Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Risk of cancer and serious disease in Danish patients with urgent referral for serious non-specific symptoms and signs of cancer in Funen 2014-2021.

BACKGROUND: In 2011, as the first European country, Denmark introduced the non-organ-specific cancer patient pathway (CPP) for patients presenting with non-specific symptoms and signs of cancer (NSSC). The proportion of patients with cancer over time is unknown. METHODS: A retrospective cohort study of all patients with a NSSC-CPP investigational course in the province of Funen to the Diagnostic Centre in Svendborg from 2014 to 2021 was performed to evaluate the proportion of patients with cancer and serious disease over time. RESULTS: A total of 6698 patients were referred to the NSSC-CPP of which 20.2% had cancer. While the crude referral rate increased from 114 per 100,000 people in 2014 and stabilised to around 214 in 2017-2021, the cancer detection rate of the total yearly new cancers in Funen diagnosed through the NSSC-CPP in DC Svendborg increased from 3 to 6%. CONCLUSIONS: With now high and stable conversion and crude referral rates, the NSSC-CPP is one of the largest CPPs in Denmark as measured by the number of new cancer cases found. Similar urgent referral programmes in other countries might fill an unmet medical need for patients presenting with serious non-specific symptoms and signs of cancer in general practice.

Comparison of cystatin C-based estimated glomerular filtration rate with measured glomerular filtration rate in a pediatric cohort of patients with chronic kidney disease.

BACKGROUND: It is essential to have an accurate assessment of the renal function of patients with chronic kidney disease to monitor, treat, and predict further development of the condition. Measurement of renal function in terms of glomerular filtration rate (GFR) requires either urine or blood sampling, but especially in children, more simple methods of measurement are preferable. The main objective of this study was to examine if the estimated GFR (eGFR) calculated with different cystatin-C-based equations was comparable to the GFR measured by a radiotracer (mGFR) in pediatric patients. METHODS: In this retrospective study, 28 pediatric patients contributed with 73 pairs of measurements collected within 5 years. Bland-Altman Limits of Agreement were used to evaluate the performance and accuracy of two different cystatin-C-based estimates, the CKiDCrea-CysC and the CKiDU25 respectively, compared to an mGFR based on plasma clearance of technetium-99m-diethylenetriaminepentaacetic acid or chromium-51-ethylenediaminetetraacetic acid. RESULTS: Using the CKiDCrea-CysC equation, 58.9% of the datasets were within P10 and 87.7% were within P30. The mean difference was 4.8 mL/min/1.73m2 (standard deviation: 8.5 mL/min/1.73m2) and tended to overestimate GFR and thereby overrate the kidney function within the entire GFR range. Using the CKiDU25 equation, 53.4% were within P10 and 93.2% within P30. The mean difference was -2.9 mL/min/1.73m2 (standard deviation: 8.4 mL/min/1.73m2), but the difference varied with the GFR value. CONCLUSIONS: A cystatin-C-based eGFR provides a viable substitute for monitoring renal function in pediatric patients with chronic kidney disease. However, it has a lower accuracy than mGFR and can therefore not replace mGFR in clinical use.

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial.

BACKGROUND: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. METHODS: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. RESULTS: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). CONCLUSIONS: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03243890.

Danish-German cardiogenic shock trial-DanGer shock: Trial design update.

BACKGROUND: The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular axial flow device Impella CP in treating patients with AMICS shock due to STEMI undergoing emergency percutaneous coronary intervention. METHODS: This statistical analysis plan represents an overview of the statistical methods which will be used for analyzing the DanGer Shock trial. RESULTS: The primary study endpoint is death from all causes through 180 days in the intention to treat population (all randomized consented patients). The secondary endpoints comprise; composite event of the need for additional mechanical support, need for cardiac transplantation, and death of all causes whichever comes first; and days alive and out of hospital. As exploratory analyses an as treated analysis of primary endpoint will be performed. Composite safety endpoint will comprise of major bleeding, vascular complications, device malfunction, damage to the aortic valve, and significant hemolysis. The primary endpoint death rate at 180 days will be analyzed using Cox proportional hazards analysis. The result will be reported as hazard ratio and corresponding 95% confidence interval (95% CI). No imputation of missing values will be performed. Additional statistical analyses for predefined hemodynamic, metabolic, renal, hematological, and health economics substudies will be specified in separate protocols. CONCLUSION: Main analyses of the primary and secondary outcomes of the DanGer Shock trial will be conducted according to this publication.

