Search

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others.

Pulmonary vascular disease is associated with poor outcomes in individuals affected by interstitial lung disease. The pulmonary vessels can be quantified with noninvasive imaging, but whether radiographic indicators of vasculopathy are associated with early interstitial changes is not known.Are pulmonary vascular volumes, quantified from CT scans, associated with interstitial lung abnormalities (ILA) in a community-based sample with a low burden of lung disease?In 2,386 participants of the Framingham Heart Study, we used CT imaging to calculate pulmonary vascular volumes, including the small vessel fraction (a surrogate of vascular pruning). We constructed multivariable logistic regression models to investigate associations of vascular volumes with ILA, progression of ILA, and restrictive pattern on spirometry. In secondary analyses, we additionally adjusted for diffusing capacity and emphysema, and performed a sensitivity analysis restricted to participants with normal FVC and diffusing capacity.In adjusted models, we found that lower pulmonary vascular volumes on CT were associated with greater odds of ILA, antecedent ILA progression, and restrictive pattern on spirometry. For example, each SD lower small vessel fraction was associated with 1.81-fold greater odds of ILA (95% CI, 1.41-2.31; P .0001), and 1.63-fold greater odds of restriction on spirometry (95% CI, 1.18-2.24; P = .003). Similar patterns were seen after adjustment for diffusing capacity for carbon monoxide, emphysema, and among participants with normal lung function.In this cohort of community-dwelling adults not selected on the basis of lung disease, more severe vascular pruning on CT was associated with greater odds of ILA, ILA progression, and restrictive pattern on spirometry. Pruning on CT may be an indicator of early pulmonary vasculopathy associated with interstitial lung disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Tumor spread through airspaces (STAS) has been identified as a new pattern of invasion in the 2015 WHO classification of lung tumors (1) and is associated with a lower overall survival in resected non-small cell lung cancers (2). As a consequence, sublobar resection may not be the best surgical option for cancers with STAS.

Pulmonary hypertension is characterized histologically by intimal and medial thickening in the small pulmonary arteries, eventually resulting in vascular “pruning.” Computed tomography (CT)-based quantification of pruning is associated with clinical measures of pulmonary hypertension, but it is not established whether CT-based pruning correlates with histologic arterial remodeling. Our sample consisted of 138 patients who underwent resection for early-stage lung adenocarcinoma. From histologic sections, we identified small pulmonary arteries and measured the relative area comprising the intima and media (VWA%), with higher VWA% representing greater histologic remodeling. From pre-operative CTs, we used image analysis algorithms to calculate the small vessel volume fraction (BV5/TBV) as a CT-based indicator of pruning (lower BV5/TBV represents greater pruning). We investigated relationships of CT pruning and histologic remodeling using Pearson correlation, simple linear regression, and multivariable regression with adjustment for age, sex, height, weight, smoking status, and total pack-years. We also tested for effect modification by sex and smoking status. In primary models, more severe CT pruning was associated with greater histologic remodeling. The Pearson correlation coefficient between BV5/TBV and VWA% was –0.41, and in linear regression models, VWA% was 3.13% higher (95% CI: 1.95–4.31%, p

As mass COVID-19 vaccination is underway, radiologists are encountering transient FDG uptake in normal or enlarged axillary, supraclavicular, and cervical lymph nodes after ipsilateral deltoid vaccination. This phenomenon may confound interpretation in patients with cancer undergoing FDG PET/CT. In this article, we present our institutional approach for management of COVID-19 vaccine-related lymphadenopathy on FDG PET/CT according to early experience. We suggest performing PET/CT at least 2 weeks after vaccination in patients with a cancer for which interpretation is anticipated to be potentially impacted by the vaccination but optimally 4-6 weeks after vaccination given increased immunogenicity of mRNA vaccines and potentially longer time for resolution than lymphadenopathy after other vaccines. PET/CT should not be delayed when clinically indicated to be performed sooner. Details regarding vaccination should be collected at the time of PET/CT to facilitate interpretation. Follow-up recommendations for postvaccination lymphadenopathy are provided, considering the lymph node's morphology and likely clinical relevance. Consideration should be given to administering the vaccine in the arm contralateral to a unilateral cancer to avoid confounding FDG uptake on the side of cancer. Our preliminary experience and suggested institutional approach should guide radiologists in management of patients with cancer undergoing PET/CT after COVID-19 vaccination.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others. This article is a simultaneous joint publication in Radiology and CHEST. The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. Published under a CC BY 4.0 license. Online supplemental material is available for this article. ispartof: RADIOLOGY vol:298 issue:3 pages:550-566 ispartof: location:United States status: published

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

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.

