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Objectives: This prospective study tested the diagnostic accuracy, and absolute agreement with MRI of a low-dose CT protocol for left ventricular ejection fraction (LVEF) measurement. Furthermore we assessed its potential for combining it with Chest-Abdomen-Pelvis CT (CAP-CT) for a one-stop examination. Materials & methods: Eighty-two patients underwent helical low-dose CT. Cardiac magnetic resonance imaging (MRI) was the reference standard. In fifty patients, CAP-CT was performed concurrently, using a modified injection protocol. In these, LVEF was measured with radioisotope cardiography (MUGA). Patients >18 years, without contrast media or MRI contraindications, were included. Bias was measured with Bland-Altman analysis, classification accuracy with Receiver Operating Characteristics, and inter-reader agreement with Intra-Class Correlation Coefficient (ICC). Correlation was examined using Pearson's correlation coefficients. CAP image quality was compared to previous scans with visual grading characteristics. Results: The mean CT dose-length-product (DLP) was 51.8 mGycm, for an estimated effective dose of 1.4 mSv, compared to 5.7 mSv for MUGA. CT LVEF bias was between 2 % and 10 %, overestimating end-diastolic volume. When corrected for bias, sensitivity and specificity of 100 and 98.5 % for classifying reduced LVEF (50 % MRI value) was achieved. ICC for MUGA was significantly lower than MRI and CT. Distinction of renal medulla and cortex was reduced in the CAP scan, but proportion of diagnostic scans was not significantly different from standard protocol. Conclusion: When corrected for inter-modality bias, CT classifies patients with reduced LVEF with high accuracy at a quarter of MUGA dose and can be combined with CAP-CT without loss of diagnostic quality.

Abstract Background Artificial intelligence (AI) systems are proposed as a replacement of the first reader in double reading within mammography screening. We aimed to assess cancer detection accuracy of an AI system in a Danish screening population. Methods We retrieved a consecutive screening cohort from the Region of Southern Denmark including all participating women between Aug 4, 2014, and August 15, 2018. Screening mammograms were processed by a commercial AI system and detection accuracy was evaluated in two scenarios, Standalone AI and AI-integrated screening replacing first reader, with first reader and double reading with arbitration (combined reading) as comparators, respectively. Two AI-score cut-off points were applied by matching at mean first reader sensitivity (AIsens) and specificity (AIspec). Reference standard was histopathology-proven breast cancer or cancer-free follow-up within 24 months. Coprimary endpoints were sensitivity and specificity, and secondary endpoints were positive predictive value (PPV), negative predictive value (NPV), recall rate, and arbitration rate. Accuracy estimates were calculated using McNemar’s test or exact binomial test. Results Out of 272,008 screening mammograms from 158,732 women, 257,671 (94.7%) with adequate image data were included in the final analyses. Sensitivity and specificity were 63.7% (95% CI 61.6%-65.8%) and 97.8% (97.7-97.8%) for first reader, and 73.9% (72.0-75.8%) and 97.9% (97.9-98.0%) for combined reading, respectively. Standalone AIsens showed a lower specificity (-1.3%) and PPV (-6.1%), and a higher recall rate (+ 1.3%) compared to first reader (p < 0.0001 for all), while Standalone AIspec had a lower sensitivity (-5.1%; p < 0.0001), PPV (-1.3%; p = 0.01) and NPV (-0.04%; p = 0.0002). Compared to combined reading, Integrated AIsens achieved higher sensitivity (+ 2.3%; p = 0.0004), but lower specificity (-0.6%) and PPV (-3.9%) as well as higher recall rate (+ 0.6%) and arbitration rate (+ 2.2%; p < 0.0001 for all). Integrated AIspec showed no significant difference in any outcome measures apart from a slightly higher arbitration rate (p < 0.0001). Subgroup analyses showed higher detection of interval cancers by Standalone AI and Integrated AI at both thresholds (p < 0.0001 for all) with a varying composition of detected cancers across multiple subgroups of tumour characteristics. Conclusions Replacing first reader in double reading with an AI could be feasible but choosing an appropriate AI threshold is crucial to maintaining cancer detection accuracy and workload.

Background: Measuring left ventricular ejection fraction (LVEF) is important for detecting heart failure, e.g., in treatment with potentially cardiotoxic chemotherapy. MRI is considered the reference standard for LVEF, but availability may be limited and claustrophobia or metal implants still present challenges. CT has been shown to be accurate and would be advantageous, as LVEF could be measured in conjunction with routine chest–abdomen–pelvis oncology CT. However, the use of CT is not recommended due to the excessive radiation dose. This study aimed to explore the potential for dose reduction using simulation. Using an anthropomorphic heart phantom scanned at 13 dose levels, a noise simulation algorithm was developed to introduce controlled Poisson noise. Filtered backprojection parameters were iteratively tested to minimise differences in myocardium-to-ventricle contrast/noise ratio, as well as structural similarity index (SSIM) differences between real and simulated images at all dose levels. Fifty-one clinical CT coronary angiographies, scanned with full dose through end-systolic and -diastolic phases, were located retrospectively. Using the developed algorithm, noise was introduced corresponding to 25, 10, 5 and 2% of the original dose level. LVEF was measured using clinical software (Syngo.via VB50) with papillary muscles in and excluded from the LV volume. At each dose level, LVEF was compared to the 100% dose level, using Bland–Altman analysis. The effective dose was calculated from DLP using a conversion factor of 0.026 mSv/mGycm. Results: In the clinical images, mean CTDIvol and DLP were 47.1 mGy and 771.9 mGycm, respectively (effective dose 20.0 mSv). Measurements with papillary muscles excluded did not exhibit statistically significant LVEF bias to full-dose images at 25, 10 and 5% simulated dose. At 2% dose, a significant bias of 4.4% was found. With papillary muscles included, small but significant biases were found at all simulated dose levels. Conclusion: Provided that measurements are performed with papillary muscles excluded from the LV volume, the dose can be reduced by a factor of 20 without significantly affecting LVEF measurements. This corresponds to an effective dose of 1 mSv. CT can potentially be used for LVEF measurement with minimal excessive radiation.

Abstract We evaluated the cost-effectiveness of 2-[18F]FDG-PET/CT compared to CE-CT for response monitoring in metastatic breast cancer (MBC) patients. The study included 300 biopsy-verified MBC patients treated at Odense University Hospital (Denmark). CE-CT was used in 144 patients, 83 patients underwent 2-[18F]FDG-PET/CT, and 73 patients received a combination of both. Hospital resource-based costs (2007–2019) were adjusted to the 2019 level. The incremental cost-effectiveness ratio (ICER) was calculated by comparing average costs per patient and gained survival with CE-CT. During a median follow-up of 33.0 months, patients in the 2-[18F]FDG-PET/CT group had more short admissions (median 6 vs. 2) and fewer overnight admissions (5 vs. 12) compared to the CE-CT group. The mean total cost per patient was €91,547 for CE-CT, €83,965 for 2-[18F]FDG-PET/CT, and €165,784 for the combined group. The ICER for 2-[18F]FDG-PET/CT compared to CE-CT was €-527/month, indicating gaining an extra month of survival at a lower cost (€527). 2-[18F]FDG-PET/CT was more cost-effective in patients with favorable prognostic factors (oligometastatic or estrogen receptor-positive disease), while CE-CT was more cost-effective in poor prognosis patients (liver/lung metastases or performance status ≥ 2 at baseline). In conclusion, our study suggests that 2-[18F]FDG-PET/CT is a cost-effective modality for response monitoring in metastatic breast cancer.

