False-positive Findings Research Articles

Abstract 4781: Evaluation of a TP53 biomarker for lung cancer risk in nasal brushings and peripheral blood

Abstract Background and Purpose: Early detection of lung cancer through annual screening with low-dose computed tomography (LDCT) scans enables potentially curative surgical or stereotactic body radiation therapy (SBRT) treatment and thereby significantly reduces mortality. However, LDCT screening among those currently eligible based primarily on age and smoking criteria yields a large number of false-positive findings and many lung cancers occur among individuals who currently are ineligible. A biomarker that identifies lung cancer risk independent from that caused by age and cigarette smoking might increase specificity and increase the number of people eligible for LDCT screening. Recently we demonstrated that a biomarker measuring TP53 somatic mutations in bronchial brush biopsy specimens from grossly normal airway epithelium was significantly associated with cancer status independent of age and smoking status. Additionally, the TP53 biomarker was synergistic with traditional risk score models (e.g. PLCOM2012 risk score). The goal of this pilot study was to test the TP53 biomarker in nasal brush biopsy specimens, a potential surrogate tissue obtained using less invasive collection methods. Methods: Nasal brushings from 10 lung cancer and 11 control subjects were collected at the University of Toledo and Vanderbilt University Medical Center under approved institutional protocols. Genomic DNA (gDNA) was extracted with the Qiagen AllPrep DNA/RNA kit using a modified protocol. Amplifiable copies of gDNA were measured using quantitative PCR. For each test a sample comprising 25,000 amplifiable copies of gDNA was combined with 50,000 copies of a TP53 internal standard and a complexity control, then PCR amplified, purified and barcoded. Samples were pooled to create two NGS libraries, each with approximately equal numbers of cases and controls, and sequenced on an Illumina MiSeq (Two V3 flow cells, 2 x 250 paired-end). Bioinformatic analysis was conducted using Qiagen CLC Workbench. Variants were called using the Basic Variant Detection Tool. Poisson Exact Test was utilized to determine the significance of endogenous variants relative to internal standard variants at the same base position and a Bonferroni correction was applied to minimize false discovery. Comparison of variant numbers between cases and controls was conducted using an f-test followed by a paired t-test. Results and Conclusions: Consistent with previous results in airway epithelium, in this pilot study the TP53 mutation biomarker measured in nasal brushing was associated with lung cancer (p=0.0085). Measurement of the TP53 biomarker in nasal brush specimens in a larger case-control study currently is underway along with a pilot study in gDNA from peripheral blood. Citation Format: Erin L. Crawford, Daniel J. Craig, Patrick T. Gorman, Mohamed Omballi, Rami Ahmad, Eric L. Grogan, Stephen A. Deppen, James C. Willey. Evaluation of a TP53 biomarker for lung cancer risk in nasal brushings and peripheral blood [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4781.

Do statistical heterogeneity methods impact the results of meta- analyses? A meta epidemiological study.

Orthodontic systematic reviews (SRs) use different methods to pool the individual studies in a meta-analysis when indicated. However, the number of studies included in orthodontic meta-analyses is relatively small. This study aimed to evaluate the direction of estimate changes of orthodontic meta-analyses (MAs) using different between-study variance methods considering the level of heterogeneity when few trials were pooled. Search and study selection: Systematic reviews (SRs) published over the last three years, from the 1st of January 2020 to the 31st of December 2022, in six main orthodontic journals with at least one MA pooling five or lesser primary studies were identified. Data collection and analysis: Data were extracted from each eligible MA, which was replicated in a random effect model using DerSimonian and Laird (DL), Paule-Mandel (PM), Restricted maximum-likelihood (REML), Hartung Knapp and Sidik Jonkman (HKSJ) methods. The results were reported using median and interquartile range (IQR) for continuous data and frequencies for categorical data and analyzed using non-parametric tests. The Boruta algorithm was used to assess the significant predictors for the significant change in the confidence interval between the different methods compared to the DL method, which was only feasible using the HKSJ method. 146 MAs were included, most applying the random effect model (n = 111; 76%) and pooling continuous data using mean difference (n = 121; 83%). The median number of studies was three (range 2, 4), and the overall statistical heterogeneity (I2 ranged from 0 to 99% with a median of 68%). Close to 60% of the significant findings became non-significant when HKSJ was applied compared to the DL method and when the heterogeneity was present I2>0%. On the other hand, 30.43% of the non-significant meta-analyses using the DL method became significant when HKSJ was used when the heterogeneity was absent I2 = 0%. Orthodontic MAs with few studies can produce different results based on the between-study variance method and the statistical heterogeneity level. Compared to DL, HKSJ method is overconservative when I2 is greater than 0% and may result in false positive findings when the heterogeneity is absent.

