. Patient electronic files were searched for further thyroid evaluation. Of 13,195 18F-FDG-PET/CT scans in 9114 patients, 312 PET/CT reports mentioned incidental thyroid FDG-uptake, and 279 patients were included in the study (3.1%). The thyroid was further investigated in 137 patients (49%), and 75 patients underwent thyroid scintigraphy. A total of 57 patients had a thyroid biopsy and 21 proceeded to surgery. Surgical specimens displayed malignancy in 10 cases, and one thyroid malignancy was found by autopsy. Hence, 11 patients were diagnosed with thyroid malignancies among 279 patients with incidental thyroid 18F-FDG uptake (3.9%). In 34 patients, a biopsy was avoided due to the results of the thyroid scintigraphy. We conclude that patients with thyroid incidentalomas can benefit from further diagnostic work-up including a thyroid scintigraphy.

Planar scan vs. SPECT/low-dose CT for estimating split renal function by 99mTc-DMSA scintigraphy in children.

In the present study, we compared estimates of split renal function (SRF) in paediatric patients of various diagnostic subgroups by 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy using either geometric mean (GM) based on planar scans or a volume of interest (VOI)-based analysis on single photon emission tomography combined with low-dose CT (SPECT/ldCT). Two experienced physicians blinded to patient diagnosis retrospectively analysed all paediatric 99mTc-DMSA scintigraphies that were conducted in our department between 2011 and 2016 and which included both a planar scan and SPECT/ldCT. All scintigraphies were performed on either a Phillips Precedence 16 slice CT or a Siemens Symbia 16 slice CT. SRF was estimated from planar scintigraphy using the geometric mean (GM), while the VOI-based analysis (VBA) was used for kidney segmentation on SPECT/ldCT. RESULTS: A total of 68 scintigraphies were included. A Bland-Altman plot-based analysis showed a bias for SRF of 2.1% with limits of agreement from - 7.5 to + 11.7% for the whole data set but showed larger differences between the two methods outside the normal range of 45-55%. In the GM-based SRF analyses, 29 cases were found to be outside the normal range, and in seven of these, VBA showed normal SRF. In the remaining 39 cases, VBA showed an abnormal SRF in only one case. CONCLUSION: Approximately a quarter of planar DMSA scintigraphies that show an abnormal SRF in paediatric patients may be normal when assessed by SPECT/ldCT, which likely reflects underestimation of the kidney with the poorest function when assessed by GM due to the lack of attenuation correction. Planar scans that show an abnormal SRF in paediatric patients should thus preferably be supplemented by SPECT/ldCT.

PPARG Pro12Ala Ala carriers exhibit greater improvements in peripheral insulin sensitivity in response to 12 weeks of aerobic exercise training.

The Ala allele of PPARG Pro12Ala ( rs1801282 ) is associated with greater improvements to the glucose metabolism in exercise studies, but whether this extends to peripheral insulin sensitivity is unknown. Our objective was to investigate the effect of PPARG Pro12Ala on exercise-induced changes in peripheral insulin sensitivity. A total of 124 (91 Pro homozygotes and 33 Ala carriers) previously physically inactive healthy young men and women with overweight or class 1 obesity who completed a 12 wk aerobic exercise intervention were included in the analysis. All participants underwent a hyperinsulinemic euglycemic clamp before and after the 12 wk intervention. The prescribed exercise frequency was 5-7 days/wk, and the exercise energy expenditure was 2,100 4,200 kcal/wk for men and 1,600 kcal/wk for women. Insulin sensitivity improved significantly in both genotype groups. However, Ala carriers had a 1.13-fold (95% confidence interval 1.01; 1.26, P = 0.032) greater improvement in insulin sensitivity from baseline compared with Pro homozygotes. Our data support that PPARG Pro12Ala modifies the effect of aerobic exercise on peripheral insulin sensitivity.

A Prospective Study Comparing 99mTc-Hydroxyethylene-Diphosphonate Planar Bone Scintigraphy and Whole-Body SPECT/CT with 18F-Fluoride PET/CT and 18F-Fluoride PET/MRI for Diagnosing Bone Metastases.

We prospectively evaluated and compared the diagnostic performance of 99mTc-hydroxyethylene-diphosphonate (99mTc-HDP) planar bone scintigraphy (pBS), 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and 18F-NaF PET/MRI for the detection of bone metastases. Methods: One hundred seventeen patients with histologically proven malignancy referred for clinical pBS were prospectively enrolled. pBS and whole-body SPECT/CT were performed followed by 18F-NaF PET/CT within 9 d. 18F-NaF PET/MRI was also performed in 46 patients. Results: Bone metastases were confirmed in 16 patients and excluded in 101, which was lower than expected. The number of equivocal scans was significantly higher for pBS than for SPECT/CT and PET/CT (18 vs. 5 and 6, respectively; P = 0.004 and 0.01, respectively). When equivocal readings were excluded, no statistically significant difference in sensitivity, specificity, positive predictive value, negative predictive value, or overall accuracy were found when comparing the different imaging techniques. In the per-patient analysis, equivocal scans were either assumed positive for metastases ("pessimistic analysis") or assumed negative for metastases ("optimistic analysis"). The percentages of misdiagnosed patients for the pessimistic analysis were 21%, 15%, 9%, and 7% for pBS, SPECT/CT, PET/CT, and PET/MRI, respectively. Corresponding figures for the optimistic analysis were 9%, 12%, 5%, and 7%. In those patients identified as having bone metastases according to the reference standard, SPECT/CT, 18F-NaF PET/CT, and PET/MRI detected additional lesions compared with pBS in 31%, 63%, and 71%, respectively. Conclusion:18F-NaF PET/CT and whole-body SPECT/CT resulted in a significant reduction of equivocal readings compared with pBS, which implies an improved diagnostic confidence. However, the clinical benefit of using, for example, 18F-NaF PET/CT or PET/MRI as compared with SPECT/CT and pBS in this patient population with a relatively low prevalence of bone metastases (14%) is likely limited. This conclusion is influenced by the low prevalence of patients with osseous metastases. There may well be significant differences in the sensitivity of SPECT/CT, PET/CT, and PET/MRI compared with pBS, but a larger patient population or a patient population with a higher prevalence of bone metastases would have to be studied to demonstrate this.