Abstract Background Prostate‐specific membrane antigen (PSMA)‐positron emission tomography/contrast‐enhanced computed tomography (PET/CT) is a sensitive imaging modality for prostate cancer (PCa). Due to lack of knowledge of the patient benefit, PSMA‐PET/CT is not yet recommended in the European guidelines for staging and treatment planning of patients with newly diagnosed PCa. We will investigate the potential difference in progression‐free survival (PFS) and quality of life (QoL) of using PSMA‐PET/CT versus sodium fluoride (NaF)‐PET/CT for staging and treatment planning in patients with newly diagnosed PCa. Study Design This is a prospective randomised controlled multicentre trial carried out at three centres in the Region of Southern Denmark. Endpoints The primary endpoint is PFS. Secondary endpoints are residual disease, stage migration, impact on treatment strategies, stage distribution, QoL and diagnostic accuracy measures. Patients and Methods Patients eligible for the study have newly diagnosed unfavourable intermediate‐ or high‐risk PCa. A total of 448 patients will be randomised 1:1 into two groups: (A) a control group staged with Na[18F]F‐PET/CT and (B) an intervention group staged with [18F]PSMA‐1007‐PET/CT. A subgroup in the intervention group will have a supplementary blinded Na[18F]F‐PET/CT performed for the purpose of performing accuracy analyses. QoL will be assessed at baseline and with regular intervals (3–12 months) during the study period. Treatment decisions are achieved at multidisciplinary team conferences based on the results of the respective scans and according to current Danish guidelines. Trial Registration The Regional Committees on Health Research Ethics for Southern Denmark (S‐20190161) and the Danish Medicines Agency (EudraCT Number 2021‐000123‐12) approved the study, and it has been registered on clinicaltrials.gov (Record 2020110469).

Stress is a ubiquitous challenge in modern societies. Symptoms range from mood swings and cognitive impairment to autonomic symptoms. This study explores the link between work-related stress and the neurobiological element of brain processing, testing the hypothesis that patients with occupational stress have altered cerebral glucose consumption compared to healthy controls. The participants’ present conditions were evaluated using an adapted WHO SCAN interview. Neural activity at rest was assessed by positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose. Participants were genotyped for the Val158Met polymorphism of the COMT gene, believed to influence stress resilience. This study included 11 women with work-related stress and 11 demographically comparable healthy controls aged 28–62 years, with an average of 46.2 years. The PET scans indicated clusters of decreased glucose consumption primarily located in the white matter of frontal lobe sub-gyral areas in stress patients. COMT Val158Met polymorphism detection indicated no immediate relation of the homozygous alleles and stress resilience; however, healthy controls mainly had the heterozygous allele. In conclusion, the results support that work-related stress does affect the brain in the form of altered glucose metabolism, suggesting neurobiological effects could be related to white matter abnormalities rather than gray matter deterioration. Genotyping indicates a more complex picture than just that of the one type being more resilient to stress. Further studies recruiting a larger number of participants are needed to confirm our preliminary findings.

Abstract This study aimed to compare CE-CT and 2-[18F]FDG-PET/CT for response monitoring metastatic breast cancer (MBC). The primary objective was to predict progression-free and disease-specific survival for responders vs. non-responders on CE-CT and 2-[18F]FDG-PET/CT. The secondary objective was to assess agreement between response categorization for the two modalities. Treatment response in women with MBC was monitored prospectively by simultaneous CE-CT and 2-[18F]FDG-PET/CT, allowing participants to serve as their own controls. The standardized response evaluation criteria in solid tumors (RECIST 1.1) and PET response criteria in solid tumors (PERCIST) were used for response categorization. For prediction of progression-free and disease-specific survival, treatment response was dichotomized into responders (partial and complete response) and non-responders (stable and progressive disease) at the first follow-up scan. Progression-free survival was defined as the time from baseline until disease progression or death from any cause. Disease-specific survival was defined as the time from baseline until breast cancer-specific death. Agreement between response categorization for both modalities was analyzed for all response categories and responders vs. non-responders. At the first follow-up, tumor response was reported more often by 2-[18F]FDG-PET/CT than CE-CT, with only fair agreement on response categorization between the two modalities (weighted Kappa 0.28). Two-year progression-free survival for responders vs. non-responders by CE-CT was 54.2% vs. 46.0%, compared with 59.1% vs. 14.3% by 2-[18F]FDG-PET/CT. Correspondingly, 2-year disease-specific survival were 83.3% vs. 77.8% for CE-CT and 84.6% vs. 61.9% for 2-[18F]FDG-PET/CT. Tumor response on 2-[18F]FDG-PET/CT was significantly associated with progression-free (HR: 3.49, P

Background The incidence of breast animation deformity (BAD) is reported to be substantial after direct-to-implant breast reconstruction with subpectoral implant placement. It has, however, never been examined if BAD can occur following prepectoral implant placement. Our primary aim was to compare the incidence and degree of BAD after direct-to-implant breast reconstruction using either subpectoral or prepectoral implant placement. Secondary aim of this study was to assess and compare the level of pain between sub- and prepectoral reconstructed women. Methods In this randomized controlled trial, patients were allocated to reconstruction by either subpectoral or prepectoral implant placement in accordance with the CONSORT guidelines. The degree of BAD was assessed by the “Nipple, Surrounding skin, Entire breast (NSE)” grading scale 12 months after surgery. The level of postoperative pain was assessed on a numerical pain rating scale. Results We found a significant difference in the degree of BAD favoring patients in the prepectoral group (23.8 vs. 100%, p

Introduction Coronary artery calcification (CAC) and especially progression in CAC is a strong predictor of acute myocardial infarction and cardiovascular mortality. Supplementation with vitamin K2 and D3 has been suggested to have a protective role in the progression of CAC. In this study, we will examine the effect of vitamins K2 and D3 in men and women with severe CAC. We hypothesise that supplementation with vitamins K2 and D3 will slow down the calcification process.Method and analysis In this multicentre and double-blinded placebo-controlled study, 400 men and women with CAC score≥400 are randomised (1:1) to treatment with vitamin K2 (720 µg/day) and vitamin D3 (25 µg/day) or placebo treatment (no active treatment) for 2 years. Among exclusion criteria are treatment with vitamin K antagonist, coagulation disorders and prior coronary artery disease. To evaluate progression in coronary plaque, a cardiac CT-scan is performed at baseline and repeated after 12 and 24 months of follow-up. Primary outcome is progression in CAC score from baseline to follow-up at 2 years. Among secondary outcomes are coronary plaque composition and cardiac events. Intention-to-treat principle is used for all analyses.Ethics and dissemination There are so far no reported adverse effects associated with the use of vitamin K2. The protocol was approved by the Regional Scientific Ethical Committee for Southern Denmark and the Data Protection Agency. It will be conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported.Trial registration number NCT05500443.

Background: Non-expandable lung (NEL) has severe implications for patient symptoms and impaired lung function, as well as crucial implications for the management of malignant pleural effusion (MPE). Indwelling pleural catheters have shown good symptom relief for patients with NEL; hence, identifying patients early in their disease is vital. With the inability of the lung to achieve pleural apposition following thoracentesis and the formation of a hydropneumothorax, traditionally, chest X-ray and clinical symptoms have been used to make the diagnosis following thoracentesis. It is our aim to investigate whether ultrasound measurement of lung movement during respiration can predict NEL before thoracentesis, thereby aiding clinicians in their planning for the optimal treatment of affected patients. Methods: A total of 49 patients were consecutively included in a single-centre trial performed at a pleural clinic. Patients underwent protocolled ultrasound assessment pre-thoracentesis with measurements of lung and diaphragm movement and shear wave elastography measurements of the pleura and pleural effusion at the planned site of thoracentesis. Results: M-mode measurements of lung movement provided the best diagnostic ROC-curve results, with an AUC of 0.81. Internal validity showed good results utilising the calibration belt test and Brier test. Conclusion: M-mode measurement of lung movement shows promise in diagnosing NEL before thoracentesis in patients with known or suspected MPE. A validation cohort is needed to confirm the results.