Frequently Encountered Artifacts in the Application of Dual-Energy Computed Tomography to Cardiovascular Imaging for Urate Crystals in Gout: A Matched-Control Study.

There is surging interest in using dual-energy computed tomography (DECT) to identify cardiovascular monosodium urate (MSU) deposits in patients with gout. We sought to examine the prevalence and characterization of cardiovascular DECT artifacts using non-electrocardiogram (EKG)-gated DECT pulmonary angiograms. We retrospectively reviewed non-EKG-gated DECT pulmonary angiograms performed on patients with and without gout at a single academic center. We noted the presence and locations of vascular green colorization using the default postprocessing two-material decomposition algorithm for MSU. The high- and low-energy grayscale images and advanced DECT measurements were used to determine whether they were true findings or artifacts. We classified artifacts into five categories: streak, contrast medium mixing, misregistration due to motion, foreign body, and noise. Our study included CT scans from 48 patients with gout and 48 age- and sex-matched controls. The majority of patients were male with a mean age of 67 years. Two independent observers attributed all areas of vascular green colorization to artifacts. The most common types of artifacts were streak (56% vs 57% between patients and controls, respectively) and contrast medium mixing (51% vs 65%, respectively). Whereas some of the default DECT measurements of cardiovascular green colorization were consistent with values reported for subcutaneous tophi, advanced DECT measurements were not consistent with that of tophi. Artifacts that could be misconstrued as cardiovascular MSU deposits were commonly identified in patients with and without gout on non-EKG-gated DECT pulmonary angiograms. These artifacts can inform future vascular DECT studies on patients with gout to minimize false-positive findings.

Reduced White Matter Fiber Density in Patients with Multiple Sclerosis.

Introduction: Improved understanding of multiple sclerosis (MS) symptomatology, disease mechanisms, and clinical effectiveness can be achieved by investigating microstructural damage. The aim was to gain deeper insights into changes in white matter (WM) tracts in MS patients. Methods: Diffusion magnetic resonance imaging-based tractography was utilized to segment WM tracts into regions of interest for further quantitative analysis. However, tractography is susceptible to false-positive findings, reducing its specificity and clinical feasibility. To address these limitations, the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) technique was used. COMMIT was used to derive measures of intracellular compartment (IC) and isotropic compartments from multishell diffusion data of 40 healthy controls (HCs) and 40 MS patients. Results: The analysis revealed a widespread pattern of significantly decreased IC values in MS patients compared with HCs across 61,581 voxels (pFWE < 0.05, threshold-free cluster enhancement [TFCE] corrected). Similar WM structures studied using the fractional anisotropy (FA) value also showed a reduction in FA among MS patients compared with HCs across 57,304 voxels (pFWE < 0.05, TFCE corrected). Out of the 61,581 voxels exhibiting lower IC, a substantial overlap of 47,251 voxels (76.72%) also demonstrated lower FA in MS patients compared with HCs. Discussion: The data suggested that lower IC values contributed to the explanation of FA reductions. In addition, IC showed promising potential for evaluating microstructural abnormalities in WM in MS, potentially being more sensitive than the frequently used FA value.