Compliance with physical exercise: using a multidisciplinary approach within a dose-dependent exercise study of moderately overweight men.

AIMS: Sixty-one healthy, sedentary, moderately overweight young men participated in a randomised controlled trial to examine the effects of two different doses of endurance exercise on health behaviour and exercise compliance. METHODS: Participants were randomised to a sedentary control group, a moderate (MOD; 300 kcal/day) or a high-dose (HIGH; 600 kcal/day) endurance exercise group for 12 weeks. A sub-set of the subjects were interviewed using pre-determined, qualitative questions to elucidate physical activity and health behaviour. In combination with the Theory of Planned Behaviour (TPB), a post hoc thematic analysis was conducted to connect qualitative and quantitative data in a joint analysis. RESULTS: Of the subjects interviewed, exercise compliance expressed as 95% CI was [96.8; 103%] in the MOD group and [82.9; 99.6%] in the HIGH group. The different doses of daily exercise equally improved various metabolic health parameters. The MOD group was untroubled by the exercise load and had a positive attitude towards exercise. The HIGH group expressed increased fatigue, less positivity and perceived exercise as time-consuming. The MOD group described themselves as more energetic, and thereby may have increased physical activity levels in areas of their everyday lives that were not related to the intervention. CONCLUSIONS: A multidisciplinary approach provided explanations for similar effects of two different doses of exercise. This could not have been determined via either qualitative or quantitative methodology alone. The preconditions of the TBP were fulfilled, and it represents a methodological model to explain the high degree of compliance and motivation to exercise.

Calibrated image-derived input functions for the determination of the metabolic uptake rate of glucose with [18F]-FDG PET.

PURPOSE: We investigated the use of a simple calibration method to remove bias in previously proposed approaches to image-derived input functions (IDIFs) when used to calculate the metabolic uptake rate of glucose (K(m)) from dynamic [(18)F]-FDG PET scans of the thigh. Our objective was to obtain nonbiased, low-variance K(m) values without blood sampling. MATERIALS AND METHODS: We evaluated eight previously proposed IDIF methods. K(m) values derived from these IDIFs were compared with Km values calculated from the arterial blood samples (gold standard). We used linear regression to extract calibration parameters to remove bias. Following calibration, cross-validation and bootstrapping were used to estimate the mean square error and variance. RESULTS: Three of the previously proposed methods failed mainly because of zero-crossings of the IDIF. The remaining five methods were improved by calibration, yielding unbiased Km values. The method with the lowest SD yielded an SD of 0.0017/min--that is, below 10% of the muscle K(m) value in this study. CONCLUSION: Previously proposed IDIF methods can be improved by using a simple calibration procedure. The calibration procedure may be used in other studies, thus obviating the need for arterial blood sampling, once the calibration parameters have been established in a subgroup of participants. The method has potential for use in other parts of the body as it is robust with regard to partial volume effects.

Appetite regulation in overweight, sedentary men after different amounts of endurance exercise: a randomized controlled trial.

Weight loss induced by endurance exercise is often disappointing, possibly due to an increase in energy intake mediated through greater appetite. The aim of this study was to evaluate fasting, postprandial, and postexercise appetite regulation after an intervention prescribing two amounts of endurance exercise. Sixty-four sedentary, overweight, healthy young men were randomized to control (CON), moderate-dose (MOD: ≈ 30 min/day), or high-dose (HIGH: ≈ 60 min/day) endurance exercise for 12 wk. Along with subjective appetite ratings, plasma ghrelin, glucagon, insulin, peptide YY3-36, glucose, free fatty acids, and glycerol were measured during fasting and in relation to a breakfast meal and an acute bout of exercise, both at baseline and at follow-up. Ad libitum lunch energy intake was evaluated 3 h after the breakfast meal. Despite different amounts of endurance exercise, the subjects lost similar amounts of fat mass (MOD: 4.2 ± 0.5 kg; HIGH: 3.7 ± 0.5 kg). Fasting and postprandial insulin decreased ≈ 20% in both exercise groups (P < 0.03 vs. CON). Appetite measurements were not upregulated in the fasting and postprandial states. On the contrary, fasting and postprandial ratings of fullness and postprandial PYY3-36 increased in HIGH (P < 0.001 vs. CON). Ad libitum lunch energy intake remained unchanged over the course of the intervention. In both exercise groups, plasma ghrelin increased in relation to acute exercise after training. Thus neither moderate nor high doses of daily endurance exercise increased fasting and postprandial measures of appetite, but a high dose of exercise was associated with an increase in fasting and meal-related ratings of fullness and satiety.

Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise--a randomized controlled trial in overweight sedentary males.

The amount of weight loss induced by exercise is often disappointing. A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited. A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to ∼30 and 60 min of daily aerobic exercise, respectively. Body weight (MOD: -3.6 kg, P < 0.001; HIGH: -2.7 kg, P = 0.01) and fat mass (MOD: -4.0 kg, P < 0.001 and HIGH: -3.8 kg, P < 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: -39.6 Mcal, HIGH: -34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise. In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.