Abstract Lymphedema affects 20% of women diagnosed with breast cancer. It is a pathology with no known cure. Animal models are essential to explore possible treatments to understand and potentially cure lymphedema. The rodent hindlimb lymphedema model is one of the most widely used. Different modalities have been used to measure lymphedema in the hindlimb of mice, and these are generally poorly assessed in terms of the interrater agreement; thus, there could be a risk of measuring bias and poor reproducibility. We examined the interrater agreement of µCT-scans, electronic caliper thickness of the paw and plethysmometer in the measurement of lymphedema in the hindlimb of mice. Three independent raters assessed 24 C57BL6 mice using these three modalities four times (week 1, 2, 4 and 8) with a total of 96 samples. The mean interrater differences were then calculated. The interrater agreement was highest in the µCT-scans, with an extremely low risk of measurement bias. The interrater agreement in the plethysmometer and electronic caliper was comparable with a low to moderate risk of measurement bias. The µCT-scanner should be used whenever possible. The electronic caliper should only be used if there is no µCT-scanner available. The plethysmometer should not be used in rodents of this size.

Abstract Background Randomized test-treatment studies aim to evaluate the clinical utility of diagnostic tests by providing evidence on their impact on patient health. However, the sample size calculation is affected by several factors involved in the test-treatment pathway, including the prevalence of the disease. Sample size planning is exposed to strong uncertainties in terms of the necessary assumptions, which have to be compensated for accordingly by adjusting prospectively determined study parameters during the course of the study. Method An adaptive design with a blinded sample size recalculation in a randomized test-treatment study based on the prevalence is proposed and evaluated by a simulation study. The results of the adaptive design are compared to those of the fixed design. Results The adaptive design achieves the desired theoretical power, under the assumption that all other nuisance parameters have been specified correctly, while wrong assumptions regarding the prevalence may lead to an over- or underpowered study in the fixed design. The empirical type I error rate is sufficiently controlled in the adaptive design as well as in the fixed design. Conclusion The consideration of a blinded recalculation of the sample size already during the planning of the study may be advisable in order to increase the possibility of success as well as an enhanced process of the study. However, the application of the method is subject to a number of limitations associated with the study design in terms of feasibility, sample sizes needed to be achieved, and fulfillment of necessary prerequisites.

Abstract Background Imaging of idiopathic inflammatory myopathies (IIMs) is challenging, and no pathognomonic signs exist. Different tracers have been tested for this purpose, mainly inflammation markers including technetium-99m-pyrophosphate (PYP). We aimed to examine the utility of fluorine-18-fluorodeoxyglucose (FDG) relative to PYP in idiopathic inflammatory myopathy (IIM). Methods Using visual grading and CT-guided muscular segmentation and standardized uptake values (SUVs), we assessed muscular tracer uptake qualitatively and quantitatively, comparing FDG uptake in eight patients with recent-onset IIM and 24 healthy control persons and FDG and PYP uptake in seven patients. Results Muscular FDG and PYP uptake was increased in all patients. However, uptake distribution and signal intensity differed considerably. FDG scans revealed clear involvement of certain muscle groups including core and swallowing muscles and, in addition, abnormality in diseased extra-muscular organs. PYP was mainly visible in bones, whereas muscular PYP uptake was generally discrete and primarily located in the extremities. Quantitatively, FDG uptake was significantly higher in patients than in controls; the volume-weighted SUVmean for all right-side muscles was 0.84 versus 0.60 g/ml (95% confidence interval (CI) for mean difference 0.14–0.34, p = 0.0001). FDG SUVmean values were up to four times higher than PYP mean values in upper limb muscles (95% CI for the mean ratio 2.37–3.77, p = 0.0004) and two–three times higher in lower limb muscles (95% CI for the mean ratio 2.28–2.71, p

Introduction Atrial fibrillation (AF) is the most common postoperative complication after surgical aortic valve replacement (SAVR) and occurs in up to 50% of the patients. Development of postoperative AF (POAF) is associated with a 2–3 fold increased risk of adverse events, including stroke, myocardial infarction and death.Several studies have implied that prophylactic Atorvastatin therapy could prevent POAF in patients undergoing coronary artery bypass graft. These studies suggest that Atorvastatin has rapid and significant pleiotropic actions that reduce the risk of POAF. However, prophylactic treatment with statins has yet to be understood in SAVR. The aim of this study is to investigate whether prophylactic administration of torvastatin reduces POAF in patients undergoing SAVR.Methods and analysis In this investigator-initiated, prospective, parallel-group, randomised, double-blind, placebo-controlled single-centre trial, 266 patients undergoing elective solitary SAVR with bioprosthetic valve, with no prior history of AF, and statin-naïve will be randomised (1:1) to treatment with Atorvastatin (80 mg once daily) or matching placebo for 1–2 weeks prior to and 30 days after surgery. The primary endpoint is POAF defined as an episode of irregular RR-intervals without a traceable p-wave of at least 30 s duration. After discharge and until day 30 after surgery, POAF will be documented by either rhythm strip or 12-lead ECG.Ethics and dissemination Protocol approval has been obtained from the Regional Scientific Ethical Committee for Southern Denmark (S-20210159), The Danish Medicines Agency (2021103821) and the Data Protection Agency (21/65621).The trial is conducted in accordance with the Declaration of Helsinki, the ICH-GCP (International Conference on Harmonisation Good Clinical Practice) guidelines and the legal regulations of Denmark. Study findings will be shared via peer-reviewed journal publication and conference presentations.Trial registration number NCT05076019.

The diagnostic accuracy of up-front 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for detecting cervical lymph node metastases in patients with T1–T2 oral squamous cell carcinoma is reported with large discrepancies across the literature. We investigated the sensitivity, specificity, positive and negative predictive value, and accuracy of up-front PET/CT for detecting cervical lymph node metastases in this patient group and compared the performance to magnetic resonance imaging (MRI). In this prospective cohort study, 76 patients with T1–T2 oral squamous cell carcinoma underwent an up-front PET/CT and MRI at the Odense University Hospital from September 2013 to February 2016. Sentinel node biopsy and elective neck dissection were used for histopathological verification of the imaging modalities. Up-front PET/CT was significantly more sensitive than neck MRI (74% vs. 27%, p = 0.0001), but less specific (60% vs. 88%, p = 0.001). The accuracy of PET/CT and neck MRI was comparable (66% vs. 63%, p = 0.85), the PPV was slightly in favor of neck MRI (56% vs. 62%, p = 0.73), the NPV was slightly in favor of PET/CT (77% vs. 63%, p = 0.16). Neither PET/CT nor neck MRI should stand alone for N-staging T1–T2 oral cavity cancer.

The study aimed to compare the metastatic pattern of breast cancer and the intermodality proportion of agreement between [18F]FDG-PET/CT and CE-CT. Women with metastatic breast cancer (MBC) were enrolled prospectively and underwent a combined [18F]FDG-PET/CT and CE-CT scan to diagnose MBC. Experienced nuclear medicine and radiology physicians evaluated the scans blinded to the opposite scan results. Descriptive statistics were applied, and the intermodality proportion of agreement was used to compare [18F]FDG-PET/CT and CE-CT. In total, 76 women with verified MBC were enrolled in the study. The reported number of site-specific metastases for [18F]FDG-PET/CT vs. CE-CT was 53 (69.7%) vs. 44 (57.9%) for bone lesions, 31 (40.8%) vs. 43 (56.6%) for lung lesions, and 16 (21.1%) vs. 23 (30.3%) for liver lesions, respectively. The proportion of agreement between imaging modalities was 76.3% (95% CI 65.2–85.3) for bone lesions; 82.9% (95% CI 72.5–90.6) for liver lesions; 57.9% (95% CI 46.0–69.1) for lung lesions; and 59.2% (95% CI 47.3–70.4) for lymph nodes. In conclusion, bone and distant lymph node metastases were reported more often by [18F]FDG-PET/CT than CE-CT, while liver and lung metastases were reported more often by CE-CT than [18F]FDG-PET/CT. Agreement between scans was highest for bone and liver lesions and lowest for lymph node metastases.