False-positive MDA findings in HRMS-based screening of putrefied postmortem blood samples-Identification of the interference as N-acetyltyramine.

An unidentified compound in putrefied postmortem blood samples showed identical accurate mass and chromatographic behavior as 3,4-methylenedioxyamphetamine (MDA) and led to false-positive preliminary screening results. The aim of the study was to identify this unknown interference. Postmortem blood samples were analyzed after protein precipitation on a QExactive Focus high-resolution mass spectrometer (Thermo Fisher, Germany) coupled to a RP C18 column (Macherey-Nagel, Germany). Based on the analysis of mass spectrometry (MS) adducts and isotope ratios using fullscan (m/z 134-330) information, the empiric formula of the protonated molecule [M + H]+ of the unknown compound was found to be C10H14O2N (+ 0.6 ppm). Product ion spectra recorded using normalized collision energy 22% showed a base peak of C8H9O1 (+ 1.5 ppm) and a low-abundant water loss to C7H9 (+ 1.9 ppm), neutral losses of C2H2O and NH3 were found. Based on fullscan and MS-MS information and under consideration of the observed order of neutral losses, the compound was presumptively identified as N-acetyltyramine. This assumption was supported by SIRIUS software showing a SIRIUS score of 99.43% for N-acetyltyramine. Finally, the putative structure annotation was confirmed by a reference compound. The described false-positive MDA findings could be attributed to the presence of N-acetyltyramine in putrefied blood samples. Being an isomer of MDA, N-acetyltyramine could not be distinguished by high-resolution data of the protonated molecules. The presented results once again highlight that false-positive findings may occur even in hyphenatedhigh-resolution mass spectrometry (HRMS) when using full-scan information only.

Fluorescence and immune-cell infiltration of nonneoplastic, postbrachytherapy brain tissue in 5-ALA-guided resection of recurrent anaplastic meningioma: illustrative case.

5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is a well-established technique for resecting high-grade gliomas. However, its application in meningiomas, especially those previously treated with radiation therapy, remains under investigation. A 48-year-old female with recurrent anaplastic meningioma, World Health Organization grade 3, underwent a right-sided craniotomy using off-label 5-ALA as a surgical adjunct. The patient had previously undergone brachytherapy seed implantation (20 × cesium 131) for tumor management. During the surgery, a large fluorescent tumor mass adjacent to the brachytherapy-treated area was resected, and the prior brachytherapy seeds were removed. Interestingly, the surrounding brain tissue in the irradiated area showed robust 5-ALA fluorescence. Pathological examination confirmed that the fluorescent brain tissue was nonneoplastic and associated with lymphocyte and macrophage infiltration. This case report presents unique 5-ALA fluorescence in nonneoplastic tissue following brachytherapy, which was found during the resection of recurrent anaplastic meningioma. This phenomenon may reflect an intricate interplay among radiation therapy, immune cells, the tumor microenvironment, and 5-ALA metabolism. Given that false-positive findings in fluorescence-guided surgery can lead to unnecessary tissue resection and increased surgical morbidity, further research is warranted to elucidate the mechanisms underlying this phenomenon and its implications for meningioma surgery.

Removing outliers from the normative database improves regional atrophy detection in single-subject voxel-based morphometry

