Detection of Interstitial Lung Disease in Rheumatoid Arthritis by Thoracic Ultrasound: A Diagnostic Test Accuracy Study.

OBJECTIVE: To determine the diagnostic accuracy of thoracic ultrasound (TUS) for detecting interstitial lung disease (ILD) in rheumatoid arthritis (RA) with respiratory symptoms. METHODS: Individuals with RA visiting rheumatologic outpatient clinics in the Region of Southern Denmark were systematically screened for dyspnea, cough, recurrent pneumonia, prior severe pneumonia, or a chest x-ray indicating interstitial abnormalities. Eighty participants with a positive screening were consecutively included. Individuals were not eligible if they had a chest high-resolution computed tomography (HRCT) less than 12 months ago or were already diagnosed with ILD. A blinded TUS expert evaluated TUS, and TUS was registered as positive for ILD if at least 10 B-lines or bilateral thickened and fragmented pleura were present. The primary outcomes were TUS's sensitivity, specificity, and positive predictive value and negative predictive value. An ILD-specialized thoracic radiologist assessed HRCT, followed by a multidisciplinary team discussion, which was the reference standard. The accepted window of HRCT was less than 30 days after TUS was performed. RESULTS: A total of 77 participants received HRCT less than 30 days after TUS, and 23 (30%) were diagnosed with ILD. TUS had a sensitivity of 82.6% (95% confidence interval [CI] 61.2%-95.0%) and a specificity of 51.9% (95% CI 37.8%-65.7%), corresponding to a positive predictive value of 42.2% (95% CI 27.7%-57.8%) and a negative predictive value of 87.5% (95% CI 71.0%-96.5%). CONCLUSION: To our knowledge, this prospective study is the first to use respiratory symptoms in RA as inclusion criteria. Systematic screening for respiratory symptoms combined with TUS can reduce the diagnostic delay of ILD in RA.

Identification and management of interstitial lung abnormalities.

Interstitial lung abnormalities (ILA) are incidentally observed specific CT findings in patients without clinical suspicion of interstitial lung disease (ILD). ILA with basal and peripheral predominance and features suggestive of fibrosis in more than 5% of any part of the lung should be referred for pulmonologist review. The strategy for monitoring as described in this review is based on clinical and radiological risk factors. ILA are associated with risk of progression to ILD and increased mortality. Early identification and assessment of risk factors for progression are essential to improve outcome.

Thoracic ultrasonographic and clinical findings at 12-month follow-up of patients admitted with COVID-19.

Introduction: Thoracic ultrasound (TUS) has proven useful in the diagnosis, risk stratification and monitoring of disease progression in patients with coronavirus disease 2019 (COVID-19). However, utility in follow-up is poorly described. To elucidate this area, we performed TUS as part of a 12-month clinical follow-up in patients previously admitted with COVID-19 and correlated findings with clinical assessment and pulmonary function tests. Methods: Adult patients discharged from our hospital following admission with COVID-19 during March to May 2020 were invited to a 12-month follow-up. Enrolled patients were interviewed regarding persisting or newly developed symptoms in addition to TUS, spirometry and a 6-min walk test. Patients were referred to high-resolution computed tomography (HRCT) of the lungs if suspicion of pulmonary fibrosis was raised. Results: Forty patients were enrolled in the study of whom had 13 developed acute respiratory distress syndrome (ARDS) during admission. Patients with ARDS were more prone to experience neurological symptoms at follow-up (p = 0.03) and showed more B-lines on TUS (p = 0.008) but did not otherwise differ significantly in terms of pulmonary function tests. Four patients had pathological findings on TUS where subsequent diagnostics revealed that two had interstitial lung abnormalities and two had heart failure. These four patients presented with a significantly lower diffusing capacity of lung for carbon monoxide (p=0.03) and 6-min walking distance (p=0.006) compared to the remaining 36 patients without ultrasound pathology. No significant difference was observed in spirometry values of % of predicted FEV1 (p=0.49) or FVC (p=0.07). No persisting cardiovascular pathology was observed in patients without ultrasonographic pathology. Conclusion: At 12-month after admission with COVID-19, a follow-up combining TUS, clinical assessment, and pulmonary function tests may improve the selection of patients requiring further diagnostic investigations such as HRCT or echocardiography.

Potential impact of texture analysis in contrast enhanced CT in non-small cell lung cancer as a marker of survival: A retrospective feasibility study.