Bland–Altman limits of agreement are very popular in method comparison studies on quantitative outcomes. However, a straightforward application of Bland–Altman analysis requires roughly normally distributed differences, a constant bias, and variance homogeneity across the measurement range. If one or more assumptions are violated, a variance-stabilizing transformation (e.g., natural logarithm, square root) may be sufficient before Bland–Altman analysis can be performed. Sometimes, fractional polynomial regression has been used when the choice of variance-stabilizing transformation was unclear and increasing variability in the differences was observed with increasing mean values. In this case, regressing the absolute differences on a function of the average and applying fractional polynomial regression to this end were previously proposed. This review revisits a previous inter-rater agreement analysis on the Agatston score for coronary calcification. We show the inappropriateness of a straightforward Bland–Altman analysis and briefly describe the nonparametric limits of agreement of the original investigation. We demonstrate the application of fractional polynomials, use the Stata packages fp and fp_select, and discuss the use of degree-2 (the default setting) and degree-3 fractional polynomials. Finally, we discuss conditions for evaluating the appropriateness of nonstandard limits of agreement.

Gwet's AC1 has been proposed as an alternative to Cohen's kappa in evaluating the agreement between two binary ratings. This approach is becoming increasingly popular, and researchers have been criticized for still using Cohen's kappa. However, a rigorous discussion of properties of Gwet's AC1 is still missing. In this paper several basic properties of Gwet's AC1 are investigated and compared with those of Cohen's kappa, in particular the dependence on the prevalence of positive ratings for a given agreement rate and the behaviour in case of no association or maximal disagreement. Both approaches compare the observed agreement rate with a comparative number. Cohen's kappa uses an expected agreement rate as comparator, whereas Gwet's AC1 uses an expected disagreement rate. Consequently, for a fixed agreement rate, Gwet's AC1 increases with increasing difference of the prevalence of positive ratings from 0.5. In contrast, Cohen's kappa decreases. Gwet's AC1 can take positive and negative values in the case of no association between the two raters, whereas Cohen's kappa is 0. Due to these fundamental differences, Gwet's AC1 should not be seen as a substitute for Cohen's kappa. In particular, the verbal classification of kappa values by Landis & Koch should not be applied to Gwet's AC1.

Bland–Altman agreement analysis has gained widespread application across disciplines, last but not least in health sciences, since its inception in the 1980s. Bayesian analysis has been on the rise due to increased computational power over time, and Alari, Kim, and Wand have put Bland–Altman Limits of Agreement in a Bayesian framework (Meas. Phys. Educ. Exerc. Sci. 2021, 25, 137–148). We contrasted the prediction of a single future observation and the estimation of the Limits of Agreement from the frequentist and a Bayesian perspective by analyzing interrater data of two sequentially conducted, preclinical studies. The estimation of the Limits of Agreement θ1 and θ2 has wider applicability than the prediction of single future differences. While a frequentist confidence interval represents a range of nonrejectable values for null hypothesis significance testing of H0: θ1 ≤ −δ or θ2 ≥ δ against H1: θ1 > −δ and θ2 < δ, with a predefined benchmark value δ, Bayesian analysis allows for direct interpretation of both the posterior probability of the alternative hypothesis and the likelihood of parameter values. We discuss group-sequential testing and nonparametric alternatives briefly. Frequentist simplicity does not beat Bayesian interpretability due to improved computational resources, but the elicitation and implementation of prior information demand caution. Accounting for clustered data (e.g., repeated measurements per subject) is well-established in frequentist, but not yet in Bayesian Bland–Altman analysis.

Abstract Background [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) has been implemented sporadically in hospital settings as the standard of care examination for recurrent breast cancer. We aimed to explore the clinical impact of implementing [18F]FDG-PET/CT for patients with clinically suspected recurrent breast cancer and validate the diagnostic accuracy. Methods Women with suspected distant recurrent breast cancer were prospectively enrolled in the study between September 2017 and August 2019. [18F]FDG-PET/CT was performed, and the appearance of incidental benign and malignant findings was registered. Additional examinations, complications, and the final diagnosis were registered to reflect the clinical consequence of such findings. The diagnostic accuracy of [18F]FDG-PET/CT as a stand-alone examination was analyzed. Biopsy and follow-up were used as a reference standard. Results [18F]FDG-PET/CT reported breast cancer metastases in 72 of 225 women (32.0%), and metastases were verified by biopsy in 52 (52/225, 23.1%). Prior probability and posterior probability of a positive test for suspected metastatic cancer and incidental malignancies were 27%/85% and 4%/20%, respectively. Suspected malignant incidental findings were reported in 46 patients (46/225, 20.4%), leading to further examinations and final detection of nine synchronous cancers (9/225, 4.0%). These cancers originated from the lung, thyroid, skin, pancreas, peritoneum, breast, kidney, one was malignant melanoma, and one was hematological cancer. False-positive incidental malignant findings were examined in 37/225 patients (16.4%), mainly in the colon (n = 12) and thyroid gland (n = 12). Ten incidental findings suspicious for benign disease were suggested by [18F]FDG-PET/CT, and further examinations resulted in the detection of three benign conditions requiring treatment. Sensitivity, specificity, and AUC-ROC for diagnosing distant metastases were 1.00 (0.93–1.0), 0.88 (0.82–0.92), and 0.98 (95% CI 0.97–0.99), respectively. Conclusion [18F]FDG-PET/CT provided a high posterior probability of positive test, and a negative test was able to rule out distant metastases in women with clinically suspected recurrent breast cancer. One-fifth of patients examined for incidental findings detected on [18F]FDG-PET/CT were diagnosed with clinically relevant conditions. Further examinations of false-positive incidental findings in one of six women should be weighed against the high accuracy for diagnosing metastatic breast cancer. Trial registration Clinical.Trials.gov. NCT03358589. Registered 30 November 2017—Retrospectively registered, http://www.ClinicalTrials.gov

We investigated the impact of 2-[18F]FDG-PET/CT on detection rate (DR) of the primary tumor and survival in patients with suspected cancer of unknown primary tumor (CUP), comparing it to the conventional diagnostic imaging method, CT. Patients who received a tentative CUP diagnosis at Odense University Hospital from 2014–2017 were included. Patients receiving a 2-[18F]FDG-PET/CT were assigned to the 2-[18F]FDG-PET/CT group and patients receiving a CT only to the CT group. DR was calculated as the proportion of true positive findings of 2-[18F]FDG-PET/CT and CT scans, separately, using biopsy of the primary tumor, autopsy, or clinical decision as reference standard. Survival analyses included Kaplan–Meier estimates and Cox proportional hazards regression adjusted for age, sex, treatment, and propensity score. We included 193 patients. Of these, 159 were in the 2-[18F]FDG-PET/CT group and 34 were in the CT group. DR was 36.5% in the 2-[18F]FDG-PET/CT group and 17.6% in the CT group, respectively (p = 0.012). Median survival was 7.4 (95% CI 0.4–98.7) months in the 2-[18F]FDG-PET/CT group and 3.8 (95% CI 0.2–98.1) in the CT group. Survival analysis showed a crude hazard ratio of 0.63 (p = 0.024) and an adjusted hazard ratio of 0.68 (p = 0.087) for the 2-[18F]FDG-PET/CT group compared with CT. This study found a significantly higher DR of the primary tumor in suspected CUP patients using 2-[18F]FDG-PET/CT compared with patients receiving only CT, with possible immense clinical importance. No significant difference in survival was found, although a possible tendency towards longer survival in the 2-[18F]FDG-PET/CT group was observed.

