Contrast Agent Dynamics Determine Radiomics Profiles in Oncologic Imaging.

BACKGROUND: The reproducibility of radiomics features extracted from CT and MRI examinations depends on several physiological and technical factors. The aim was to evaluate the impact of contrast agent timing on the stability of radiomics features using dynamic contrast-enhanced perfusion CT (dceCT) or MRI (dceMRI) in prostate and lung cancers. METHODS: Radiomics features were extracted from dceCT or dceMRI images in patients with biopsy-proven peripheral prostate cancer (pzPC) or biopsy-proven non-small cell lung cancer (NSCLC), respectively. Features that showed significant differences between contrast phases were identified using linear mixed models. An L2-penalized logistic regression classifier was used to predict class labels for pzPC and unaffected prostate regions-of-interest (ROIs). RESULTS: Nine pzPC and 28 NSCLC patients, who were imaged with dceCT and/or dceMRI, were included in this study. After normalizing for individual enhancement patterns by defining seven individual phases based on a reference vessel, 19, 467 and 128 out of 1204 CT features showed significant temporal dynamics in healthy prostate parenchyma, prostate tumors and lung tumors, respectively. CT radiomics-based classification accuracy of healthy and tumor ROIs was highly dependent on contrast agent phase. For dceMRI, 899 and 1027 out of 1118 features were significantly dependent on time after contrast agent injection for prostate and lung tumors. CONCLUSIONS: CT and MRI radiomics features in both prostate and lung tumors are significantly affected by interindividual differences in contrast agent dynamics.

Metabolic tumor volume and sites of organ involvement predict outcome in NSCLC immune-checkpoint inhibitor therapy.

PURPOSE: The purpose of this study was to assess the ability of pretreatment PET parameters and peripheral blood biomarkers to predict progression-free survival (PFS) and overall survival (OS) in NSCLC patients treated with ICIT. METHODS: We prospectively included 87 patients in this study who underwent pre-treatment [18F]-FDG PET/CT. Organ-specific and total metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured using a semiautomatic software. Sites of organ involvement (SOI) were assessed by PET/CT. The log-rank test and Cox-regression analysis were used to assess associations between clinical, laboratory, and imaging parameters with PFS and OS. Time dependent ROC were calculated and model performance was evaluated in terms of its clinical utility. RESULTS: MTV increased with the number of SOI and was correlated with neutrophil and lymphocyte cell count (Spearman's rho = 0.27 or 0.32; p =.02 or 0.003; respectively). Even after adjustment for known risk factors, such as PD-1 expression and neutrophil cell count, the MTV and the number of SOI were independent risk factors for progression (per 100 cm3; adjusted hazard ratio [aHR]: 1.13; 95% confidence interval [95%CI]: 1.01-1.28; p =.04; single SOI vs. ≥ 4 SOI: aHR: 2.26, 95%CI: 1.04-4.94; p =.04). MTV and the number of SOI were independent risk factors for overall survival (per 100 cm3 aHR: 1.11, 95%CI: 1.01-1.23; p =.03; single SOI vs. ≥ 4 SOI: aHR: 4.54, 95%CI: 1.64-12.58; p =.04). The combination of MTV and the number of SOI improved the risk stratification for PFS and OS (log-rank test p <.001; C-index: 0.64 and 0.67). CONCLUSION: The MTV and the number of SOI are simple imaging markers that provide complementary information to facilitate risk stratification in NSCLC patients scheduled for ICIT.

Neoadjuvant immune-checkpoint inhibitors in lung cancer - a primer for radiologists.

The introduction of neoadjuvant immune checkpoint inhibitors plus platinum-based chemotherapy has changed treatment regimens of patient's early-stage lung cancer. This treatment combination induces high rates of complete pathologic response and improves clinical endpoints. Imaging plays a fundamental role in assessment of treatment response, monitoring of (immune-related) adverse events and enables both the surgeon and pathologist optimal treatment and diagnostic workup of the resected tumor samples. Knowledge of the strengths and weaknesses of diagnostic imaging in this setting are essential for radiologists to provide valuable input in multidisciplinary team decisions.

[Mediastinum-new compartment classification]. / Mediastinum ­ neue Kompartimenteinteilung.