The objective of this feasibility study was to assess computed tomography (CT) texture analysis (CTTA) of pulmonary lesions as a predictor of overall survival in patients with suspected lung cancer on contrast-enhanced computed tomography (CECT). In a retrospective pilot study, 94 patients (52 men and 42 women; mean age, 67.2 ±â€…10.8 yrs) from 1 center with non-small cell lung cancer (NSCLC) underwent CTTA on the primary lesion by 2 individual readers. Both simple and multivariate Cox regression analyses correlating textural parameters with overall survival were performed. Statistically significant parameters were selected, and optimal cutoff values were determined. Kaplan-Meier plots based on these results were produced. Simple Cox regression analysis showed that normalized uniformity had a hazard ratio (HR) of 16.059 (3.861-66.788, P < .001), and skewness had an HR of 1.914 (1.330-2.754, P < .001). The optimal cutoff values for both parameters were 0.8602 and 0.1554, respectively. Normalized uniformity, clinical stage, and skewness were found to be prognostic factors for overall survival in multivariate analysis. Tumor heterogeneity, assessed by normalized uniformity and skewness on CECT may be a prognostic factor for overall survival.

Using thoracic ultrasound to detect interstitial lung disease in patients with rheumatoid arthritis: a protocol for the diagnostic test accuracy AURORA study.

INTRODUCTION: Pulmonary diseases are significant contributors to morbidity and mortality in patients with rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) may be prevalent in up to 30% and clinically evident in 10% of patients with RA. Feasible methods to detect concomitant ILD in RA are warranted. Our objective is to determine the diagnostic accuracy of thoracic ultrasound (TUS) for ILD in patients with RA with respiratory symptoms, by using chest high-resolution CT (HRCT) as the reference standard. Further, we aim to evaluate the diagnostic accuracy for the promising blood biomarkers surfactant protein-D and microfibrillar-associated protein 4 in the detection of ILD in this group of patients. METHODS AND ANALYSIS: By use of a standardised 14 zone protocol patients suspected of having RA-ILD will undergo TUS as index test performed by a junior resident in rheumatology (BKS), who is certified by the European Respiratory Society in performing TUS assessments. Participants form a consecutive series of up to 80 individuals in total. The anonymised TUS images will be stored and scored by the junior resident as well as two senior rheumatologists, who have received training in TUS, and a TUS-experienced pulmonologist. HRCT will be used as the gold standard for ILD diagnosis (reference standard). The two basic measures for quantifying the diagnostic test accuracy of the TUS test are the sensitivity and specificity in comparison to the HRCT. ETHICS AND DISSEMINATION: Data will be collected and stored in the Research Electronic Data Capture database. The study is approved by the Committees on Health Research Ethics and the Danish Data Protection Agency. The project is registered at clinicaltrials.gov (NCT05396469, pre-results) and data will be published in peer-reviewed journals.

A rare case of metastatic atypical meningioma that highlights the shortcomings of treatment options at present.

We report a case of a locally invasive recurrent atypical meningioma in the temporal region with late onset of meningioma lung metastasis. The patient was diagnosed in early adolescence with an atypical meningioma believed to be radiotherapy induced following treatment of a benign pilocytic astrocytoma in the hypothalamus region at 6 years of age. Even though the patient underwent several surgical and radiotherapy treatments, the intracranial meningioma kept growing and was locally invasive. The patient received experimental treatment with bevacizumab, a vascular endothelial growth factor A (VEGF-A)-inhibitor, for 4 years from age 26. Treatment was withdrawn after proven tumor growth on routine control MRI. A DOTA-TOC PET-CT-scan was performed to evaluate the DOTA-TOC somatostatin receptor number for possible SSTR (somatostatin receptor targeted therapy). In the included scan plan multiple lung metastasis were detected and later verified. Genomic tumor sequencing was performed, but no targeted treatment options were found. Instead, the patient finally, as the last treatment option, underwent 4 series of SSTR-targeted therapy (Lutetium DOTA-TOC). Unfortunately, the intracranial tumor component significantly progressed during the final stages of the treatment and the patient died less than a year after treatment was withdrawn at age 32. This case story illustrates the shortcomings of atypical/anaplastic meningioma treatment strategies at present and highlights the possibility of extracranial metastasis.

Increased use of diagnostic CT imaging increases the detection of stage IA lung cancer: pathways and patient characteristics.