Abstract Background Diagnostic accuracy studies aim to examine the diagnostic accuracy of a new experimental test, but do not address the actual merit of the resulting diagnostic information to a patient in clinical practice. In order to assess the impact of diagnostic information on subsequent treatment strategies regarding patient-relevant outcomes, randomized test-treatment studies were introduced. Various designs for randomized test-treatment studies, including an evaluation of biomarkers as part of randomized biomarker-guided treatment studies, are suggested in the literature, but the nomenclature is not consistent. Methods The aim was to provide a clear description of the different study designs within a pre-specified framework, considering their underlying assumptions, advantages as well as limitations and derivation of effect sizes required for sample size calculations. Furthermore, an outlook on adaptive designs within randomized test-treatment studies is given. Results The need to integrate adaptive design procedures in randomized test-treatment studies is apparent. The derivation of effect sizes induces that sample size calculation will always be based on rather vague assumptions resulting in over- or underpowered study results. Therefore, it might be advantageous to conduct a sample size re-estimation based on a nuisance parameter during the ongoing trial. Conclusions Due to their increased complexity, compared to common treatment trials, the implementation of randomized test-treatment studies poses practical challenges including a huge uncertainty regarding study parameters like the expected outcome in specific subgroups or disease prevalence which might affect the sample size calculation. Since research on adaptive designs within randomized test-treatment studies is limited so far, further research is recommended.

Abstract Background Although dorsal/palmar tilt, radial inclination (RI), and ulnar variance (UV) are measurements commonly performed in wrist radiographs, the impact of forearm rotation on those measurements during the radiographic procedure is uncertain. Our aim was to determine the impact of supination and pronation on the reliability of measurements of tilt, RI, and UV. Methods Tantalum markers were inserted into the distal radius of 21 unfractured cadaver forearms. The forearms were radiographed in different degrees of supination and pronation. The exact degree of rotation was calculated with radiostereometric analyses. Tilt, RI, and UV were measured by two independent readers in a random and anonymised fashion. Association between forearm rotation and radiographic measurements was examined using linear regression. Results Forearm rotation significantly impacted the radiographically measured tilt. One degree of supination and pronation respectively increased and decreased palmar tilt with 0.68° and 0.44°, observers 1 and 2, respectively. As opposed to observer 1, observer 2 found that RI was significantly impacted by rotation with a slope of 0.08. Ulnar variance was not significantly impacted by rotation with linear regression slopes of 0.01° (95% confidence interval [CI] − 0.02–0.05, p = 0.490) and 0.02° (95% CI − 0.02–0.07; p = 0.288), observer 1 and observer 2, respectively. Conclusion In unfractured forearms, the radiographically measured tilt was significantly affected by rotation. Palmar tilt increased with supination and decreased with pronation. Rotation significantly affected radial inclination, although of a magnitude that is probably not clinically relevant. No significant impact on UV was found.

Abstract Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients’ outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p

We compared the image quality and quantification parameters through bayesian penalized likelihood reconstruction algorithm (Q.Clear) and ordered subset expectation maximization (OSEM) algorithm for 2-[18F]FDG-PET/CT scans performed for response monitoring in patients with metastatic breast cancer in prospective setting. We included 37 metastatic breast cancer patients diagnosed and monitored with 2-[18F]FDG-PET/CT at Odense University Hospital (Denmark). A total of 100 scans were analyzed blinded toward Q.Clear and OSEM reconstruction algorithms regarding image quality parameters (noise, sharpness, contrast, diagnostic confidence, artefacts, and blotchy appearance) using a five-point scale. The hottest lesion was selected in scans with measurable disease, considering the same volume of interest in both reconstruction methods. SULpeak (g/mL) and SUVmax (g/mL) were compared for the same hottest lesion. There was no significant difference regarding noise, diagnostic confidence, and artefacts within reconstruction methods; Q.Clear had significantly better sharpness (p < 0.001) and contrast (p = 0.001) than the OSEM reconstruction, while the OSEM reconstruction had significantly less blotchy appearance compared with Q.Clear reconstruction (p < 0.001). Quantitative analysis on 75/100 scans indicated that Q.Clear reconstruction had significantly higher SULpeak (5.33 ± 2.8 vs. 4.85 ± 2.5, p < 0.001) and SUVmax (8.27 ± 4.8 vs. 6.90 ± 3.8, p < 0.001) compared with OSEM reconstruction. In conclusion, Q.Clear reconstruction revealed better sharpness, better contrast, higher SUVmax, and higher SULpeak, while OSEM reconstruction had less blotchy appearance.

The assessment of agreement in method comparison and observer variability analysis of quantitative measurements is usually done by the Bland–Altman Limits of Agreement, where the paired differences are implicitly assumed to follow a normal distribution. Whenever this assumption does not hold, the 2.5% and 97.5% percentiles are obtained by quantile estimation. In the literature, empirical quantiles have been used for this purpose. In this simulation study, we applied both sample, subsampling, and kernel quantile estimators, as well as other methods for quantile estimation to sample sizes between 30 and 150 and different distributions of the paired differences. The performance of 15 estimators in generating prediction intervals was measured by their respective coverage probability for one newly generated observation. Our results indicated that sample quantile estimators based on one or two order statistics outperformed all of the other estimators and they can be used for deriving nonparametric Limits of Agreement. For sample sizes exceeding 80 observations, more advanced quantile estimators, such as the Harrell–Davis and estimators of Sfakianakis–Verginis type, which use all of the observed differences, performed likewise well, but may be considered intuitively more appealing than simple sample quantile estimators that are based on only two observations per quantile.

Objective To define the proportions of agreement between fluorine‐18‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT), clinical diagnosis, and temporal artery biopsy (TAB) in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Furthermore, the association of 18F‐FDG PET/CT uptake patterns and clinical presentation of newly diagnosed PMR and GCA was investigated. Methods Eighty patients newly suspected of having PMR, GCA, or concomitant PMR and GCA were included and followed for 40 weeks. Every patient underwent an 18F‐FDG PET/CT scan before or within 3 days of initiation of steroids in case of GCA. FDG uptakes in 8 paired articular/periarticular sites and 14 arterial segments were evaluated based on a 4‐point visual grading scale. Results Of the 80 patients (female: 50 [62.5%]; mean age ± SD: 72.0 ± 7.9), 64 (80.0%) patients were diagnosed with pure PMR, 3 (3.7%) with pure GCA, and 10 (12.5%) with concomitant PMR and GCA. Additionally, three (3.7%) patients were diagnosed with seronegative rheumatoid arthritis during the follow‐up period. For the diagnosis of PMR, 18F‐FDG PET/CT had a proportion of agreement of 75.3 (64.2‐84.4), compared with clinical diagnosis. When comparing findings of 18F‐FDG PET/CT with TAB, 18F‐FDG PET/CT had a proportion of agreement of 93.0 (84.3‐97.7) in all included patients and 69.2 (38.6‐90.9) in the subgroup of patients with vasculitis. C‐reactive protein was significantly higher in patients with PMR activity on 18F‐FDG PET/CT compared with those without 18F‐FDG PET/CT activity (P value = 0.006). Conclusions 18F‐FDG PET/CT is a powerful imaging technique in PMR and GCA that was in good agreement with clinical diagnosis and TAB.