PurposeSingle-subject voxel-based morphometry (VBM) compares an individual T1-weighted MRI to a sample of normal MRI in a normative database (NDB) to detect regional atrophy. Outliers in the NDB might result in reduced sensitivity of VBM. The primary aim of the current study was to propose a method for outlier removal (“NDB cleaning”) and to test its impact on the performance of VBM for detection of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsT1-weighted MRI of 81 patients with biomarker-confirmed AD (n = 51) or FTLD (n = 30) and 37 healthy subjects with simultaneous FDG-PET/MRI were included as test dataset. Two different NDBs were used: a scanner-specific NDB (37 healthy controls from the test dataset) and a non-scanner-specific NDB comprising 164 normal T1-weighted MRI from 164 different MRI scanners. Three different quality metrics based on leave-one-out testing of the scans in the NDB were implemented. A scan was removed if it was an outlier with respect to one or more quality metrics. VBM maps generated with and without NDB cleaning were assessed visually for the presence of AD or FTLD.ResultsSpecificity of visual interpretation of the VBM maps for detection of AD or FTLD was 100% in all settings. Sensitivity was increased by NDB cleaning with both NDBs. The effect was statistically significant for the multiple-scanner NDB (from 0.47 [95%-CI 0.36–0.58] to 0.61 [0.49–0.71]).ConclusionNDB cleaning has the potential to improve the sensitivity of VBM for the detection of AD or FTLD without increasing the risk of false positive findings.

Automated detection of focal cortical dysplasia based on magnetic resonance imaging and positron emission tomography

Purpose: Focal cortical dysplasia (FCD) is a common etiology of drug-resistant focal epilepsy. Visual identification of FCD is usually time-consuming and depends on personal experience. Herein, we propose an automated type II FCD detection approach utilizing multi-modal data and 3D convolutional neural network (CNN). Methods: MRI and positron emission tomography (PET) data of 82 patients with FCD were collected, including 55 (67.1%) histopathologically, and 27 (32.9%) radiologically diagnosed patients. Three types of morphometric feature maps and three types of tissue maps were extracted from the T1-weighted images. These maps, T1, and PET images formed the inputs for CNN. Five-fold cross-validations were carried out on the training set containing 62 patients, and the model behaving best was chosen to detect FCD on the test set of 20 patients. Furthermore, ablation experiments were performed to estimate the value of PET data and CNN. Results: On the validation set, FCD was detected in 90.3% of the cases, with an average of 1.7 possible lesions per patient. The sensitivity on the test set was 90.0%, with 1.85 possible lesions per patient. Without the PET data, the sensitivity decreased to 80.0%, and the average lesion number increased to 2.05 on the test set. If an artificial neural network replaced the CNN, the sensitivity decreased to 85.0%, and the average lesion number increased to 4.65. Significance: Automated detection of FCD with high sensitivity and few false-positive findings is feasible based on multi-modal data. PET data and CNN could improve the performance of automated detection.

The Diagnostic Value of CEUS in Assessing Non-Ossified Thyroid Cartilage Invasion in Patients with Laryngeal Squamous Cell Carcinoma

Background: Accurate assessment of thyroid cartilage invasion in squamous cell carcinoma (SCC) of the larynx remains a challenge in clinical practice. The aim of this study was to assess the diagnostic performance of contrast-enhanced ultrasound (CEUS), contrast-enhanced computed tomography (CECT), and magnetic resonance imaging (MRI) in the detection of non-ossified thyroid cartilage invasion in patients with SCC. Methods: CEUS, CECT, and MRI scans of 27 male patients with histologically proven SCC were evaluated and compared. A total of 31 cases were assessed via CEUS and CECT. The MR images of five patients and six cases were excluded (one patient had two suspected sites), leaving twenty-five cases for analysis via MRI. Results: CEUS showed the highest accuracy and specificity compared with CECT and MRI (87.1% vs. 64.5% and 76.0% as well as 84.0% vs. 64.0% and 72.7%, respectively). The sensitivity and negative predictive value of CEUS and MRI were the same (100%). CEUS yielded four false-positive findings. However, there were no statistically significant differences among the imaging modalities (p &gt; 0.05). Conclusions: CEUS showed better diagnostic performance than CECT and MRI. Therefore, CEUS has the potential to accurately assess non-ossified thyroid cartilage invasion and guide appropriate treatment decisions, hopefully leading to improved patient outcomes.

A pictorial view on false positive findings of 68Ga-PSMA-11 PET/CT and their prognostic value in patients with prostate carcinoma after radical prostatectomy and undetectable PSA values.