These recommendations for measuring pulmonary nodules at computed tomography (CT) are a statement from the Fleischner Society and, as such, incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. The recommendations address nodule size measurements at CT, which is a topic of importance, given that all available guidelines for nodule management are essentially based on nodule size or changes thereof. The recommendations are organized according to practical questions that commonly arise when nodules are measured in routine clinical practice and are, together with their answers, summarized in a table. The recommendations include technical requirements for accurate nodule measurement, directions on how to accurately measure the size of nodules at the workstation, and directions on how to report nodule size and changes in size. The recommendations are designed to provide practical advice based on the available evidence from the literature; however, areas of uncertainty are also discussed, and topics needing future research are highlighted. © RSNA, 2017 Online supplemental material is available for this article.

Objectives The aims of this study were to quantify the relationship between computed tomography (CT) size, volume, density, and roundness of lung adenocarcinomas (ACs) manifesting as pure ground-glass nodules (pGGNs) on CT images and to correlate these parameters with histologic features of invasiveness. Methods From 2005 to 2015, 63 ACs manifesting as pGGNs on CT images were surgically resected at our institution. CT size was measured, and roundness, volumes and densities were computed. CT parameters were correlated to age and sex, as well as to size and number of invasive foci and histologic AC subcategories. Correlations were quantified with Spearman rank correlation coefficients. Results Of 63 ACs, 28 (44%) were AC in situ, 25 (40%) were minimally invasive AC, and 10 (16%) were invasive AC. Six of 35 nodules with invasive foci (17%) were smaller than 10 mm. Correlations between age and CT size, volume, density, and roundness were not significant (range r = –0.061 to 0.144, p = 0.285 to 0.902). Correlations between size and number of invasive foci with CT size ( r = 0.417, p r = 0.389, p = 0.003, respectively) were similar to the correlations with volume ( r = 0.401, p = 0.001 and r = 0.350, p = 0.005, respectively) and stronger than the correlation with density ( r = 0.237, p = 0.062 and r = 0.222, p = 0.081, respectively) and roundness ( r = 0.059, p = 0.648 and r = –0.030, p = 0.831, respectively). Conclusions In ACs manifesting as pGGNs on CT images, nodule size is positively related to size and number of histologically invasive foci. However, invasive foci can be found in pGGNs smaller than 10 mm. Measuring volume and density of pGGNs provides no advantage over two-dimensional size measurements, which appear sufficient for risk estimation in clinical practice.

Rationale and Objectives This study aimed to compare long-axis diameter to average computed tomography (CT) diameter measurements of lung adenocarcinomas manifesting as solid lung nodules ≤30 mm on CT, as referenced to pathologic measurements, and to determine the impact of the two CT measurement approaches on tumor (T)-staging of nodules. Materials and Methods This institutional review board-approved study included all 274 radiologic solid adenocarcinomas resected at our institution over 10 years. Two observers measured long- and short-axis diameters on pre-resection chest CT in lung and mediastinal windows. T-stages were determined. CT measurements and T-stages were compared to pathology measurements and T-stages using Wilcoxon signed rank test and McNemar test. Inter- and intraobserver variability was determined with intraclass correlation coefficients (ICC) and Bland-Altman plots. Results For lung and mediastinal windows, nodule size was significantly larger using long-axis diameter rather than average diameter (16.93 vs. 14.92 mm, P .001; and 14.02 vs. 12.17 mm, P .001, respectively). The correlation of CT with pathologic measurements was stronger with long-axis than with average diameter (ICC 0.808 vs. 0.730; and 0.731 vs. 0.621, respectively). Lung window measurements correlated stronger with pathology than mediastinal window measurements. CT T-stages differed from pathology T-stages in more than 20% of nodules ( P .001). Inter- and intraobserver variability was small with long-axis and average diameter (ICC range 0.96–0.991, and 0.970–0.993, respectively), but long-axis diameter showed wider scatter on Bland-Altman plots. Conclusions Long-axis CT diameter is preferable for T-staging because it better reflects the pathology T-stage. Average CT diameter might be used for longitudinal nodule follow-up because it shows less measurement variability and is more conservative in size assessment.