Population-wide evaluation of artificial intelligence and radiologist assessment of screening mammograms.

OBJECTIVES: To validate an AI system for standalone breast cancer detection on an entire screening population in comparison to first-reading breast radiologists. MATERIALS AND METHODS: All mammography screenings performed between August 4, 2014, and August 15, 2018, in the Region of Southern Denmark with follow-up within 24 months were eligible. Screenings were assessed as normal or abnormal by breast radiologists through double reading with arbitration. For an AI decision of normal or abnormal, two AI-score cut-off points were applied by matching at mean sensitivity (AIsens) and specificity (AIspec) of first readers. Accuracy measures were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and recall rate (RR). RESULTS: The sample included 249,402 screenings (149,495 women) and 2033 breast cancers (72.6% screen-detected cancers, 27.4% interval cancers). AIsens had lower specificity (97.5% vs 97.7%; p < 0.0001) and PPV (17.5% vs 18.7%; p = 0.01) and a higher RR (3.0% vs 2.8%; p < 0.0001) than first readers. AIspec was comparable to first readers in terms of all accuracy measures. Both AIsens and AIspec detected significantly fewer screen-detected cancers (1166 (AIsens), 1156 (AIspec) vs 1252; p < 0.0001) but found more interval cancers compared to first readers (126 (AIsens), 117 (AIspec) vs 39; p < 0.0001) with varying types of cancers detected across multiple subgroups. CONCLUSION: Standalone AI can detect breast cancer at an accuracy level equivalent to the standard of first readers when the AI threshold point was matched at first reader specificity. However, AI and first readers detected a different composition of cancers. CLINICAL RELEVANCE STATEMENT: Replacing first readers with AI with an appropriate cut-off score could be feasible. AI-detected cancers not detected by radiologists suggest a potential increase in the number of cancers detected if AI is implemented to support double reading within screening, although the clinicopathological characteristics of detected cancers would not change significantly. KEY POINTS: • Standalone AI cancer detection was compared to first readers in a double-read mammography screening population. • Standalone AI matched at first reader specificity showed no statistically significant difference in overall accuracy but detected different cancers. • With an appropriate threshold, AI-integrated screening can increase the number of detected cancers with similar clinicopathological characteristics.

Response monitoring in metastatic breast cancer: a comparison of survival times between FDG-PET/CT and CE-CT.

BACKGROUND: We compared overall survival for metastatic breast cancer (MBC) patients monitored with CE-CT, FDG-PET/CT or a combination of them in an observational setting. METHODS: Patients with biopsy-verified (recurrent or de novo) MBC (n = 300) who were treated at Odense university hospital (Denmark) and response monitored with FDG-PET/CT (n = 83), CE-CT (n = 144), or a combination of these (n = 73) were followed until 2019. Survival was compared between the scan groups, and were adjusted for clinico-histopathological variables representing potential confounders in a Cox proportional-hazard regression model. RESULTS: The study groups were mostly comparable regarding baseline characteristics, but liver metastases were reported more frequently in CE-CT group (38.9%) than in FDG-PET/CT group (19.3%) and combined group (24.7%). Median survival was 30.0 months for CE-CT group, 44.3 months for FDG-PET/CT group and 54.0 months for Combined group. Five-year survival rates were significantly higher for FDG-PET/CT group (41.9%) and combined group (43.3%), than for CE-CT group (15.8%). Using the CE-CT group as reference, the hazard ratio was 0.44 (95% CI: 0.29-0.68, P = 0.001) for the FDG-PET/CT group after adjusting for baseline characteristics. FDG-PET/CT detected the first progression 4.7 months earlier than CE-CT, leading to earlier treatment change. CONCLUSIONS: In this single-center, observational study, patients with metastatic breast cancer who were response monitored with FDG-PET/CT alone or in combination with CE-CT had longer overall survival than patients monitored with CE-CT alone. Confirmation of these findings by further, preferably randomised clinical trials is warranted.