Recently, gallium-68-prostate-specific membrane antigen-11 (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) has become a key imaging method in prostate carcinoma staging and biochemical progression, with varying sensitivities in different studies (from 40% to 80%). After four years of experience with 68Ga-PSMA-11 PET/CT, we found that it is possible to detect lesions with increased PSMA expression in patients with undetectable prostate specific antigen (PSA) levels after radical prostatectomy. The key questions we wanted to answer were as follows: if those lesions were malignant and could the early detection of those malignant lesions have a role in patient management? We aimed to identify and follow up PSMA-positive findings for a period of 4 years in patients with prostate cancer after radical prostatectomy and undetectable PSA values at the time of the examination. We also explored false-positive lesions in detail. The study included all patients who underwent radical prostatectomy and had undetectable PSA values <0.05ng/mL and who underwent 68Ga-PSMA-11 PET/CT between July 2019 and December 2019. We performed 220 studies and found 40 patients with these characteristics; these patients were included in this study. All of them were followed up until July 2023. Any finding with increased radiopharmaceutical accumulation above the background activity in the respective area was considered a false positive. Prostate-specific membrane antigen accumulation in established lesions was assessed semi-quantitatively by the maximum standardized uptake value (SUVmax) and qualitatively by the four-point visual scale proposed in the E-PSMA recommendations. We found 15/40 (37.5%) patients with PSMA-positive findings. These were predominantly bone changes without a corresponding CT abnormality or discrete cystic or osteoblastic lesions with above-background increased PSMA expression. The mean SUVmax of these non-specific lesions was 3.02 (SD 2.86). After 3.5-4 years of follow-up, biochemical progression was found in only two of the patients.The great sensitivity of the method nowadays is a powerful engine for the development of new therapeutic options. On the other side, the lower specificity due to false positive findings, if misinterpreted, might lead to switching to a higher stage, with the planned radical treatment replaced by palliative treatment. The presence of 68Ga-PSMA-11 PET/CT-positive findings in patients after radical prostatectomy and an undetectable PSA had a low predictive value for future progression. The interpretation of 68Ga-PSMA-11 PET/CT should always include a complex assessment of the clinical setting-the risk group, PSA value and degree of PSMA accumulation in the lesions. In these situations, further clarification of PSMA-positive findings is appropriate before deciding to change treatment.

Minimal pericardial effusion on iodine 131 whole-body scan could be a false-positive finding.

Minimal pericardial effusion on iodine 131 whole-body scan could be a false-positive finding.

Autoantibody diagnostics in idiopathic inflammatory myopathy

Idiopathic inflammatory myopathy (IIM) is agroup of rare and heterogeneous systemic diseases that manifest not only in the muscles but also in the skin, joints, and lungs. Initial symptoms can be isolated and variable and thus the diagnosis poses challenges to various specialist groups. As autoantibodies are sometimes the only specific findings that lead to the diagnosis and appropriate treatment, basic knowledge of them is essential. This article explains the available test systems, names the clinical indications necessary for the initiation of autoantibody diagnostics, provides information on the etymology, antigens, synonyms, and first descriptors, describes indirect immunofluorescence on HEp‑2 cells induced by myositis antibodies, and provides clinical-serological associations. The comparison of the autoantibody findings with the clinical symptoms and laboratory findings enables the identification of false positive or false negative laboratory findings in the sense of aplausibility check.

Assessment of Distinct Gut Microbiome Signatures in a Diverse Cohort of Patients Undergoing Definitive Treatment for Rectal Cancer.