Objectives The eighth edition of the AJCC Cancer Staging Manual now stratifies the T descriptor for lung cancers by each increasing 1.0 cm increment, up to 5.0 cm, with an additional category for tumor greater than 7.0 cm. Bias in pathologic versus radiologic measurements may impact tumor staging. Methods The gross pathologic measurements of 493 resected lung adenocarcinomas were compared with presurgical computed tomography radiologic measurements. Also, pathologic tumor measurement data from the Surveillance, Epidemiology, and End Results (SEER) program database were examined. Results The distribution of pathologic measurements showed clustering at 0.5-cm increments, with 43.0% of pathologic measurements falling on 0.5-cm increments compared to only 20.3% of radiologic measurements. This pathologic measurement clustering was also observed for both 591,691 resected lung cancers and 3,597,685 tumors of any type from the SEER database. Conclusions Compared to radiologic measurements, gross pathologic measurements cluster around whole- and half-cm values. This measurement bias could lead to incorrect pathologic tumor staging and influence clinical treatment plans.

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.

To determine the prevalence and sociodemographic and hospitalization history of genetic conditions in a sample of inpatients in a pediatric hospital in 2017, and to compare results with unpublished studies from 1985, 1995, and 2007. Two weeks of admissions were classified according to a pre-existing categorization, based on genetic etiology, encompassing chromosomal and monogenic conditions, multifactorial (MF) conditions, and no known genetic cause. In 2017, 299 (16%) patients had chromosomal or monogenic conditions, 6–7% more than 2007 and 1995, but similar to 1985. Autosomal dominant (AD) conditions increased from

Purpose The purpose of this study was to investigate the prevalence of the nodular reverse halo sign (NRHS) in chest computed tomography (CT) in patients with active pulmonary tuberculosis. Materials and methods From March 2018 to March 2019, 29 consecutive patients with a culture-confirmed active pulmonary tuberculosis and who underwent chest CT examination during hospital-admission were retrospectively included in the study. There were 24 men and 5 women with a mean age of 40.9 ± 16.7 (SD) years (range: 18–80 years). Chest CT examinations of included patients were evaluated for the presence of NRHS and other tuberculosis-related CT signs. Results CT revealed the NRHS in 5 patients (5/29; 17%). The other CT signs of tuberculosis included consolidations in 18 patients (18/29; 62%), tree-in-bud pattern in 14 patients (14/29; 48%), cavitation in 12 patients (12/29; 41%), sparse nodules in 10 patients (10/29; 34%), and pleural effusion in 8 patients (8/29; 28%). Conclusion CT shows NRHS in 17% of patients with active pulmonary tuberculosis, indicating that the sign is not as rare as previously thought in patients with this condition.

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.

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, 2019 Supplemental material is available for this article. See also the commentary by Elicker in this issue.

IntroductionPeople of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a BRCA1/2 pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific BRCA1/2 pathogenic variants, referred to as BRCA-Jewish founder mutations (B-JFM), account for >90% of BRCA1/2 pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for BRCA testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study—a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia.Methods and analysisTo rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared.Ethics and disseminationInstitutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125.Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.