BACKGROUND: At Silkeborg Regional Hospital, Denmark, the number of stage IA lung cancer increased after implementation of increased use of CT investigations and a corresponding reduction in chest X-ray. The aim of the present study was to understand the changes in referral pathways, patient characteristics and imaging procedures behind the observed increase in early-stage lung cancer. METHODS: The referral and imaging pathways for all patients diagnosed with lung cancer in 2013-2018 were described based on manually curated information from the electronic health care systems and staging information from the Danish Lung Cancer Registry. We compared the clinical characteristics of patients diagnosed in 2013-2015 and in 2016-2018 after implementation of a change in the use of low dose CT scan (LDCT). For patients diagnosed in 2016-2018, stage IA lung cancer were compared to higher stages using univariable logistic regression analysis. RESULTS: Five hundred and forty-seven patients were diagnosed with lung cancer in 2013-2018. Stage IA constituted 13.8% (34/247) in 2013-2015, and 28.3% (85/300) in 2016-2018. Stage IA patients in 2016-2018 were characterised by more comorbidity, fewer packyears and tended to be older than patients with higher stages. In 2016-2018, the largest proportion of stage IA patients (55%) came from within-hospital referrals. The majority of these lung cancers were detected due to imaging procedures with other indications than suspicion of lung cancer. The proportion of stage IA increased from 12% (12/99) to 36% (47/129) (p < 0.001) for hospital referrals and from 17% (22/129) to 23% (38/165) for GP referrals (p = 0.21). The imaging procedures contributing to the increase in stage IA was contrast enhanced CT (22%¸11/51), LDCT (35%; 18/51) and X-ray followed by LDCT (25%; 13/51). CONCLUSION: The increased access to LDCT for patients referred from general practice and the increased hospital requested CT activity resulted in an increase in the number of stage IA lung cancers. Incidental findings on imaging performed for diagnostic purposes unrelated to suspicion of lung cancer contributed a large proportion of the increase.

Intrapleural fibrinolysis and DNase versus video-assisted thoracic surgery (VATS) for the treatment of pleural empyema (FIVERVATS): protocol for a randomised, controlled trial - surgery as first-line treatment.

INTRODUCTION: Pleural empyema is a frequent disease with a high morbidity and mortality. Current standard treatment includes antibiotics and thoracic ultrasound (TUS)-guided pigtail drainage. Simultaneously with drainage, an intrapleural fibrinolyticum can be given. A potential better alternative is surgery in terms of video-assisted thoracoscopic surgery (VATS) as first-line treatment. The aim of this study is to determine the difference in outcome in patients diagnosed with complex parapneumonic effusion (stage II) and pleural empyema (stage III) who are treated with either VATS surgery or TUS-guided drainage and intrapleural therapy (fibrinolytic (Alteplase) with DNase (Pulmozyme)) as first-line treatment. METHODS AND ANALYSIS: A national, multicentre randomised, controlled study. Totally, 184 patients with a newly diagnosed community acquired complicated parapneumonic effusion or pleural empyema are randomised to either (1) VATS procedure with drainage or (2) TUS-guided pigtail catheter placement and intrapleural therapy with Actilyse and DNase. The total follow-up period is 12 months. The primary endpoint is length of hospital stay and secondary endpoints include for example, mortality, need for additional interventions, consumption of analgesia and quality of life. ETHICS AND DISSEMINATION: All patients provide informed consent before randomisation. The research project is carried out in accordance with the Helsinki II Declaration, European regulations and Good Clinical Practice Guidelines. The Scientific Ethics Committees for Denmark and the Danish Data Protection Agency have provided permission. Information about the subjects is protected under the Personal Data Processing Act and the Health Act. The trial is registered at www. CLINICALTRIALS: gov, and monitored by the regional Good clinical practice monitoring unit. The results of this study will be published in peer-reviewed journals and presented at various national and international conferences. TRIAL REGISTRATION NUMBER: NCT04095676.

[The no-need-to-see process for adrenal incidentalomas].

With wider application and technical improvement of imaging the discovery of adrenal incidentalomas (AI) has been skyrocketing. AI need to be investigated for evidence of hormonal hypersecretion and malignancy, and this causes a considerable use of health resources and potential medicalisation. In the "no-need-to-see" process, the clinical assessment of the citizen will only take place, if the diagnostic tests are abnormal. In this review, we examine the predictive values of imaging and paraclinical testing and argue, that normal test results in people without extra-adrenal cancer exclude disease.

Can visual assessment of blood flow patterns by dynamic contrast-enhanced computed tomography distinguish between malignant and benign lung tumors?