Disparities in incidence and outcome of rectal cancer are multifactorial in etiology but may be due, in part, to differences in gut microbiome composition. We used serial robust statistical approaches to assess baseline gut microbiome composition in a diverse cohort of patients with rectal cancer receiving definitive treatment. Microbiome composition was compared by age at diagnosis (< 50 vs ≥ 50 years), race and ethnicity (White Hispanic vs non-Hispanic), and response to therapy. Alpha diversity was assessed using the Shannon, Chao1, and Simpson diversity measures. Beta diversity was explored using both Bray-Curtis dissimilarity and Aitchison distance with principal coordinate analysis. To minimize false-positive findings, we used two distinct methods for differential abundance testing: LinDA and MaAsLin2 (all statistics two-sided, Benjamini-Hochberg corrected false discovery rate < 0.05). Among 64 patients (47% White Hispanic) with median age 51 years, beta diversity metrics showed significant clustering by race and ethnicity (p < 0.001 by both metrics) and by onset (Aitchison p = 0.022, Bray-Curtis p = 0.035). White Hispanic patients had enrichment of bacterial family Prevotellaceae (LinDA fold change 5.32, MaAsLin2 fold change 5.11, combined adjusted p = 0.0007). No significant differences in microbiome composition were associated with neoadjuvant therapy response. We identified distinct gut microbiome signatures associated with race and ethnicity and age of onset in a diverse cohort of patients undergoing definitive treatment for rectal cancer.

Development of RLK-Unet: a clinically favorable deep learning algorithm for brain metastasis detection and treatment response assessment.

Previous deep learning (DL) algorithms for brain metastasis (BM) detection and segmentation have not been commonly used in clinics because they produce false-positive findings, require multiple sequences, and do not reflect physiological properties such as necrosis. The aim of this study was to develop a more clinically favorable DL algorithm (RLK-Unet) using a single sequence reflecting necrosis and apply it to automated treatment response assessment. A total of 128 patients with 1339 BMs, who underwent BM magnetic resonance imaging using the contrast-enhanced 3D T1 weighted (T1WI) turbo spin-echo black blood sequence, were included in the development of the DL algorithm. Fifty-eight patients with 629 BMs were assessed for treatment response. The detection sensitivity, precision, Dice similarity coefficient (DSC), and agreement of treatment response assessments between neuroradiologists and RLK-Unet were assessed. RLK-Unet demonstrated a sensitivity of 86.9% and a precision of 79.6% for BMs and had a DSC of 0.663. Segmentation performance was better in the subgroup with larger BMs (DSC, 0.843). The agreement in the response assessment for BMs between the radiologists and RLK-Unet was excellent (intraclass correlation, 0.84). RLK-Unet yielded accurate detection and segmentation of BM and could assist clinicians in treatment response assessment.

Emerging Role of [18F]FLT PET/CT in Lymphoid Malignancies: A Review of Clinical Results.

Fluorine-18 fluorodeoxyglucose ([18F]FDG) is nowadays the leading positron emission tomography (PET) tracer for routine clinical work-ups in hematological malignancies; however, it is limited by false positive findings. Notably, false positives can occur in inflammatory and infective cases or in necrotic tumors that are infiltrated by macrophages and other inflammatory cells. In this context, 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been shown to be a promising imaging biomarker of hematological malignant cell proliferation. In this review, a total of 15 papers were reviewed to collect literature data regarding the clinical application of [18F]FLT PET/CT in hematological malignancies. This imaging modality seems to be a suitable tool for noninvasive assessment of tumor grading, also showing a correlation with Ki-67 immunostaining. Moreover, [18F]FLT PET/CT demonstrated high sensitivity in detecting aggressive lymphoma lesions, especially when applying a standardized uptake value (SUV) cutoff of 3. At baseline, the potential of [18F]FLT imaging as a predictive tool is demonstrated by the low tracer uptake in patients with a complete response. However, its use is limited in evaluating bone diseases due to its high physiological uptake in bone marrow. Interim [18F]FLT PET/CT (iFLT) has the potential to identify high-risk patients with greater precision than [18F]FDG PET/CT, optimizing risk-adapted therapy strategies. Moreover, [18F]FLT uptake showed a greater ability to differentiate tumor from inflammation compared to [18F]FDG, allowing the reduction of false-positive findings and making the first one a more selective tracer. Finally, FLT emerges as a superior independent predictor of PFS and OS compared to FDG and ensures a reliable early response assessment with greater accuracy and predictive value.