Item does not contain fulltext Purpose To quantify the reproducibility and accuracy of experienced thoracic radiologists in differentiating between subsolid and solid pulmonary nodules at CT. Materials and Methods The institutional review board of Beth Israel Deaconess Medical Center approved this multicenter study. Six thoracic radiologists, with a mean of 21 years of experience in thoracic radiology (range, 17-22 years), selected images of 10 solid and 10 subsolid nodules to create a database of 120 nodules; this selection served as the reference standard. Each radiologist then interpreted 120 randomly ordered nodules in two different sessions that were separated by a minimum of 3 weeks. The radiologists classified whether or not each nodule was subsolid. Inter- and intraobserver agreement was assessed with a κ statistic. The number of correct classifications was calculated and correlated with nodule size by using Bland-Altman plots. The relationship between disagreement and nodule morphologic characteristics was analyzed by calculating the intraclass correlation coefficient. Results Interobserver agreement (κ) was 0.619 (range, 0.469-0.745; 95\% confidence interval (CI): 0.576, 0.663) and 0.670 (range, 0.440-0.839; 95\% CI: 0.608, 0.733) for interpretation sessions 1 and 2, respectively. Intraobserver agreement (κ) was 0.792 (95\% CI: 0.750, 0.833). Averaged for interpretation sessions, correct classification was achieved by all radiologists for 58\% (70 of 120) of nodules. Radiologists agreed with their initial determination (the reference standard) in 77\% of cases (range, 45\%-100\%). Nodule size weakly correlated with correct classification (long axis: Spearman rank correlation coefficient, rs = 0.161 and P = .049; short axis: rs = 0.128 and P = .163). Conclusion The reproducibility and accuracy of thoracic radiologists in classifying whether or not a nodule is subsolid varied in the retrospective study. This inconsistency may affect surveillance recommendations and prognostic determinations. (©) RSNA, 2015 Online supplemental material is available for this article.

Objective: Accurate assessment of lymph node (LN) status is essential for proper staging of resected lung cancer specimens. Here, we assessed pathology-centric interventions to increase the number of peribronchial LNs identified and evaluated in anatomic lung cancer resection specimens as part of a quality improvement initiative. Materials and Methods: All non-small cell lung cancer (NSCLC) anatomic resection specimens from 2017 to 2020 were evaluated, comprising two years pre-intervention and one year post-intervention. We instituted 3 measures to increase peribronchial LN yield: 1) educational grossing sessions for pathology assistants and residents, 2) directions to submit additional peribronchial tissue if no LNs were identified grossly, and 3) a hard-stop prior to sign-out by the attending pathologist if no peribronchial LNs were identified. Results: Of the total 227 resection specimens for NSCLC, 107/151 (70.9%) of specimens prior to the intervention had peribronchial LNs identified, whereas after the intervention significantly more (66/76, 86.8%, p

We would like to thank the authors of the three editorials (1-3) for their interest in and comments on our article “ Lung Adenocarcinoma Manifesting as Pure Ground-Glass Nodules: Correlating CT Size, Volume, Density, and Roundness with Histopathologic Invasion and Size ” (4).

Purpose To assess inter-observer variability in identifying traction bronchiectasis on computed tomography (CT) using additional criteria for chronic fibrosing interstitial pneumonia. Methods Seven experts categorized CT image set representing 39 patients into three groups on the basis of the presence of traction bronchiectasis, using a three-point scale: 3-definitely/probably yes; 2-possibly yes; and 1-definitely/probably no. This scale served as a reference standard. The image set included cases of chronic fibrosing interstitial pneumonia, non-interstitial lung disease, and difficult-to-determine cases. Forty-eight observers similarly assessed the same image set, first according to the Fleischner Society definition, and second with additional criteria, in which traction bronchiectasis was observed exclusively in chronic fibrosing interstitial pneumonia. The agreement level between the reference standard and each observer's evaluation in each session was calculated using weighted kappa values which were compared between the two sessions using a paired t test. Results The mean weighted kappa value for all observers was significantly higher in the second reading session (mean 0.75) than in the first reading session (mean 0.62) (p < 0.001). Conclusion Inter-observer agreement in identifying traction bronchiectasis improves when using the additional criteria which specify chronic fibrosing interstitial pneumonia as the underlying disease.

Conventional chest radiography, computed tomography (CT), and with restrictions, magnetic resonance imaging (MRI) are the three most commonly used imaging modalities for evaluating patients with suspected pulmonary vascular disease. Very recently, the clinical usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) and FDG-PET/CT in the diagnosis of large-vessel vasculitis also has been recognized. However, in daily general clinical routine, most patients with suspected pulmonary vascular disease will be evaluated by CT. Moreover, the utility of CT has been improved by technical developments such as dual-source and dual-energy scanners, which simultaneously generate morphological and functional information from a sole dataset. In patients with pulmonary vascular diseases, this approach is of major interest for three main reasons: (1) Pulmonary vascular disorders require a thorough morphological evaluation, not only of the vascular tree per se, but also of the surrounding lung parenchyma; (2) given that we have reached an upper limit in terms of morphologic image resolution, but can simultaneously obtain functional information, CT ideally combines high-end morphologic imaging with perfusion and ventilation imaging; and (3) it is becoming increasingly important to determine the cardiac consequences or causes of pulmonary vascular diseases, which requires all of the advantages that CT can provide. For these reasons, and because of the general importance of CT, it is the focus of this chapter. Other imaging modalities are not ignored; rather, they are discussed in case-based presentations and in their distinct clinical contexts.