Myositis-specific autoantibodies and QTc changes by ECG in idiopathic inflammatory myopathies.

OBJECTIVES: The aim of this study was to investigate cardiac involvement detected by ECG in patients with idiopathic inflammatory myopathies (IIMs) and to evaluate possible associations between the autoantibody profile and ECG changes in these patients. METHODS: In a Scandinavian cross-sectional study, patients were included from two Danish centres and one Swedish centre. Resting 12-lead ECG was investigated in 261 patients with IIM compared with 102 patients with systemic sclerosis (SSc) and 48 healthy controls (HCs). ECG changes were correlated to clinical manifestations and myositis-specific and myositis-associated autoantibodies (MSAs and MAAs, respectively). RESULTS: Patients with IIM had a longer mean corrected QT (QTc) duration and more frequently presented with prolonged QTc (≥450 ms; P = 0.038) compared with HCs. A longer QTc duration was recorded in SSc compared with IIM [433 ms (s.d. 23) vs 426 (24); P = 0.011], yet there was no significant difference in the fraction with prolonged QTc (SSc: 22%, IIM: 16%; P = 0.19). In multivariable regression analyses, anti-Mi2 (P = 0.01, P = 0.035) and anti-Pl-7 (P = 0.045, P = 0.014) were associated with QTc duration and prolonged QTc in IIM. Elevated CRP was associated with prolonged QTc (P = 0.041). CONCLUSION: The presence of QTc abnormalities was as common in patients with IIM as in patients with SSc, including prolonged QTc seen in almost one-fifth of the patients. Anti-Mi2, anti-Pl-7 and elevated CRP may serve as biomarkers for cardiac disease in IIM, but needs to be confirmed in a larger prospective study.

The diagnostic accuracy and clinical impact of FDG-PET/CT follow-up for patients on adjuvant immunotherapy for high-risk malignant melanoma.

OBJECTIVE: The benefit of FDG-PET/CT in follow-up of patients treated with adjuvant immunotherapy after resection of high-risk malignant melanoma (MM) is debated. This study evaluated the diagnostic accuracy and clinical impact of FDG-PET/CT for diagnosing MM recurrence during the first year after surgery. METHODS: We retrospectively included 124 patients with resected high-risk MM, who received adjuvant immunotherapy and follow-up FDG-PET/CT. Clinical information and AJCC-8 stage was obtained from patients' medical records. Recurrence was verified by biopsy/progression on a subsequent scan leading to change of treatment. Non-recurrence was assumed when no metastases were observed until the subsequent follow-up scan. Incidence of recurrence, sensitivity, specificity, positive and negative predictive values (PPV and NPV) were outcome measures. RESULTS: Incidence rate of MM recurrence was 0.27 [95% CI 0.17-0.37] per person-year during the first-year. Recurrence was detected in 13 patients (10%) at 3-month FDG-PET/CT, in 10 patients (8.1%) at 6 months, 1 patient (0.8%) at 9 months, 3 patients (2.4%) at 12 months. The overall sensitivity, specificity, PPV, and NPV were 97% [86-99], 82% [78-86], 39% [29-50], and 99% [98-99], respectively. The PPV trended towards higher values as disease stage increased. At the 3-month scan, the majority of actions derived from positive findings were surgery or earlier expedition of the subsequent follow-up scan. CONCLUSION: The high rate of recurrence in patients with high-risk MM treated with adjuvant immunotherapy emphasizes the need for follow-up. The potential harm by a moderately low specificity reflecting a high number of false-positive results must be weighed against the benefit of early detection of recurrence.

Improved stratification of stage-specific survival for cervical uterine cancer by integrating FDG-PET/CT and MRI for lymph node staging in 2018 FIGO classification.