Objective(s): We aimed to assess the association between blood pressure and LV myocardial uptake of FDG, hypothesizing that subjects with raised blood pressure would have higher FDG uptake. Methods: We analyzed 86 healthy controls who underwent PET/CT imaging 180 minutes following FDG (4 MBq/Kg) administration. LV myocardial analysis was performed on axial sections using standard operator guided computer software (OsiriX MD). The average LV myocardial SUVmean (MSUVmean) was calculated for each subject. Subjects were assessed according to the 2017 ACC/AHA guidelines for high blood pressure in adults. Mean arterial blood pressure (MABP) was calculated for each patient. Regression models were employed for statistical analysis. Results: The association of MSUVmean was more pronounced with DP (r=0.32, p=0.003) than SP (r=0.28, p=0.010); MABP was comparable (r=0.33, p=0.002). Correlations of MSUVmean with categorized BPs were: normal SP (r=0.27, p=0.010), elevated SP (r=0.28, p=0.009), stage 1 SP (r=0.27, p=0.010), stage 2 SP (r=0.28, p=0.008); normal DP (r=0.33, p=0.001), stage 1 DP (r=0.34, p=0.001), stage 2 DP (r=0.35, p=0.001). Multivariate analysis demonstrated DP (p=0.006), MABP (p=0.007), and SP (0.026). Conclusion: LV myocardial FDG uptake was higher in subjects with elevated blood pressure and correlated positively with SBP and in particular DBP and MABP.

ABSTRACT: Norm curves for the head circumference, height, and weight of newborns and infants are widely known examples of percentile curves over age, and early accounts date back 50 years. The advent of the Agatston score for coronary calcification based on coronary computed tomography in 1990 heralded the era of a new marker in preventive medicine, in addition to well-known cardiovascular risk factors. A peculiarity of the nonnegative Agatston score in populations that are free of coronary artery disease is the overexpression of zeros. In a case study, we have demonstrated a nonparametric approach for percentile curve estimation using markers such as the Agatston score. This method is based on lowess smoothing of marker-positive scores on age, and the resulting percentile curves are subsequently transposed according to the estimated proportions of zeros. The approach does not involve any parametric assumptions, is robust against outliers, and fulfills the noncrossing property for percentile curves. A simulation study using samples of N=1,000, 2,000, 5,000, and 10,000 subjects illuminates the closeness of the estimated 50th, 75th, and 90th percentile curves to the respective true curves, assuming an exponentially distributed marker and a proportion of zero scores that increase with age. • The method is applicable to highly skewed data and exemplified here with subgroup data of the referenced procedure. • The consistency and general performance of the method is shown by means of simulation. • The method is an explicit, transferable, and reproducible procedure that is applicable to a wide spectrum of markers and scores across various scientific disciplines, far beyond cardiovascular medicine.

The method of 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) of atherosclerosis was introduced 12 years ago. This approach is particularly interesting because it demonstrates microcalcification as an incipient sign of atherosclerosis before the development of arterial wall macrocalcification detectable by CT. However, this method has not yet found its place in the clinical routine. The more exact association between NaF uptake and future arterial calcification is not fully understood, and it remains unclear to what extent NaF-PET may replace or significantly improve clinical cardiovascular risk scoring. The first 10 years of publications in the field were characterized by heterogeneity at multiple levels, and it is not clear how the method may contribute to triage and management of patients with atherosclerosis, including monitoring effects of anti-atherosclerosis intervention. The present review summarizes findings from the recent 2¾ years including the ability of NaF-PET imaging to assess disease progress and evaluate response to treatment. Despite valuable new information, pertinent questions remain unanswered, not least due to a pronounced lack of standardization within the field and of well-designed long-term studies illuminating the natural history of atherosclerosis and effects of intervention.

Method comparison studies comprised simple scatterplots of paired measurements, a 45-degree line as benchmark, and correlation coefficients up to the advent of Bland–Altman analysis in the 1980s. The Agatston score for coronary calcification is based on computed tomography of the heart, and it originated in 1990. A peculiarity of the Agatston score is the often-observed skewed distribution in screening populations. As the Agatston score has manifested itself in preventive cardiology, it is of interest to investigate how reproducibility of the Agatston score has been established. This review is based on literature findings indexed in MEDLINE/PubMed before 20 November 2021. Out of 503 identified articles, 49 papers were included in this review. Sample sizes were highly variable (10–9761), the main focus comprised intra- and interrater as well as intra- and interscanner variability assessments. Simple analysis tools such as scatterplots and correlation coefficients were successively supplemented by first difference, later Bland–Altman plots; however, only very few publications were capable of deriving Limits of Agreement that fit the observed data visually in a convincing way. Moreover, several attempts have been made in the recent past to improve the analysis and reporting of method comparison studies. These warrant increased attention in the future.

The area under the receiver operating characteristics curve is a popular measure of the overall discriminatory power of a continuous variable used to indicate the presence of an outcome of interest, such as disease or disease progression. In clinical practice, the use of cut-off points as benchmark values for further treatment planning is greatly appreciated, despite the loss of information that such a dichotomization implies. Optimal cut-off points are often derived from fixed sample size studies, and the aim of this study was to investigate the convergence behavior of optimal cut-off points with increasing sample size and to explore a heuristic and path-based algorithm for cut-off point determination that targets stagnating cut-off point values. To this end, the closest-to-(0,1) criterion in receiver operating characteristics curve analysis was used, and the heuristic and path-based algorithm aimed at cut-off points that deviated less than 1% from the cut-off point of the previous iteration. Such a heuristic determination stopped after only a few iterations, thereby implicating practicable sample sizes; however, the result was, at best, a rough estimate of an optimal cut-off point that was unbiased and positively and negatively biased for a prevalence of 0.5, smaller than 0.5, and larger than 0.5, respectively.

Hip dysplasia (HD) is a frequent cause of hip pain in skeletally mature patients and may lead to osteoarthritis (OA). An accurate and early diagnosis may postpone, reduce or even prevent the onset of OA and ultimately hip arthroplasty at a young age. The overall aim of this study was to assess the reliability of an algorithm, designed to read pelvic anterior-posterior (AP) radiographs and to estimate the agreement between the algorithm and human readers for measuring (i) lateral center edge angle of Wiberg (LCEA) and (ii) Acetabular index angle (AIA). The algorithm was based on deep-learning models developed using a modified U-net architecture and ResNet 34. The newly developed algorithm was found to be highly reliable when identifying the anatomical landmarks used for measuring LCEA and AIA in pelvic radiographs, thus offering highly consistent measurement outputs. The study showed that manual identification of the same landmarks made by five specialist readers were subject to variance and the level of agreement between the algorithm and human readers was consequently poor with mean measured differences from 0.37 to 9.56° for right LCEA measurements. The algorithm displayed the highest agreement with the senior orthopedic surgeon. With further development, the algorithm may be a good alternative to humans when screening for HD.

Arteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated.