Accurate size measurements of pulmonary nodules on CT are a prerequisite for accurate nodule management, given that all current management guidelines are based on nodule size (1-4). Nodule size is most commonly measured manually using electronical calipers, with the long- and perpendicular short-axis being measured on two-dimensional images (5). As a management criterion alternative to size, three-dimensional nodule volume has been discussed in the literature (6) and has also received mention in recent management guidelines for incidental nodules (1,3).

OBJECTIVE. Recent technical advances, including the routine use of CT thin sections and techniques such as 2D minimum-intensity-projection and 3D volume images, have increased our ability to detect large airways diseases. Furthermore, dedicated CT protocols allow the evaluation of dynamic airway dysfunction. CONCLUSION. With diseases of the large airways more commonly seen in daily practice, it is important that radiologists be familiar with the appearances, differential diagnosis, and clinical implications of these entities.

RATIONALE AND OBJECTIVES Pulmonary vascular complications of liver disease have a substantial impact on morbidity and mortality in patients who undergo liver transplant. The effect of liver transplantation on the pulmonary vasculature in patients without pulmonary vascular disease, however, has not been described. This study was undertaken to characterize the regional effect of liver transplant on the cross-sectional area (CSA) of pulmonary vessels. MATERIALS AND METHODS We performed a single-center, retrospective, cohort study of patients who had a liver transplant between 2002 and 2012 and who had chest computed tomography scans within 1 year before and after transplant. Using ImageJ software, we measured the CSA of small pulmonary vessels (0-5 mm(2)) and the total lung CSA to calculate the percent CSA of pulmonary vessels

Context The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. Objective To review these changes and discuss issues for the reporting pathologist. Data Sources Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database; mesothelioma (N = 3519); thymic epithelial tumors (10 808); and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). Conclusions These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017; however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth.

To compare CT lung volumetry (CTLV) measurements provided by different software packages, and to provide normative data for lung densitometric measurements in healthy individuals.This retrospective study included 51 chest CTs of 17 volunteers (eight men and nine women; mean age, 30 ± 6 years), who underwent spirometrically monitored CT at total lung capacity (TLC), functional residual capacity (FRC), and mean inspiratory capacity (MIC). Volumetric differences assessed by four commercial software packages were compared with analysis of variance (ANOVA) for repeated measurements and benchmarked against the threshold for acceptable variability between spirometric measurements. Mean lung density (MLD) and parenchymal heterogeneity (MLD-SD) were also compared with ANOVA.Volumetric differences ranged from 12 to 213 ml (0.20 % to 6.45 %). Although 16/18 comparisons (among four software packages at TLC, MIC, and FRC) were statistically significant (P 0.001 to P = 0.004), only 3/18 comparisons, one at MIC and two at FRC, exceeded the spirometry variability threshold. MLD and MLD-SD significantly increased with decreasing volumes, and were significantly larger in lower compared to upper lobes (P 0.001).Lung volumetric differences provided by different software packages are small. These differences should not be interpreted based on statistical significance alone, but together with absolute volumetric differences.• Volumetric differences, assessed by different CTLV software, are small but statistically significant. • Volumetric differences are smaller at TLC than at MIC and FRC. • Volumetric differences rarely exceed spirometric repeatability thresholds at MIC and FRC. • Differences between CTLV measurements should be interpreted based on comparison of absolute differences. • MLD increases with decreasing volumes, and is larger in lower compared to upper lobes.

Item does not contain fulltext The Fleischner Society Guidelines for management of solid nodules were published in 2005, and separate guidelines for subsolid nodules were issued in 2013. Since then, new information has become available; therefore, the guidelines have been revised to reflect current thinking on nodule management. The revised guidelines incorporate several substantive changes that reflect current thinking on the management of small nodules. The minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences. The guidelines for solid and subsolid nodules have been combined in one simplified table, and specific recommendations have been included for multiple nodules. These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. Changes from the previous guidelines issued by the Fleischner Society are based on new data and accumulated experience. (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 13, 2017.