OBJECTIVE: Staging carcinoma of the uterine cervix (CCU) by FIGO-2018 suggests stage migration of FIGO-2009 stage I-III patients with lymph node metastasis into FIGO-2018 stage IIIC. We aimed to investigate the prognostic value of lymph node metastases identified by imaging. METHODS: We enrolled all patients with biopsy-verified CCU from 2007 to 2016 at Odense University Hospital, Denmark. FDG-PET/CT and MRI were performed before clinical examination in general anesthesia. Disease-specific mortality was compared between women with lymph node-positive and lymph node-negative imaging. RESULTS: In total, 488 patients underwent clinical staging according to FIGO-2009. Lymph node-positive imaging was identified in 146 (30%) patients: 0/36 (0%) in stage IA, 22/195 (11%) in IBI, 14/30 (47%) in IB2, 70/164 (43%) in II and 40/63 (63%) in III. The 5-year cumulative incidence of death due to CCU lymph node-negative vs. lymph node-positive patients was 0.8% vs. 7.1% (p = 0.034) in stage IBI, 0% vs. 34.5% (p = 0.003) in stage IB2, 15.1% vs. 41.4% (p < 0.0001) in stage II, and 33.3% vs. 46.6% (p = 0.28) in stage III by FIGO-2009. CONCLUSIONS: One of three women with FIGO-2009 stage I-III CCU had suspected lymph node metastasis on imaging and is upstaged to stage IIIC according to FIGO-2018. The cancer-specific mortality by CCU was significantly lower in the lymph node-negative women stages IBI-II, thus supporting stage migration due to suspected lymph node metastasis. However, the exact prognostic value within stage IIIC is challenged, and future revision of FIGO stages may include new sub-stages.

Partial Nephrectomy versus Percutaneous Cryoablation of Small Renal Cell Carcinomas: A Comparison of Adverse Events in a Prospective Multicenter Cohort Study.

PURPOSE: To assess and compare complications and readmissions after partial nephrectomy and percutaneous cryoablation of cT1 renal cell carcinoma (RCC). MATERIALS AND METHODS: Patients treated for cT1 RCC between 2019 and 2021 were prospectively and consecutively enrolled. Complications recorded within 30 and 90 days were graded according to the Clavien-Dindo classification, and percutaneous cryoablation was graded according to the Society of Interventional Radiology classification of adverse events. Major complications were defined as complications with a grade of ≥3 based on the Clavien-Dindo classification. Readmission within 30 days was recorded. RESULTS: The cohort included 86 partial nephrectomies and 104 cryoablations. The complication rate within 90 days was 23% after partial nephrectomy and cryoablation (P = .98), with major complication rates of 3% after partial nephrectomy and 10% after cryoablation (P = .15). The readmission rates were 14% and 11% after partial nephrectomy and cryoablation, respectively (P = .48). Double-J stents were associated with overall complications (odds ratio [OR], 9.88; 95% confidence interval [CI], 2.18-44.68; P = .003) and readmissions (OR, 5.39; 95% CI, 1.37-21.06; P = .015) after cryoablation. A high versus low radius-endophytic-nearness-anterior-location score (OR, 5.86; 95% CI, 1.08-31.81; P = .040) and endophytic location (OR, 7.70; 95% CI, 1.72-34.50; P = .008) were associated with a higher complication rate after cryoablation. The Charlson Comorbidity Index (CCI) was associated with major complications after partial nephrectomy (OR, 2.12; 95% CI, 1.05-4.30; P = .036). CONCLUSIONS: Partial nephrectomy and cryoablation are comparable regarding complications within 90 days after treatment. Tumor complexity and double-J stents were associated with complications after cryoablation, and a high CCI was associated with complications after partial nephrectomy.

Sample size recalculation based on the prevalence in a randomized test-treatment study.

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.

Aortic wall segmentation in 18F-sodium fluoride PET/CT scans: Head-to-head comparison of artificial intelligence-based versus manual segmentation.