Initial Experience with 68Ga-FAP-2286 PET Imaging in Patients with Urothelial Cancer.

Improved imaging modalities are needed to accurately stage patients with muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Imaging with small-molecule ligands or inhibitors of fibroblast activation protein (FAP) is a promising modality that has demonstrated initial efficacy across a broad range of tumors. We present our experience with the novel FAP-peptide binder 68Ga-FAP-2286 in patients with MIBC. Methods: Patients with histopathologically confirmed bladder cancer who had either localized disease at diagnosis (localized cohort, n = 13) or known metastatic disease (metastatic cohort, n = 8) were imaged with 68Ga-FAP-2286 PET as part of a clinical trial (NCT04621435). The SUVmax of 68Ga-FAP-2286 PET-positive lesions and lesion size were documented. In patients who had available 18F-FDG PET performed within 45 d of 68Ga-FAP-2286 PET (n = 5), uptake on the 2 scans was compared. When there was a discrepancy between imaging modalities on retrospective review, biopsy of suggestive lesions was performed as the standard of care. Results: In the metastatic and localized cohorts, 36 and 18 68Ga-FAP-2286-avid lesions, respectively, were identified across multiple anatomic locations, including lymph nodes, visceral metastases, and bones. Fourteen of 36 lesions in the metastatic cohort and 14 of 18 lesions in the localized cohort were lymph nodes measuring less than 1 cm. Among lesions measuring less than 0.5 cm, 0.5-1 cm, and more than 1 cm, average SUVmax was 5.2 ± 2.6, 9.6 ± 3.7, and 13.0 ± 4.3, respectively, in the metastatic cohort and 10.5 ± 5.1, 10.8 ± 5.7, and 9.9 ± 5.4, respectively, in the localized cohort. Five patients had 18F-FDG PET available for comparison. The average SUVmax for lesions avid on 68Ga-FAP-2286 PET and 18F-FDG PET was 9.9 ± 3.4 versus 4.2 ± 1.9, respectively (n = 16 lesions). For 3 patients in the localized cohort, 68Ga-FAP-2286 PET informed clinical management, including identification of both false-positive findings on 18F-FDG PET and false-negative findings on conventional CT. Conclusion: 68Ga-FAP-2286 imaging is highly sensitive in patients with urothelial cancer and is effective in identifying metastatic lesions across a variety of anatomic sites, including subcentimeter lymph nodes that would not have raised suspicion on conventional scans. This novel imaging modality may inform clinical decision-making in patients with MIBC both by refining local nodal staging and by defining metastatic disease that would otherwise be undetectable on conventional imaging.

Fat tails and the need to disclose distribution parameters of qEEG databases.

Neurometry (a.k.a. quantitative EEG or qEEG) is a popular method to assess clinically relevant abnormalities in the electroencephalogram. Neurometry is based on norm values for the distribution of specific EEG parameters and believed to show good psychometric properties such as test-retest reliability. Many psychometric properties only hold under the Gaussian distribution and become problematic when distributions are fat-tailed. EEG signals are typically fat-tailed and do not show fast convergence to a Gaussian distribution. To circumvent this property of EEG, log-transformations have frequently, but not always been employed. In Monte Carlo simulations, we investigated the impact of fat-tails (i.e. deviations from Gaussian) on the cut-off criteria and changeability of what in neurometry is termed "abnormal EEG". Even slight deviations from the Gaussian distribution as measured by skewness and kurtosis lead to large inflation in the number of false positive qEEG findings. The more stringent the cutoff value adopted, the larger the inflation. Moreover, "abnormal EEG" seems to recover spontaneously at rates not compatible with the alleged test-retest reliability of qEEG. Alternative methods should be employed to determine cut-off values for diagnostics purposes, since a large number of false positive results emerge even when slight deviations from the Gaussian distribution are present. We argue that distribution properties of qEEG databases should be disclosed in much more detail by commercial providers to avoid questionable research practices and promote diagnostic transparency. We provide recommendations for the improvement of psychometric properties of existing qEEG databases.