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

Radiation exposure from computed tomography (CT) has received much attention lately in the medical literature and the media, given the relatively high radiation dose that characterizes a CT examination. Although there are a variety of possible strategies for reducing radiation exposure from CT in an individual patient, optimal CT image acquisition requires that the radiologist understand new scanner technology and how to implement the most effective means of dose reduction while maintaining image quality. The authors describe a practical approach to dose reduction in cardiothoracic radiology, discussing CT radiation dose metrics (eg, CT dose index, dose-length product, effective diameter, and size-specific dose estimate) as well as CT scanner parameters that directly or indirectly influence radiation dose (eg, scan length, x-ray tube output, tube current modulation, pitch, image reconstruction techniques [including iterative reconstruction], and noise reduction). These variables are discussed in terms of their relative importance to image quality and the implications of parametric changes for image quality and diagnostic content, and practical recommendations are made for their immediate implementation in the clinical setting. Taken together, the principles of physics and key parameters involved in reducing radiation dose while maintaining image quality can serve as a "survival guide" for a diagnostic radiology practice.

Internationally, Tay-Sachs disease (TSD) preconception screening of Ashkenazi Jewish (AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre-conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost-benefit and cost-utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting.

Aim To determine the range of tracheal collapse at end-expiration among chronic obstructive pulmonary disease (COPD) patients and to compare the extent of tracheal collapse between static end-expiratory and dynamic forced-expiratory multidetector-row computed tomography (MDCT). Materials and methods After institutional review board approval and obtaining informed consent, 67 patients meeting the National Heart, Lung, and Blood Institute (NHLBI)/World Health Organization (WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD were sequentially imaged using a 64-detector-row CT machine at end-inspiration, during forced expiration, and at end-expiration. Standardized respiratory coaching and spirometric monitoring were employed. Mean percentage tracheal collapse at end-expiration and forced expiration were compared using correlation analysis, and the power of end-expiratory cross-sectional area to predict excessive forced-expiratory tracheal collapse was computed following construction of receiver operating characteristic (ROC) curves. Results Mean percentage expiratory collapse among COPD patients was 17 ± 18% at end-expiration compared to 62 ± 16% during forced expiration. Over the observed range of end-expiratory tracheal collapse (approximately 10–50%), the positive predictive value of end-expiratory collapse to predict excessive (≥80%) forced expiratory tracheal collapse was Conclusion COPD patients demonstrate a wide range of end-expiratory tracheal collapse. The magnitude of static end-expiratory tracheal collapse does not predict excessive dynamic expiratory tracheal collapse.

Radiographic abnormalities of the pulmonary vessels, such as vascular pruning, are common in advanced airways disease, but it is unknown if pulmonary vascular volumes are related to measures of lung health and airways disease in healthier populations.In 2388 participants of the Framingham Heart Study computed tomography (CT) sub-study, we calculated total vessel volumes and the small vessel fraction using automated CT image analysis. We evaluated associations with measures of lung function, airflow obstruction on spirometry and emphysema on CT. We further tested if associations of vascular volumes with lung function were present among those with normal forced expiratory volume in 1 s and forced vital capacity.In fully adjusted linear and logistic models, we found that lower total and small vessel volumes were consistently associated with worse measures of lung health, including lower spirometric volumes, lower diffusing capacity and/or higher odds of airflow obstruction. For example, each standard deviation lower small vessel fraction (indicating more severe pruning) was associated with a 37% greater odds of obstruction (OR 1.37, 95% CI 1.11–1.71, p=0.004). A similar pattern was observed in the subset of participants with normal spirometry.Lower total and small vessel pulmonary vascular volumes were associated with poorer measures of lung health and/or greater odds of airflow obstruction in this cohort of generally healthy adults without high burdens of smoking or airways disease. Our findings suggest that quantitative CT assessment may detect subtle pulmonary vasculopathy that occurs in the setting of subclinical and early pulmonary and airways pathology.