BACKGROUND: We aimed to establish and test an automated AI-based method for rapid segmentation of the aortic wall in positron emission tomography/computed tomography (PET/CT) scans. METHODS: For segmentation of the wall in three sections: the arch, thoracic, and abdominal aorta, we developed a tool based on a convolutional neural network (CNN), available on the Research Consortium for Medical Image Analysis (RECOMIA) platform, capable of segmenting 100 different labels in CT images. It was tested on 18F-sodium fluoride PET/CT scans of 49 subjects (29 healthy controls and 20 angina pectoris patients) and compared to data obtained by manual segmentation. The following derived parameters were compared using Bland-Altman Limits of Agreement: segmented volume, and maximal, mean, and total standardized uptake values (SUVmax, SUVmean, SUVtotal). The repeatability of the manual method was examined in 25 randomly selected scans. RESULTS: CNN-derived values for volume, SUVmax, and SUVtotal were all slightly, i.e., 13-17%, lower than the corresponding manually obtained ones, whereas SUVmean values for the three aortic sections were virtually identical for the two methods. Manual segmentation lasted typically 1-2 hours per scan compared to about one minute with the CNN-based approach. The maximal deviation at repeat manual segmentation was 6%. CONCLUSIONS: The automated CNN-based approach was much faster and provided parameters that were about 15% lower than the manually obtained values, except for SUVmean values, which were comparable. AI-based segmentation of the aorta already now appears as a trustworthy and fast alternative to slow and cumbersome manual segmentation.

"Global" cardiac atherosclerotic burden assessed by artificial intelligence-based versus manual segmentation in 18F-sodium fluoride PET/CT scans: Head-to-head comparison.

BACKGROUND: Artificial intelligence (AI) is known to provide effective means to accelerate and facilitate clinical and research processes. So in this study it was aimed to compare a AI-based method for cardiac segmentation in positron emission tomography/computed tomography (PET/CT) scans with manual segmentation to assess global cardiac atherosclerosis burden. METHODS: A trained convolutional neural network (CNN) was used for cardiac segmentation in 18F-sodium fluoride PET/CT scans of 29 healthy volunteers and 20 angina pectoris patients and compared with manual segmentation. Parameters for segmented volume (Vol) and mean, maximal, and total standardized uptake values (SUVmean, SUVmax, SUVtotal) were analyzed by Bland-Altman Limits of Agreement. Repeatability with AI-based assessment of the same scans is 100%. Repeatability (same conditions, same operator) and reproducibility (same conditions, two different operators) of manual segmentation was examined by re-segmentation in 25 randomly selected scans. RESULTS: Mean (± SD) values with manual vs. CNN-based segmentation were Vol 617.65 ± 154.99 mL vs 625.26 ± 153.55 mL (P = .21), SUVmean 0.69 ± 0.15 vs 0.69 ± 0.15 (P = .26), SUVmax 2.68 ± 0.86 vs 2.77 ± 1.05 (P = .34), and SUVtotal 425.51 ± 138.93 vs 427.91 ± 132.68 (P = .62). Limits of agreement were - 89.42 to 74.2, - 0.02 to 0.02, - 1.52 to 1.32, and - 68.02 to 63.21, respectively. Manual segmentation lasted typically 30 minutes vs about one minute with the CNN-based approach. The maximal deviation at manual re-segmentation was for the four parameters 0% to 0.5% with the same and 0% to 1% with different operators. CONCLUSION: The CNN-based method was faster and provided values for Vol, SUVmean, SUVmax, and SUVtotal comparable to the manually obtained ones. This AI-based segmentation approach appears to offer a more reproducible and much faster substitute for slow and cumbersome manual segmentation of the heart.

Sample size determination in method comparison and observer variability studies.

The comparison of two quantitative measuring devices is often performed with the Limits of Agreement proposed by Bland and Altman in their seminal Lancet paper back in 1986. Sample size considerations were rare for such agreement analyses in the past, but recently several proposals have been made depending on how agreement is to be assessed and the number of replicates to be used. We have summarized recent developments and recommendations in various situations including a distinction between method comparison and observer variability studies. These include current state-of-the-art analysis of and reporting guidelines for agreement studies. General recommendations close the paper.