BACKGROUND: Mediastinal masses are common and comprise a heterogeneous spectrum of disorders. Correct diagnosis has prognostic and therapeutic consequences, which is why precise localization of lesions and interdisciplinary management are essential in clinical practice. This article describes traditional divisions of mediastinum lesions and presents the new classification based on cross-sectional imaging, which was developed by the International Thymic Malignancy Interest Group (ITMIG). OBJECTIVES: Which divisions of the mediastinum have been used so far and how does the division developed by the ITMIG differ? What are the advantages of the new mediastinal classification? MATERIALS AND METHODS: Comparison of the previously used mediastinal classification with the new mediastinal classification developed by ITMIG and visualization of the respective methods. In addition, pathologies typical for the respective compartments are explained. RESULTS AND CONCLUSION: The traditional compartmentalization of the mediastinum into an anterior, middle, and posterior mediastinum is not clearly defined and may lead to confusing interdisciplinary communication. Since these classifications are mostly based on projection radiographs, the proposed three-dimensional classification of the ITMIG is a development that suits the modern clinical workflow and promotes standardization. The three mediastinal compartments should thus be termed prevascular, visceral, and paravertebral.

Impact of a content-based image retrieval system on the interpretation of chest CTs of patients with diffuse parenchymal lung disease.

OBJECTIVES: Content-based image retrieval systems (CBIRS) are a new and potentially impactful tool for radiological reporting, but their clinical evaluation is largely missing. This study aimed at assessing the effect of CBIRS on the interpretation of chest CT scans from patients with suspected diffuse parenchymal lung disease (DPLD). MATERIALS AND METHODS: A total of 108 retrospectively included chest CT scans with 22 unique, clinically and/or histopathologically verified diagnoses were read by eight radiologists (four residents, four attending, median years reading chest CT scans 2.1± 0.7 and 12 ± 1.8, respectively). The radiologists read and provided the suspected diagnosis at a certified radiological workstation to simulate clinical routine. Half of the readings were done without CBIRS and half with the additional support of the CBIRS. The CBIRS retrieved the most likely of 19 lung-specific patterns from a large database of 6542 thin-section CT scans and provided relevant information (e.g., a list of potential differential diagnoses). RESULTS: Reading time decreased by 31.3% (p < 0.001) despite the radiologists searching for additional information more frequently when the CBIRS was available (154 [72%] vs. 95 [43%], p < 0.001). There was a trend towards higher overall diagnostic accuracy (42.2% vs 34.7%, p = 0.083) when the CBIRS was available. CONCLUSION: The use of the CBIRS had a beneficial impact on the reading time of chest CT scans in cases with DPLD. In addition, both resident and attending radiologists were more likely to consult informational resources if they had access to the CBIRS. Further studies are needed to confirm the observed trend towards increased diagnostic accuracy with the use of a CBIRS in practice. KEY POINTS: • A content-based image retrieval system for supporting the diagnostic process of reading chest CT scans can decrease reading time by 31.3% (p < 0.001). • The decrease in reading time was present despite frequent usage of the content-based image retrieval system. • Additionally, a trend towards higher diagnostic accuracy was observed when using the content-based image retrieval system (42.2% vs 34.7%, p = 0.083).

[Smoking-related interstitial lung diseases]. / Raucherassoziierte interstitielle Lungenerkrankungen.

CLINICAL ISSUE: Smoking-related interstitial lung diseases are a heterogeneous group of pulmonary abnormalities. The correct diagnosis has prognostic and therapeutic implications. This article introduces the most common smoking-related interstitial lung diseases and describes a structured approach to support the diagnostic workflow. PRACTICAL RECOMMENDATIONS: Computed tomography is pivotal in the diagnostic workflow of smoking-related interstitial lung diseases and may reduce the number of unnecessary lung biopsies. To achieve high diagnostic accuracy, a standardized scanning protocol, and a structured assessment approach should be utilized. During inflammatory stages of respiratory bronchiolitis (RB), respiratory bronchiolitis interstitial lung diseases (RB-ILD), and desquamative interstitial pneumonia (DIP), cessation of smoking as well as the use of steroids are the treatment of choice. In case of fibrotic changes (e.g., in idiopathic pulmonary fibrosis [IPF]), antifibrotic therapy with nintedanib and pirfenidone may be used. Patients with suspected smoking-related interstitial lung disease should be discussed in interdisciplinary board meetings.