Background Transcatheter aortic valve replacement (TAVR) is a novel technique developed in the last decade to treat severe aortic stenosis in patients who are non-surgical candidates because of multiple comorbidities. Methods Since the technique is performed using a transvascular approach, pre-procedural assessment of the aortic valve apparatus, ascending aorta and vascular access is of paramount importance for both appropriate patient selection and correct device selection. This assessment is performed by a multi-disciplinary team with radiology being an integral and important part. Results Among imaging modalities, there is growing scientific evidence supporting the crucial role of MDCT in the assessment of the aortic valve apparatus, suitability of the iliofemoral or alternative pathway, and determination of appropriate coaxial angles. MDCT also plays an important role in post-procedure imaging in the assessment of valve integrity and position. Conclusion This review outlines the principal aspects of TAVR, the multidisciplinary approach and utilisation of different imaging modalities, as well as a step-by-step approach to MDCT acquisition protocols, reconstruction techniques, pre-procedure measurements and post-procedure assessment. Teaching Points • TAVR is a new technique to treat severe aortic stenosis in high-risk and nonsurgical candidates. • MDCT assessment of the aortic annulus is important for appropriate patient and device selection. • Multidisciplinary approach is required for patient selection, procedure planning and performance. • MDCT is required for assessment of the aortic root, iliofemoral or alternative vascular pathway.

Chronic obstructive pulmonary disease (COPD) is a complex syndrome encompassing potentially overlapping diseases such as pulmonary emphysema, chronic bronchitis, and small airways disease. The management of COPD relies on distribution and severity of those processes, which clinically can manifest similarly. Relative contribution and severity of each of those pathologic changes can be assessed using qualitative and quantitative analysis of computed tomographic imaging data. Studies are under way to establish potential links among the imaging, clinical, and genetic manifestations of COPD.

To determine the best radiographic landmark for the cavoatrial junction (CAJ) using electrocardiographic-gated, 64-row multidetector coronary computed tomographic angiography (CTA).Institutional Review Board approval was obtained. Patient age, sex, weight, and height were recorded. The CAJ was localized by 2 readers using multiplanar CTA, cross-referenced with a scout topogram. Designated radiographic landmarks (the carina, intersection between the bronchus intermedius and the right heart border, and the inflection of the right heart border) were assessed for visibility and vertical distance from the CAJ.Sixty consecutive CTA studies (39 men, 21 women; age range, 27 to 98 y; mean±SD, 55±15 y) were analyzed. The closest radiographic landmark to the CAJ was the intersection between the bronchus intermedius and the right heart border (0.9±0.8 cm above the CAJ), visible in 71% of patients. The second closest radiographic landmark was the inflection of the right heart border (1±0.8 cm above the CAJ), visible in 84% of patients. The carina was visible on 100% of topograms, 4.2±1.1 cm above the CAJ. There was no strong correlation between age, weight, height, or sex and the visibility or distance of landmarks from the CAJ.The intersection of the bronchus intermedius with the right heart border and the inflection of the right heart border are the closest radiographic landmarks to the CAJ. When these landmarks are not identifiable, the most uniformly visible radiographic landmark is the carina.

Fig. 1— Flowchart shows differential diagnosis of unilateral and bilateral pulmonary hyperlucencies. D ecreased lung density on images can be described as pulmonary hyperlucency on conventional chest radiographs and hypoattenuation on CT scans. For the purpose of this review, we call both findings hyperlucency. Abnormal lucency of the lung can be unilateral or bilateral, focal or diffuse. Hyperlucency on images can result from an excess of air in the pulmonary parenchyma or a decrease in mass of the pulmonary parenchyma caused by a reduction in vasculature or blood flow, reduction or obliteration of airways, or a combination of these potential causes. Even in adults, pulmonary hyperlucency can be caused by congenital and acquired conditions. An understanding of the broad differential diagnosis of pulmonary hyperlucency is necessary to determine the underlying cause and provide appropriate patient care. The most common causes of pulmonary hyperlucency in adults are summarized in Figure 1.