General practitioners' perspectives on statutory skin cancer screening-A questionnaire-based cross-sectional survey in Germany.

In Germany, skin cancer screening (SCS) is available free of charge every two years to all those with statutory health insurance over the age of 35. General Practitioners (GP) can carry out the screening if they have completed an 8-hour training course. GPs play a crucial role in the implementation of SCS and act as gatekeepers between initial patient contact and referral to dermatologists. To record how comprehensively GPs carry out SCS in terms of patient information and body examination, as well as to explore GPs opinions on the feasibility of SCS. A cross-sectional survey was conducted. A questionnaire was sent to GPs with permission to perform SCS in two regions of Germany (Bavaria and Saxony) between August and September 2021. Data were analyzed using descriptive analysis. Subgroup analysis was performed according to regions (federal state, location of physician´s office), professional experience (experience in years, number of monthly screenings, age) and gender. Open questions were evaluated using qualitative content analysis. In the survey, 204 GPs responded. Genitalia (40.7%, 83/203), anal fold (62.3%, 127/204) and oral mucosa (66.7%, 136/204) were the least examined body regions during screening. Information on risks (false-positive findings: 18.6%, 38/203; false-negative findings: 13.2%, 27/203; overdiagnosis: 7.8%, 16/203) and benefits (48.0%, 98/202) were not always provided. GPs who performed screenings more frequently were more likely to provide information about the benefits of SCS (p<0.001; >10 vs. <5 screenings per month). Opinions were provided on uncertainties, knowledge requirements, structural and organizational requirements of SCS, SCS training and evaluation. The organization and remuneration of the SCS programme was seen as a barrier to implementation. GPs expressed uncertainties especially in unclear findings and in dermatoscopy. Uncertainties in the implementation of the SCS should be addressed by offering refresher courses. Good networking between GPs and dermatologists is essential to improve SCS quality.

Rationalizing polyp matching criteria in colon capsule endoscopy: an international expert consensus through RAND (modified DELPHI) process.

Colon capsule endoscopy (CCE) has gained momentum as an alternative modality for the investigation of the lower gastrointestinal tract. Of the few challenges that remain, the comparison and - eventually - matching of polyps at different timestamps leads to the potential for double reporting and can contribute to false-positive findings and inaccuracies. With the impending artificial intelligence integration, the risk of double reporting the same polyp due to the lack of information on spatial orientation underscores the necessity for establishing criteria for polyp matching. This RAND/University of California, Los Angeles (modified Delphi) process aims to identify the key factors or components used to match polyps within a CCE video. This involves exploring the attributes of each factor to create comprehensive polyp-matching criteria based on international expert consensus. A systematic qualitative study using surveys. A panel of 11 international CCE experts convened to assess a survey comprised of 60 statements. Participants anonymously rated statement appropriateness on a 1-9 scale (1-3: inappropriate, 4-6: uncertain and 7-9: appropriate). Following a virtual group discussion of the Round 1 results, a Round 2 survey was developed and completed before the final analysis. The factors that were agreed to be essential for polyp matching include (1) timestamp, (2) polyp localization, (3) polyp vascular pattern, (4) polyp size, (5) time interval of the polyp appearance between the green and yellow camera, (6) surrounding tissue, (7) polyp morphology and (8) polyp surface and contour. When five or more factors are satisfied, it was agreed that the comparing polyps are likely the same polyp. This study has established the first complete criteria for polyp matching in CCE. While it might not provide a definitive solution for matching difficult, small and common polyps, these criteria serve as a framework to guide and facilitate the process of polyp-matching.

The diagnostic yield of exome sequencing in liver diseases from a curated gene panel

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10–4 for dominant disorders and MAF ≤ 10–3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06–8.18, p value = 4.5e−12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.