[Chest radiography findings in diffuse parenchymal lung diseases]. / Röntgenbefunde bei diffusen parenchymatösen Lungenerkrankungen.

CLINICAL ISSUE: Diffuse parenchymal lung diseases include a heterogeneous group of diseases of the lung parenchyma, the alveolar spaces, the vessels and the airways, which can be triggered by various pathomechanisms, such as inflammation and fibrotic changes. Since the therapeutic approaches and prognoses differ significantly between the diseases, the correct diagnosis is of fundamental importance. In routine clinical practice, next to the patients' history, the clinical presentation, the laboratory findings and the bronchoscopy, imaging plays a central role in establishing a diagnosis. PRACTICAL RECOMMENDATIONS: The diagnosis of diffuse parenchymal lung diseases is an enormous challenge for clinicians, radiologists as well as pathologists and should therefore preferably be carried out in a multidisciplinary setting. Since patients often present with unspecific, respiratory symptoms, chest radiographs are the first imaging method used. Many patterns of diffuse parenchymal lung diseases (e.g., ground-glass opacities and consolidations), their distribution (e.g., cranial-caudal) and the presence of additional findings (e.g., mediastinal lymphadenopathy) are often already detectable on chest X­rays. However, the imaging reference standard and thus, an integral part of the assessment of diffuse parenchymal lung disease, is the chest HR-CT. In some cases, the pattern of the HR-CT is pathognomonic, in others it is unspecific for a disease, so that further diagnostic steps are necessary.

Assessing invasiveness of subsolid lung adenocarcinomas with combined attenuation and geometric feature models.

The aim of this study was to develop and test multiclass predictive models for assessing the invasiveness of individual lung adenocarcinomas presenting as subsolid nodules on computed tomography (CT). 227 lung adenocarcinomas were included: 31 atypical adenomatous hyperplasia and adenocarcinomas in situ (class H1), 64 minimally invasive adenocarcinomas (class H2) and 132 invasive adenocarcinomas (class H3). Nodules were segmented, and geometric and CT attenuation features including functional principal component analysis features (FPC1 and FPC2) were extracted. After a feature selection step, two predictive models were built with ordinal regression: Model 1 based on volume (log) (logarithm of the nodule volume) and FPC1, and Model 2 based on volume (log) and Q.875 (CT attenuation value at the 87.5% percentile). Using the 200-repeats Monte-Carlo cross-validation method, these models provided a multiclass classification of invasiveness with discriminative power AUCs of 0.83 to 0.87 and predicted the class probabilities with less than a 10% average error. The predictive modelling approach adopted in this paper provides a detailed insight on how the value of the main predictors contribute to the probability of nodule invasiveness and underlines the role of nodule CT attenuation features in the nodule invasiveness classification.

The Growth Rate of Subsolid Lung Adenocarcinoma Nodules at Chest CT.

Background Confirming that subsolid adenocarcinomas show exponential growth is important because it would justify using volume doubling time to assess their growth. Purpose To test whether the growth of lung adenocarcinomas manifesting as subsolid nodules at chest CT is accurately represented by an exponential model. Materials and Methods Patients with lung adenocarcinomas manifesting as subsolid nodules surgically resected between January 2005 and May 2018, with three or more longitudinal CT examinations before resection, were retrospectively included. Overall volume (for all nodules) and solid component volume (for part-solid nodules) were measured over time. A linear mixed-effects model was used to identify the growth pattern (linear, exponential, quadratic, or power law) that best represented growth. The interactions between nodule growth and clinical, CT morphologic, and pathologic parameters were studied. Results Sixty-nine patients (mean age, 70 years ± 9 [standard deviation]; 48 women) with 74 lung adenocarcinomas were evaluated. Overall growth and solid component growth were better represented by an exponential model (adjusted R2 = 0.89 and 0.95, respectively) than by a quadratic model (r2 = 0.88 and 0.93, respectively), a linear model (r2 = 0.87 and 0.92, respectively), or a power law model (r2 = 0.82 and 0.93, respectively). Faster overall volume growth was associated with a history of lung cancer (P < .001), a baseline nodule volume less than 500 mm3 (P = .03), and histologic findings of invasive adenocarcinoma (P < .001). The median volume doubling time of noninvasive adenocarcinoma was significantly longer than that of invasive adenocarcinoma (939 days [interquartile range, 588-1563 days] vs 678 days [interquartile range, 392-916 days], respectively; P = .01). Conclusion The overall volume growth of adenocarcinomas manifesting as subsolid nodules at chest CT was best represented by an exponential model compared with the other tested models. This justifies the use of volume doubling time for the growth assessment of these nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kuriyama and Yanagawa in this issue.