Cisplatin-Resistant CD44+ Lung Cancer Cells Are Sensitive to Auger Electrons.

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.

Atherosclerosis Burdens in Diabetes Mellitus: Assessment by PET Imaging.

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.

FDG-PET/CT in high-risk primary breast cancer-a prospective study of stage migration and clinical impact.

PURPOSE: To investigate the clinical impact of FDG-PET/CT for staging and treatment planning in high-risk primary breast cancer. METHODS: Women with high-risk primary breast cancer were enrolled between September 2017 and August 2019 at Odense University Hospital, Denmark. Conventional mammography with/without MRI was performed before staging by FDG-PET/CT. We studied the accuracy of FDG-PET/CT for the detection of distant metastases, the effect on the change of treatment, and the prevalence of incidental findings. Biopsy and follow-up were used as a reference standard for the accuracy analysis. RESULTS: Of 103 women, 24 (23%) were diagnosed with distant metastases by FDG-PET/CT. Among these, breast surgery was omitted in 18 and could have been spared in six. Another sixteen (16%) patients were upstaged to more advanced loco-regional disease, leading to more extensive radiotherapy. Sensitivity and specificity for diagnosing distant metastases were 1.00 (95% confidence interval: 0.86-1.00) and 0.95 (0.88-0.99), respectively. Twenty-nine incidental findings were detected in 24 women (23%), leading to further examinations in 22 and diagnosis of eight (8/22, 36%) synchronous diseases: cancer (n = 4), thyroiditis (n = 2), aorta aneurysm (n = 1), and meningioma (n = 1). CONCLUSIONS: FDG-PET/CT had a substantial impact on staging and change of treatment in women with high-risk primary breast cancer, and further examination of incidental findings was considered clinically relevant. Our findings suggest that FDG-PET/CT should be considered for primary staging in high-risk primary breast cancer to improve treatment planning.

Hybrid PET/MRI in non-small cell lung cancer (NSCLC) and lung nodules-a literature review.

BACKGROUND: The use of hybrid PET/MRI for clinical staging is growing in several cancer forms and, consequently, PET/MRI has also gained interest in the assessment of non-small cell lung cancer (NSCLC) and lung lesions. However, lung evaluation with PET/MRI is associated with challenges related to technical issues and diagnostic image quality. We, therefore, investigated the published literature on PET/MRI for clinical staging in NSCLC or lung nodule detection specifically addressing diagnostic accuracy and technical issues. METHODS: The data originates from a systematic search performed in PubMed/MEDLINE, Embase, and Cochrane Library on hybrid PET/MRI in patients with cancer for a scoping review published earlier ( https://doi.org/10.1007/s00259-019-04402-8 ). Studies in English and German evaluating the diagnostic performance of hybrid PET/MRI for NSCLC or lung nodule detection in cancer patients were selected. Data reported in peer-reviewed journals without restrictions to year of publication were included. RESULTS: A total of 3138 publications were identified from which 116 published 2012-2018 were included. Of these, nine studies addressed PET/MRI in NSCLC (4) or lung nodule detection (5). Overall, PET/MRI did not provide advantages in preoperative T- and N-staging in NSCLC compared to PET/CT. The data on M-staging were too few for conclusions to be drawn. The lung nodule detection rate of PET/MRI was comparable to that of PET/CT for FDG-avid nodules larger than 10 mm, but the sensitivity of PET/MRI for detection of non-FDG-avid nodules smaller than 5 mm was low. CONCLUSION: PET/MRI did not provide advantages in T- and N-staging of NSCLC compared to PET/CT. PET/MRI had a comparable sensitivity for detection of FDG-avid lung nodules and nodules over 10 mm, but PET/CT yielded a higher detection rate in non FDG-avid lung nodules under 5 mm. With PET/MRI, the overall detection rate for lung nodules in various cancer types remains inferior to that of PET/CT due to the lower diagnostic performance of MRI than CT in the lungs.

Randomized test-treatment studies with an outlook on adaptive designs.

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.