BACKGROUND: Dynamic contrast-enhanced computed tomography (DCE-CT) is a tool, which, in theory, can quantify the blood flow and blood volume of tissues. In structured qualitative analysis, parametric color maps yield a visual impression of the blood flow and blood volume within the tissue being studied, allowing for quick identification of the areas with the highest or lowest blood flow and blood volume. PURPOSE: To examine whether DCE-CT could be used to distinguish between malignant and benign lung tumors in patients with suspected lung cancer. MATERIAL AND METHODS: Fifty-nine patients with suspected lung cancer and a lung tumor on their chest radiograph were included for DCE-CT. The tumors were categorized using structured qualitative analysis of tumor blood flow patterns. Histopathology was used as reference standard. RESULTS: Using structured qualitative analysis of tumor blood flow patterns, it was possible to distinguish between malignant and benign lung tumors (Fisher-Freeman-Halton exact test, P = 0.022). The inter-reader agreement of this method of analysis was slight to moderate (kappa = 0.30; 95% confidence interval [CI] = 0.13-0.46). CONCLUSION: DCE-CT in suspected lung cancer using structured qualitative analysis of tumor blood flow patterns is accurate as well as somewhat reproducible. However, there are significant limitations to DCE-CT.

CT texture analysis can help differentiate between malignant and benign lymph nodes in the mediastinum in patients suspected for lung cancer.

BACKGROUND: In patients with non-small-cell lung carcinoma NSCLC the lymph node staging in the mediastinum is important due to impact on management and prognosis. Computed tomography texture analysis (CTTA) is a postprocessing technique that can evaluate the heterogeneity of marked regions in images. PURPOSE: To evaluate if CTTA can differentiate between malignant and benign lymph nodes in a cohort of patients with suspected lung cancer. MATERIAL AND METHODS: With tissue sampling as reference standard, 46 lymph nodes from 29 patients were analyzed using CTTA. For each lymph node, CTTA was performed using a research software "TexRAD" by drawing a region of interest (ROI) on all available axial contrast-enhanced computed tomography (CT) slices covering the entire volume of the lymph node. Lymph node CTTA comprised image filtration-histogram analysis undertakes two stages: the first step comprised an application of a Laplacian of Gaussian filter to highlight fine to coarse textures within the ROI, followed by a quantification of textures via histogram analysis using mean gray-level intensity from the entire volume of the lymph nodes. RESULTS: CTTA demonstrated a statistically significant difference between the malignant and the benign lymph nodes (P = 0.001), and by binary logistic regression we obtained a sensitivity of 53% and specificity of 97% in the test population. The area under the receiver operating curve was 83.4% and reproducibility was excellent. CONCLUSION: CTTA may be helpful in differentiating between malignant and benign lymph nodes in the mediastinum in patients suspected for lung cancer, with a low intra-observer variance.

Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography.

BACKGROUND: After the diagnosis Non-Small-Cell Lung Carcinoma (NSCLC) has been established, consideration must turn toward the stage of disease, because this will impact directly on management and prognosis. Staging is used to predict survival and to guide the patient toward the most appropriate treatment regimen or clinical trial. Distinguishing malignant involvement of the mediastinal lymph nodes (N2 or N3) from the hilar lymph nodes, or no lymph nodes (N0 or N1) is critical, because malignant involvement of N2 or N3 lymph nodes usually indicates non-surgically resectable disease. The purpose of this study was to examine and compare CT versus integrated F18-FDG PET/low dose CT (FDG PET/CT) for mediastinal staging in NSCLC, and the desire was to safely distinguish between malignant and benign lesions without the need for invasive procedures. All results were controlled for reproducibility. METHODS: 114 participants with NSCLC were included in a prospective cohort study. Blinded CT and FDG PET/CT images were reviewed. The participants' mediastinums were staged based on lymph node sizes (CT), or on FDG uptake (FDG PET/CT). Reference standard was tissue sampling. RESULTS: We found that there was no measureable difference between CT and FDG PET/CT mediastinal staging results; overall two-thirds of the participants in the study were correctly staged, and almost one-third of the participants were falsely staged. CONCLUSION: Neither CT nor FDG PET/CT could obviate the need for further invasive staging prior to thoracotomy in patients with NSCLC; for that purpose, the results of both modalities were too meagre. Therefore, these patients still depend on invasive staging methods. In our study, invasive staging was accomplished by mediastinoscopy. However, today this is increasingly replaced by EBUS or EUS.

LUCIS: lung cancer imaging studies.