Preoperative bronchial cytology for the assessment of tumor spread through air spaces in lung adenocarcinoma resection specimens.

BACKGROUND: Tumor spread through air spaces (STAS), a significant prognostic indicator, has been described recently as a pattern of invasion in pulmonary carcinomas. However, questions remain regarding preoperative identification of STAS and whether it represents an in vivo phenomenon versus an ex vivo artifact. METHODS: We retrospectively reviewed 67 paired preoperative bronchoalveolar lavage (BAL) or bronchial washing (BW) cytology specimens with the subsequent lung adenocarcinoma surgical resection specimen to determine whether preoperative cytology could predict STAS. Other clinical, radiologic, and pathologic features of the resected lesions were also correlated with preoperative bronchial cytology results. RESULTS: Positive bronchial cytology was observed in 28 cases (41.8%), 24 of which had STAS (85.7%); however, negative BAL/BW cytology was observed in 39 cases (58.2%), 29 of which had STAS (74.4%) (x2  = 1.27, P = .26, not significant). High-STAS burden was observed in 44 cases (83.0%), 21 (47.7%) with negative BAL/BW and 23 (52.3%) with positive BAL/BW. Low-STAS burden was observed in 9 cases (17.0%), 8 (88.9%) with negative BAL/BW and only 1 (11.1%) with positive BAL/BW (x2  = 5.11, P = .024, significant). For tumors with STAS, a statistically significant difference was identified in the maximal STAS distance from the main tumor edge between BAL/BW-positive and BAL/BW-negative groups (P = .007). Of the remaining clinicopathologic and radiologic features, only visceral pleural invasion was significantly associated with BAL/BW positivity. CONCLUSION: Presurgical bronchial cytology alone cannot adequately predict tumor STAS; however, it may provide useful information regarding the extent and overall burden of STAS on the subsequent resection specimen.

Growth Assessment of Pulmonary Adenocarcinomas Manifesting as Subsolid Nodules on CT: Comparison of Diameter-Based and Volume Measurements.

RATIONALE AND OBJECTIVES: To analyze the performances of diameter-based measurements, either using diameters, or by calculating diameter-based volumes, as compared to volume measurements in assessing growth of pulmonary adenocarcinomas manifesting as subsolid nodules on CT. MATERIALS AND METHODS: In this IRB-approved, retrospective study, 74 pulmonary adenocarcinomas presenting as subsolid nodules and resected in 69 patients (21 men, 48 women, mean age 70 ± 9 years) were included. Three CTs were available for each patient. Nodule size on each CT was assessed with diameter measurements, calculated volume based on diameter measurements, and measured volume. Nodule growth was defined as an increase of measured volume ≥25% between two sequential CTs. Sensitivity, specificity, accuracy, positive and negative predictive values of diameter-based measurements for growth assessment were calculated. Nodule characteristics were compared with nonparametric tests and analysis of variance. RESULTS: There were fewer growing nodules during CT1-CT2 interval (n = 22, 30%) than during CT2-CT3 interval (n = 33, 45%, p =.060). Specificity and negative predictive value of diameter-based measurements for growth assessment ranged respectively from 52 to 77% and 81 to 83% between CT1 and CT2, and from 66 to 76% and 79 to 90% between CT2 and CT3. Nongrowing nodules tended to be larger, regardless how size was measured, and some of these differences in size were statistically significant (p =.002 to .046). CONCLUSION: For pulmonary adenocarcinomas presenting as subsolid nodules on CT, diameter-based assessment of nodule volume is reasonably accurate at confirming a lack of nodule growth but may overestimate actual growth, as compared to growth assessment based on measured volume.

Visceral Pleural Invasion in Pulmonary Adenocarcinoma: Differences in CT Patterns between Solid and Subsolid Cancers.