Background: The use of molecular imaging in staging of prostate cancer (PC) is debated. In patients with newly diagnosed PC we investigated the diagnostic value of 18F-flouromethylcholine positron emission tomography/computed tomography (18F-FCH-PET/CT) for the detection of bone and lymph node metastases compared to whole-body bone scintigraphy (WBS) with technetium-99-methylene diphosphonate (99mTc-MDP) and results of extended pelvic lymph node dissection, respectively. Materials and methods: Between January 2013 and April 2016, 143 patients, aged 49-83, mean 69, years with newly diagnosed PC and disease characteristics necessitating WBS underwent both WBS and 18F-FCH-PET/CT using magnetic resonance imaging as standard. Eighty of these patients underwent pelvic lymph node dissection as part of radical prostatectomy or prior to external beam radiation and in these results of 18F-FCH-PET/CT were compared to histologic findings. Results: Bone metastases were detected in 8/143 patients and sensitivity and specificity of WBS were 37.5% and 85.2% versus 100.0% and 96.3% with 18F-FCH-PET/CT, P=0.63 and 0.002, respectively. Histologically confirmed metastases to regional lymph nodes were found in 25/80 patients. Suspicious choline uptake on PET/CT in pelvic lymph nodes was found in 35 patients. Sensitivity, specificity, PPV, NPV and accuracy of 18F-FCH-PET/CT in detection of lymph node metastases were 62.5%, 69.6%, 46.9%, 81.3% and 67.5%, respectively. Conclusions: Findings in this study suggested that 18F-FCH-PET/CT is a more sensitive and specific method for detection of bone metastases from PC than WBS and could potentially reduce the need for confirmatory imaging if used instead of WBS. However, 18F-FCH-PET/CT performs sub-optimally in pre-operative staging of lymph node metastases in patients undergoing extended pelvic lymph node dissection. Keywords: Choline, Diagnostic imaging, Positron emission tomography, Prostatic neoplasms

Abstract Background FDG-PET/CT is increasingly used for oncologic and inflammatory diseases. Focal incidental FDG uptake occurs rarely in breast tissue but has often significant consequences. This study aimed to systematically review literature regarding focal incidental breast uptake (FIBU) on FDG-PET/CT in order to yield an update on the prevalence and risk of malignancy for FIBU. Methods A systematic search for relevant articles published between 2012 and 2018 was performed through MEDLINE, Embase, and Cochrane databases. Studies addressing the detection of FIBU in patients without a previous history of breast malignancy were included. The QUADAS-2 was used for quality assessment, and eligible data were pooled using a fixed-effects model. I 2 was calculated for the heterogeneity between studies. Results Eight studies containing 180,002 scans were included in the systematic review. The median prevalence of FIBU for both genders was 0.52% (range 0.18–22.5%). Prevalence for women was mentioned separately in five studies and varied from 0.51 to 23.5%. One study reporting a high prevalence was based on patients being staged for known malignancy, and the word “breast” was used in the search, which may have caused selection bias. Data from four studies were eligible for meta-analysis. A high degree of heterogeneity was observed for prevalence data (I 2 of 97.5%), while moderate heterogeneity was observed for data on malignancy risk assessment (I 2 of 62.8%). The pooled prevalence of FIBU in women was 0.61% (range 0.56–0.66%), and the pooled prevalence of malignancy of FIBUs was 38.7% (range 34.4–43.0%). The most commonly detected malignancy was invasive ductal carcinoma. Conclusion FIBU occurs rarely on FDG-PET/CT for female patients but yields a high risk of malignancy according to the results of published papers. Therefore, it should be considered relevant to further elucidate patients with incidentally detected FDG uptake in breast in clinical practice.

Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44− populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2′-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44− and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations.

Abstract Objective This proof of concept study investigated whether dual time point FDG-PET/CT with image acquisition after 1 and 3 h could be useful in preoperative staging of patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection for high-risk prostate cancer. Results Twenty patients with high-risk prostate cancer underwent dual time point FDG-PET/CT before undergoing surgery. Histologically confirmed lymph node metastases were found in 9/20 (45%). A median of 19 (range 10–41; n = 434) lymph nodes were removed per patient. Pelvic lymph nodes with detectable FDG uptake were seen in two patients only, but the FDG-avid lesion on PET did not correspond with pathological findings in either patient. We found a significant increase in maximal standardized uptake value of the prostate of around 30% between early and late imaging. We found no correlation between clinical findings after radical prostatectomy and PET measurements.

We compared lesion-based sensitivity of dual-time-point FDG-PET/CT, bone scintigraphy (BS), and low-dose CT (LDCT) for detection of various types of bone metastases in patients with metastatic breast cancer. Prospectively, we included 18 patients with recurrent breast cancer who underwent dual-time-point FDG-PET/CT with LDCT and BS within a median time interval of three days. A total of 488 bone lesions were detected on any of the modalities and were categorized by the LDCT into osteolytic, osteosclerotic, mixed morphologic, and CT-negative lesions. Lesion-based sensitivity was 98.2% (95.4–99.3) and 98.8% (96.8–99.5) for early and delayed FDG-PET/CT, respectively, compared with 79.9% (51.1–93.8) for LDCT, 76.0% (36.3–94.6) for BS, and 98.6% (95.4–99.6) for the combined BS+LDCT. BS detected only 51.2% of osteolytic lesions which was significantly lower than other metastatic types. SUVs were significantly higher for all lesion types on delayed scans than on early scans (P

In the original publication [...]

Background and aimsVitamin K antagonists (VKA) remain the most frequently prescribed oral anticoagulants worldwide despite the introduction of non-vitamin K antagonist oral anticoagulants (NOAC). VKA interfere with the regeneration of Vitamin K1 and K2, essential to the activation of coagulation factors and activation of matrix-Gla protein, a strong inhibitor of arterial calcifications. This study aimed to clarify whether VKA treatment was associated with the extent of coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD).MethodsWe collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n = 9,672) or research studies (n = 14,166) in the period 2007-2017. Data on use of anticoagulation were obtained from the Danish National Health Service Prescription Database. The association between duration of anticoagulation and categorized CAC score (0, 1-99, 100-399, ≥400) was investigated by ordered logistic regression adjusting for covariates.ResultsThe final study population consisted of 17,254 participants with no prior CVD, of whom 1,748 and 1,144 had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories. For each year of VKA treatment, the odds of being in a higher CAC category increased (odds ratio (OR) = 1.032, 95%CI 1.009-1.057). In contrast, NOAC treatment duration was not associated with CAC category (OR = 1.002, 95%CI 0.935-1.074). There was no significant interaction between VKA treatment duration and age on CAC category.ConclusionsAdjusted for cardiovascular risk factors, VKA treatment-contrary to NOAC-was associated to higher CAC category.

Left atrium (LA) size is associated with adverse cardiovascular events. The purpose of this study was to investigate the association of LA enlargement measured by non-contrast CT (NCCT) with traditional cardiovascular risk factors. Individuals aged 60–75 years from the population-based multicentre Danish Cardiovascular Screening (DANCAVAS) trial were included in this cross-sectional study. The LA was manually traced on the NCCT scans, and the largest cross-section area was indexed to body surface area. All traditional risk factors were recorded, and a subgroup received an echocardiographic examination. We enrolled 14,987 individuals. Participants with known cardiovascular disease or lacking measurements of LA size or body surface area were excluded, resulting in 10,902 men for the main analysis and 616 women for a sensitivity analysis. Adjusted multivariable analysis showed a significantly increased indexed LA size by increasing age and pulse pressure, while smoking, HbA1c, and total cholesterol were associated with decreased indexed LA size. The findings were confirmed in a supplementary analysis including left ventricle ejection fraction and mass. In this population-based cohort of elderly men, an association was found between age and pulse pressure and increasing LA size. Surprisingly, smoking, HbA1c, and total cholesterol were associated with a decrease in LA size. This indicates that the pathophysiology behind atrial cardiomyopathy is not only reflected by enlargement, but also shrinking.