Pulmonary nodules are of high clinical importance, as they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal opacities that may be solitary or multiple. A solitary pulmonary nodule (SPN) is a single, small (= 30 mm in diameter) radiographic opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of SPNs remains unclear. Current strategies include tissue sampling or CT follow-up. The aim of this PhD was to examine current non-invasive methods used to characterise pulmonary nodules and masses in patients with suspected lung cancer and to stage NSCLC. In doing so, this PhD helps to validate the existing methods used to diagnose and stage lung cancer correctly and, hopefully, aids in the development of new methods. In the first study, 213 participants with pulmonary nodules on CT were examined with an additional HRCT. In this study, it was concluded that HRCT of a solitary pulmonary nodule, assessed using attenuation and morphological criteria is a fast, widely available and effective method for diagnosing lung cancer correctly, and especially for ruling out cancer. In the second study, 168 patients with pulmonary lesions on CT were examined with an additional F-18-FDG PET/CT. It was concluded that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point at which further diagnostic imaging examination could be considered redundant. Standard contrast-enhanced CT seems better suited to identify patients with lung cancer than to rule out cancer. Finally, the overall diagnostic accuracy as well as the classification probabilities and predictive values of the two modalities were not significantly different. The reproducibility of the above results was substantial. In the third study, 59 patients with pulmonary nodules or masses on chest radiography were examined with an additional DCE-CT. A qualitative as well as a quantitative assessment method was examined. It was concluded that although the results of the qualitative approach were acceptable in their own right, they did not, however, add anything new when compared to standard CT. The quantitative approach gave rise to several conclusions concerning DCE-CT analysis as well as the use of DCE-CT in the diagnosis of lung cancer: First, that DCE-CT is best analysed using logarithmic scale data transformation; second, that irrespective of the ROI method applied, it was not possible to discriminate malignant and benign; and, third, that the lack of reproducibility should be addressed. These results show us that DCE-CT is currently not a clinically feasible method for analysing pulmonary lesions. This does not necessarily mean that DCE-CT should be abandoned, but it does signify the need for further development of the current DCE-CT methods. Finally, in the fourth study, 114 patients with NSCLC were examined with both a CT and with an additional F-18-FDG PET/CT. It was concluded that there was no significant difference in the overall diagnostic accuracy of the two modalities when imaging the mediastinum for staging purposes. In conclusion, although standard contrast-enhanced CT has brought us far in the characterisation of pulmonary nodules and masses, the last decade has seen a constant move away from strictly anatomical approaches to imaging, towards more functional or analytical approaches. The desire is, of course, to be able to safely distinguish between malignant and benign nodules without the need for invasive procedures.

Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [¹8F] fluorodeoxyglucose-positron emission tomography/computed tomography.

Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (<-30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial.

High resolution spiral CT for determining the malignant potential of solitary pulmonary nodules: refining and testing the test.

BACKGROUND: A solitary pulmonary nodule (SPN) may represent early stage lung cancer. Lung cancer is a devastating disease with an overall 5-year mortality rate of approximately 84% but with early detection and surgery as low as 47%. Currently a contrast-enhanced multiple-row detector CT (MDCT) scan is the first examination when evaluating patients with suspected lung cancer. PURPOSE: To apply an additional high resolution CT (HRCT) to SPNs to test whether certain morphological characteristics are associated with malignancy, to assess the diagnostic accuracy of HRCT in the characterization of SPNs, and to address the reproducibility of all measures. MATERIAL AND METHOD: Two hundred and thirteen participants with SPNs were included in a follow-up study. Blinded HRCT images were assessed with regard to margin risk categories (MRCs), calcification patterns and certain other characteristics and overall malignancy potential ratings (MPRs) were given. Morphological characteristics were tested against reference standard and ROC methodology was applied to assess diagnostic accuracy. Reproducibility was measured with Kappa statistics and 95% confidence intervals were computed for all results. Histopathology (90%) and CT follow-up (10%) were used as reference standard. RESULTS: MRCs (P < 0.001), calcification patterns (P = 0.003), and pleural retraction (P < 0.001) were all statistically significantly associated to malignancy. Reproducibility was moderate to substantial. Sensitivity, specificity, and overall diagnostic accuracy of HRCT were 98%, 23% and 87%, respectively. Reproducibility was substantial. CONCLUSION: Statistically significant associations between SPN MRCs, calcification patterns, pleural retraction and malignancy were found. HRCT yielded a very high sensitivity and a somewhat lower specificity for malignancy. Reproducibility was high.