PURPOSE: To analyze the incidence and CT patterns of visceral pleural invasion (VPI) in adenocarcinomas on the basis of their CT presentation as solid or subsolid nodules. MATERIALS AND METHODS: A total of 286 adenocarcinomas in direct contact with a pleural surface, resected at an institution between 2005 and 2016, were included in this retrospective, institutional review board-approved study. CT size and longest contact length with a pleural surface were measured and their ratios computed. Pleural deviation, pleural thickening, spiculations, different pleural tag types, pleural effusion, and the CT appearance of transgression into an adjacent lobe or infiltration of surrounding tissue were evaluated. Fisher exact tests and simple and multiple logistic regression models were used. RESULTS: Of the 286 nodules, 179 of 286 (62.6%) were solid and 107 of 286 (37.4%) were subsolid. VPI was present in 49 of 286 (17.1%) nodules and was significantly more frequent in solid (44 of 179; 24.6%) than in subsolid nodules (five of 107; 4.7%; P < .001). In solid nodules, multiple regression analysis showed an association of higher contact length-to-size ratio (adjusted odds ratio [OR], 1.02; P = .007) and the presence of multiple pleural tag types (adjusted OR, 5.88; P = .002) with VPI. In subsolid nodules, longer pleural contact length of the solid nodular component (adjusted OR, 1.27; P = .017) and the CT appearance of transgression or infiltration (adjusted OR, 10.75; P = .037) were associated with VPI. CONCLUSION: During preoperative evaluation of adenocarcinomas for the likelihood of VPI, whether a tumor manifests as a solid or a subsolid nodule is important to consider because the incidence of VPI is significantly higher in solid than in subsolid nodules. In addition, this study showed that the CT patterns associated with VPI differ between solid and subsolid nodules.© RSNA, 2019Supplemental material is available for this article.See also the commentary by Elicker in this issue.

Longitudinal Follow-up of Patients With Tracheobronchomalacia After Undergoing Tracheobronchoplasty: Computed Tomography Findings and Clinical Correlation.

PURPOSE: The purpose of this study was to evaluate intermediate and long-term changes in expiratory tracheal collapsibility by computed tomography (CT) in patients with tracheobronchomalacia following surgical treatment with tracheobronchoplasty and to correlate CT findings with clinical findings. MATERIALS AND METHODS: Between 2003 and 2016, 18 patients with tracheobronchomalacia underwent tracheobronchoplasty and were imaged preoperatively and postoperatively at both intermediate and long-term intervals. Imaging included end-inspiratory and dynamic expiratory phase scans. The cross-sectional area of the airway lumen was measured at 2 standard levels (1 cm above the aortic arch and carina). These measurements were used to calculate % collapsibility. Clinical findings recorded included a questionnaire on symptomatology and a 6-minute walk test. RESULTS: Before surgery, expiratory collapsibility of the upper trachea was 72%±25% (mean±SD) and that of the lower trachea was 68%±22%. On intermediate follow-up (mean, 1.5 y), collapsibility significantly decreased to 37%±21% at the upper trachea and 35%±19% at the lower trachea (P<0.001). On long-term follow-up (mean, 6 y), collapsibility increased to 51%±20% at the upper trachea and 47%±17% at the lower trachea and was significantly worse than on intermediate follow-up (P=0.002). However, collapsibility on long-term follow-up remained significantly lower than preoperative collapsibility (P=0.015). Clinical findings showed a similar trend as quantitative CT measurements. CONCLUSION: Expiratory tracheal collapsibility substantially decreases after tracheobronchoplasty on intermediate follow-up. At long-term follow-up, tracheal collapsibility shows a modest increase, but remains significantly lower than the preoperative baseline. Quantitative measurements from dynamic CT have the potential to play an important role as imaging biomarkers for assessing response to tracheobronchoplasty.

CT Manifestations of Tumor Spread Through Airspaces in Pulmonary Adenocarcinomas Presenting as Subsolid Nodules.