Abstract Background Several studies have shown the advantage of delayed-time-point imaging with 18F-FDG-PET/CT to distinguish malignant from benign uptake. This may be relevant in cancer diseases with low metabolism, such as breast cancer. We aimed at examining the change in SUV from 1 h (1h) to 3 h (3h) time-point imaging in local and distant lesions in patients with recurrent breast cancer. Furthermore, we investigated the effect of partial volume correction in the different types of metastases, using semi-automatic quantitative software (ROVER™). Methods One-hundred and two patients with suspected breast cancer recurrence underwent whole-body PET/CT scans 1h and 3h after FDG injection. Semi-quantitative standardised uptake values (SUVmax, SUVmean) and partial volume corrected SUVmean (cSUVmean), were estimated in malignant lesions, and as reference in healthy liver tissue. The change in quantitative measures from 1h to 3h was calculated, and SUVmean was compared to cSUVmean. Metastases were verified by biopsy. Results Of the 102 included patients, 41 had verified recurrent disease with in median 15 lesions (range 1-70) amounting to a total of 337 malignant lesions included in the analysis. SUVmax of malignant lesions increased from 6.4 ± 3.4 [0.9-19.7] (mean ± SD, min and max) at 1h to 8.1 ± 4.4 [0.7-29.7] at 3h. SUVmax in breast, lung, lymph node and bone lesions increased significantly (p

Abstract Background Nuclear imaging is increasingly being used in the diagnostic work-up of idiopathic inflammatory myopathy (IIM). Increased muscular uptake of technetium-99m-pyrophosphate (99mTc-PYP) has hitherto been assessed qualitatively by planar scintigraphy. We set out to perform quantitative tomographic scintigraphy in IIM. Results Ninety IIM patients and 48 control subjects underwent 99mTc-PYP single-photon emission computed tomography (SPECT)/CT of the upper and lower body. Scans were evaluated visually by an intensity score (1–4) and quantitatively by the mean standardized uptake value (SUVmean) in thigh muscles after semi-automated segmentation of these. Furthermore, a SUVmean gradient down along the thighs was determined by linear regression of the slice-by-slice activity. Interobserver analyses were performed on qualitative evaluations. Compared to controls, patients more often had a high intensity score (p

The purpose of this study was to assess the image quality of the low dose 2D/3D slot scanner (LDSS) imaging system compared to conventional digital radiography (DR) imaging systems. Visual image quality was assessed using the visual grading analysis (VGA) method. This method is a subjective approach that uses a human observer to evaluate and optimise radiographic images for different imaging technologies. Methods and materials: ten posterior-anterior (PA) and ten lateral (LAT) images of a chest anthropomorphic phantoms and a knee phantom were acquired by an LDSS imaging system and two conventional DR imaging systems. The images were shown in random order to three (chest) radiologists and three experienced (knee) radiographers, who scored the images against a number of criteria. Inter- and intraobserver agreement was assessed using Fleiss’ kappa and weighted kappa. Results: the statistical comparison of the agreement between the observers showed good interobserver agreement, with Fleiss’ kappa coefficients of 0.27–0.63 and 0.23–0.45 for the chest and knee protocols, respectively. Comparison of intraobserver agreement also showed good agreement with weighted kappa coefficients of 0.27–0.63 and 0.23–0.45 for the chest and knee protocols, respectively. The LDSS imaging system achieved significantly higher VGA image quality compared to the DR imaging systems in the AP and LAT chest protocols (p < 0.001). However, the LDSS imaging system achieved lower image quality than one DR system (p ≤ 0.016) and equivalent image quality to the other DR systems (p ≤ 0.27) in the knee protocol. The LDSS imaging system achieved effective dose savings of 33–52% for the chest protocol and 30–35% for the knee protocol compared with DR systems. Conclusions: this work has shown that the LDSS imaging system has the potential to acquire chest and knee images at diagnostic quality and at a lower effective dose than DR systems.

The aim of this study was to determine the quantitative image quality metrics of the low-dose 2D/3D EOS slot scanner X-ray imaging system (LDSS) compared with conventional digital radiography (DR) X-ray imaging systems. The effective detective quantum efficiency (eDQE) and effective noise quantum equivalent (eNEQ) were measured using chest and knee protocols. Methods: A Nationwide Evaluation of X-ray Trends (NEXT) of a chest adult phantom and a PolyMethylmethacrylate (PMMA) phantom were used for the chest and knee protocols, respectively. Quantitative image quality metrics, including effective normalised noise power spectrum (eNNPS), effective modulation transfer function (eMTF), eDQE and eNEQ of the LDSS and DR imaging systems were assessed and compared. Results: In the chest acquisition, the LDSS imaging system achieved significantly higher eNEQ and eDQE than the DR imaging systems at lower and higher spatial frequencies (0.001 ≤ p ≤ 0.044). For the knee acquisition, the LDSS imaging system also achieved significantly higher eNEQ and eDQE than the DR imaging systems at lower and higher spatial frequencies (0.001 ≤ p ≤ 0.002). However, there was no significant difference in eNEQ and eDQE between DR systems 1 and 2 at lower and higher spatial frequencies (0.10 < p < 1.00) for either chest or knee protocols. Conclusion: The LDSS imaging system performed well compared to the DR systems. Thus, we have demonstrated that the LDSS imaging system has the potential to be used for clinical diagnostic purposes.

Multislice cardiac CT characterizes late stage macrocalcification in epicardial arteries as opposed to PET/CT, which mirrors early phase arterial wall changes in epicardial and transmural coronary arteries. With regard to tracer, there has been a shift from using mainly 18F-fluorodeoxyglucose (FDG), indicating inflammation, to applying predominantly 18F-sodium fluoride (NaF) due to its high affinity for arterial wall microcalcification and more consistent association with cardiovascular risk factors. To make NaF-PET/CT an indispensable adjunct to clinical assessment of cardiac atherosclerosis, the Alavi–Carlsen Calcification Score (ACCS) has been proposed. It constitutes a global assessment of cardiac atherosclerosis burden in the individual patient, supported by an artificial intelligence (AI)-based approach for fast observer-independent segmentation. Common measures for characterizing epicardial coronary atherosclerosis by NaF-PET/CT as the maximum standardized uptake value (SUV) or target-to-background ratio are more versatile, error prone, and less reproducible than the ACCS, which equals the average cardiac SUV. The AI-based approach ensures a quick and easy delineation of the entire heart in 3D to obtain the ACCS expressing ongoing global cardiac atherosclerosis, even before it gives rise to CT-detectable coronary calcification. The quantification of global cardiac atherosclerotic burden by the ACCS is suited for management triage and monitoring of disease progression with and without intervention.

Abstract Background Group-sequential testing is widely used in pivotal therapeutic, but rarely in diagnostic research, although it may save studies, time, and costs. The purpose of this paper was to demonstrate a group-sequential analysis strategy in an intra-observer study on quantitative FDG-PET/CT measurements, illuminating the possibility of early trial termination which implicates significant potential time and resource savings. Methods Primary lesion maximum standardised uptake value (SUVmax) was determined twice from preoperative FDG-PET/CTs in 45 ovarian cancer patients. Differences in SUVmax were assumed to be normally distributed, and sequential one-sided hypothesis tests on the population standard deviation of the differences against a hypothesised value of 1.5 were performed, employing an alpha spending function. The fixed-sample analysis (N = 45) was compared with the group-sequential analysis strategies comprising one (at N = 23), two (at N = 15, 30), or three interim analyses (at N = 11, 23, 34), respectively, which were defined post hoc. Results When performing interim analyses with one third and two thirds of patients, sufficient agreement could be concluded after the first interim analysis and the final analysis. Other partitions did not suggest early stopping after adjustment for multiple testing due to one influential outlier and our small sample size. Conclusions Group-sequential testing may enable early stopping of a trial, allowing for potential time and resource savings. The testing strategy must, though, be defined at the planning stage, and sample sizes must be reasonably large at interim analysis to ensure robustness against single outliers. Group-sequential testing may have a place in accuracy and agreement studies.