PURPOSE: The aim of this study was to identify potential computed tomography manifestations of pulmonary adenocarcinomas presenting as subsolid nodules and associated with the histologic evidence of spread of tumor through air spaces (STAS). MATERIALS AND METHODS: From a radiologic-pathologic repository of resected pulmonary adenocarcinomas including 203 subsolid nodules, 40 STAS-positive nodules were randomly selected and matched to 40 STAS-negative nodules. Total average diameter, as well as average and long-axis diameters of the solid component, was measured. The proportion of solid component diameter to total average diameter was calculated. Measurements and proportions between STAS-positive and STAS-negative nodules were compared with paired samples t test, χ test, or the Fisher exact test. RESULTS: The total average diameter in STAS-positive nodules was significantly larger than in STAS-negative nodules (P=0.024). The average and long-axis diameters of the solid component of STAS-positive nodules were significantly larger than that of STAS-negative nodules (P=0.001 and 0.003). The proportion of solid component to total average diameter was significantly larger in STAS-positive than in STAS-negative nodules (P=0.041). At a threshold of ≥10 mm for the average and the solid component long-axis diameters, significantly more nodules were STAS-positive than STAS-negative (P=0.015 and 0.001). CONCLUSIONS: Total average diameter, average and long-axis diameters of the solid component, and a high proportion of solid component diameter compared with total average diameter are computed tomography manifestations of subsolid pulmonary adenocarcinomas with STAS. These findings could serve as an in-vivo tool for the likelihood estimation of STAS, and consequently influence management of subsolid adenocarcinomas.

Pathologic T Descriptor of Nonmucinous Lung Adenocarcinomas Now Based on Invasive Tumor Size: How Should Pathologists Measure Invasion?

OBJECTIVES: The eighth edition of the American Joint Committee on Cancer staging manual now stratifies nonmucinous lung adenocarcinomas (nmLACAs) by the size of the invasive component only. This is determined by direct gross or microscopic measurement; however, a calculated invasive size based on the percentage of invasive growth patterns has been proposed as an alternative option. METHODS: To compare radiologic with different pathologic assessments of invasive tumor size, we retrospectively reviewed a cohort of resected nmLACAs with a part-solid appearance on computed tomography (CT) scan (n = 112). RESULTS: The median direct microscopic pathologic invasive measurements were not significantly different from the median calculated pathologic invasive measurements; however, the median CT invasive measurements were 0.26 cm larger than the median direct pathologic measurements (P < .001). CONCLUSIONS: Our results show that pathologic calculated invasive tumor measurements are comparable to direct microscopic measurements of invasive tumor, thereby supporting the recommendation for use of calculated invasive tumor size by the pathologist if necessary.

Software-based risk stratification of pulmonary adenocarcinomas manifesting as pure ground glass nodules on computed tomography.

OBJECTIVES: To assess the performance of the "Computer-Aided Nodule Assessment and Risk Yield" (CANARY) software in the differentiation and risk assessment of histological subtypes of lung adenocarcinomas manifesting as pure ground glass nodules on computed tomography (CT). METHODS: 64 surgically resected and histologically proven adenocarcinomas manifesting as pure ground-glass nodules on CT were assessed using CANARY software, which classifies voxel-densities into three risk components (low, intermediate, and high risk). Differences in risk components between histological adenocarcinoma subtypes were analysed. To determine the optimal threshold reflecting the presence of an invasive focus, sensitivity, specificity, negative predictive value, and positive predictive value were calculated. RESULTS: 28/64 (44%) were adenocarcinomas in situ (AIS); 26/64 (41%) were minimally invasive adenocarcinomas (MIA); and 10/64 (16%) were invasive ACs (IAC). The software showed significant differences in risk components between histological subtypes (P<0.001-0.003). A relative volume of 45% or less of low-risk components was associated with histological invasiveness (specificity 100%, positive predictive value 100%). CONCLUSIONS: CANARY-based risk assessment of ACs manifesting as pure ground glass nodules on CT allows the differentiation of their histological subtypes. A threshold of 45% of low-risk components reflects invasiveness in these groups. KEY POINTS: • CANARY-based risk assessment allows the differentiation of their histological subtypes. • 45% or less of low-risk component reflects histological invasiveness. • CANARY has potential role in suspected adenocarcinomas manifesting as pure ground-glass nodules.

Harms of off-label erythropoiesis-stimulating agents for critically ill people.

BACKGROUND: Anaemia is a common problem experienced by critically-ill people. Treatment with erythropoiesis-stimulating agents (ESAs) has been used as a pharmacologic strategy when the blunted response of endogenous erythropoietin has been reported in critically-ill people. The use of ESAs becomes more important where adverse clinical outcomes of transfusing blood products is a limitation. However, this indication for ESAs is not licensed by regulatory authorities and is called off-label use. Recent studies concern the harm of ESAs in a critical care setting. OBJECTIVES: To focus on harms in assessing the effects of erythropoiesis-stimulating agents (ESAs), alone or in combination, compared with placebo, no treatment or a different active treatment regimen when administered off-label to critically-ill people. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO via OvidSP, CINAHL, all evidence-based medicine (EBM) reviews including IPA and SCI-Expanded, Conference Proceedings Citation Index- Science, BIOSIS Previews and TOXLINE up to February 2017. We also searched trials registries, checked reference lists of relevant studies and tracked their citations by using SciVerse Scopus. SELECTION CRITERIA: We considered randomized controlled trials (RCTs) and controlled observational studies, which compared scheduled systemic administration of ESAs versus other effective interventions, placebo or no treatment in critically-ill people. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and evaluated the eligibility of retrieved records, extracted data and assessed the risks of bias and quality of the included studies. We resolved differences in opinion by consensus or by involving a third review author. We assessed the evidence using GRADE and created a 'Summary of findings' table. We used fixed-effect or random-effects models, depending on the heterogeneity between studies. We fitted three-level hierarchical Bayesian models to calculate overall treatment effect estimates. MAIN RESULTS: Of the 27,865 records identified, 39 clinical trials and 14 observational studies, including a total of 945,240 participants, were eligible for inclusion. Five studies are awaiting classification. Overall, we found 114 adverse events in 33 studies (30 RCTs and three observational studies), and mortality was reported in 41 studies (32 RCTs and nine observational studies). Most studies were at low to moderate risk of bias for harms outcomes. However, overall harm assessment and reporting were of moderate to low quality in the RCTs, and of low quality in the observational studies. We downgraded the GRADE quality of evidence for venous thromboembolism and mortality to very low and low, respectively, because of risk of bias, high inconsistency, imprecision and limitations of study design.It is unclear whether there is an increase in the risk of any adverse events (Bayesian risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.21; 3099 participants; 9 studies; low-quality evidence) or venous thromboembolism (Bayesian RR 1.04, 95% CI 0.70 to 1.41; 18,917 participants; 18 studies; very low-quality evidence).There was a decreased risk of mortality with off-label use of ESAs in critically-ill people (Bayesian RR 0.76, 95% CI 0.61 to 0.92; 930,470 participants; 34 studies; low-quality evidence). AUTHORS' CONCLUSIONS: Low quality of evidence suggests that off-label use of ESAs may reduce mortality in a critical care setting. There was a lack of high-quality evidence about the harm of ESAs in critically-ill people. The information for biosimilar ESAs is less conclusive. Most studies neither evaluated ESAs' harm as a primary outcome nor predefined adverse events. Any further studies of ESA should address the quality of evaluating, recording and reporting of adverse events.

"Rounding" the Size of Pulmonary Nodules: Impact of Rounding Methods on Nodule Management, as Defined by the 2017 Fleischner Society Guidelines.

RATIONALE AND OBJECTIVES: The objective of this study was to quantify the impact of different rounding methods on size measurements of pulmonary nodules and to determine the number of nodules that change management categories as a result of rounding. MATERIALS AND METHODS: For this retrospective institutional review board-approved study, we included 503 incidental pulmonary nodules (308 solid and 195 subsolid) from a data repository. Long and short axes were measured. Average diameters were calculated using four different rounding methods (method 1: no rounding; method 2: rounding only the average diameter to the closest millimeter; method 3: rounding only short and long axes; and method 4: rounding short and long axes and the average diameter to the closest millimeter). Nodules were classified for each rounding method according to the 2017 Fleischner Society guideline management categories. Measurements were compared among the four rounding methods using analysis of variance. RESULTS: Without rounding, the average nodule diameter was 15.67 ± 5.97 mm. This increased between 0.03 and 0.29 mm using rounding methods 2-4 (range: P < 0.001-0.017). The nodule size was more frequently rounded up (range: 52.1%-77.5%) than rounded down (range: 17.7%-42.5%) using rounding methods 2-4, as compared to no rounding. In the 308 solid nodules, up to 2.9% of the nodules changed management category, whereas none of the 195 subsolid nodules changed category. CONCLUSIONS: Rounding methods have a small absolute but statically significant effect on nodule size, impacting management category in less than 3% of the nodules. This suggests that, in clinical practice, any rounding method can be used for determining nodule size without substantially biasing individual nodules toward given management categories.