OBJECTIVE The objective of this study was to analyze pulmonary computed tomography angiography image quality and pulmonary embolism (PE) depiction comparing 2 blends of adaptive statistical iterative reconstruction (ASIR) to filtered back-projection alone. METHODS Seventy-nine consecutive patients (49 women, 30 men; 52 ± 18 years) underwent pulmonary computed tomography angiography (120 kVp, 100-600 mA) reconstructed with filtered back-projection alone (ASIR0), 30% ASIR (ASIR30), and 50% ASIR (ASIR50) for this institutional review board-approved study. Two radiologists independently assessed PE depiction and vascular characterization, which was correlated with body mass index. RESULTS Twelve patients (15%) had PE. No difference in PE depiction (P = 0.536), pulmonary arterial attenuation (P = 0.22-0.99), or subjective vascular characterization score (P = 0.58-.016) was observed for either blend. ASIR30 and ASIR50 achieved higher signal-to-noise ratio (P = 0.001-0.003). Body mass index inversely correlated with vascular characterization scores (P < 0.001). CONCLUSIONS ASIR0, ASIR30, and ASIR50 accurately depict PE using the imaging parameters described. ASIR30 and ASIR50 improve objective image quality without altering subjective vascular characterization scores particularly when body mass index was less than 30 kg/m.

Item does not contain fulltext This report is to complement the original Fleischner Society recommendations for incidentally detected solid nodules by proposing a set of recommendations specifically aimed at subsolid nodules. The development of a standardized approach to the interpretation and management of subsolid nodules remains critically important given that peripheral adenocarcinomas represent the most common type of lung cancer, with evidence of increasing frequency. Following an initial consideration of appropriate terminology to describe subsolid nodules and a brief review of the new classification system for peripheral lung adenocarcinomas sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS), six specific recommendations were made, three with regard to solitary subsolid nodules and three with regard to multiple subsolid nodules. Each recommendation is followed first by the rationales underlying the recommendation and then by specific pertinent remarks. Finally, issues for which future research is needed are discussed. The recommendations are the result of careful review of the literature now available regarding subsolid nodules. Given the complexity of these lesions, the current recommendations are more varied than the original Fleischner Society guidelines for solid nodules. It cannot be overemphasized that these guidelines must be interpreted in light of an individual's clinical history. Given the frequency with which subsolid nodules are encountered in daily clinical practice, and notwithstanding continuing controversy on many of these issues, it is anticipated that further refinements and modifications to these recommendations will be forthcoming as information continues to emerge from ongoing research.

The aim of this study was to analyze the impact that a clinical history of an oncologic disease may have on the management decisions for incidentally detected lung nodules on chest computed tomographic (CT) examinations.An electronic survey was sent to all 796 members of the Society of Thoracic Radiology regarding criteria for the management of incidentally detected lung nodules in oncologic patients, as well as recommendations for nodule follow-up. Nodule characteristics and clinical parameters used by respondents were analyzed. Differences between variables were examined using the χ test.Of the 796 Society of Thoracic Radiology members, 178 (22.36%) replied. Most respondents were subspecialized in cardiothoracic imaging (92.70%) and practiced in an "academic or teaching hospital setting" (75.28%) with a "dedicated oncology center" (94.03%). "History of oncologic disease" was the most important factor (98.87%) for management decisions. In patients with such a history, respondents most commonly used "experience and common sense" (56.74%) and reported "all incidentally found lung nodules" (65.73%, P0.0001). "Size" and "shape" were the 2 most important nodule characteristics (33.61% and 27.05%, respectively) used to consider a nodule "clinically relevant," and "size" (44.07%) was also the most important nodule characteristic prompting recommendation for short-term CT follow-up. Follow-up CT examinations in oncologic patients were recommended by 75.84% of respondents.In patients with a history of oncologic disease, radiologists tend to report every detected nodule and to routinely recommend follow-up CT examinations. Although most radiologists rely on "experience and common sense" in managing these nodules, greater standardization of lung nodule management in oncologic patients is needed, ideally through guidelines tailored to this patient population.

Background The use of preimplantation genetic diagnosis (PGD) to select genetically ‘normal’ human embryos and to transfer them to the uterus of a woman has generated considerable controversy. Debate has occurred over the implications of PGD, sex selection, safety of embryonic manipulation and eugenics. This study evaluates a range of social and moral concerns of couples towards PGD and assisted reproductive technologies (ART) prior to treatment to obtain unbiased authentic attitudes independent of the treatment cycle and the outcome. Methods A total of 121 subjects were administered a structured questionnaire after each couple's in vitro fertilization (IVF) or genetic counselling session. Group A consisted of 41 subjects presenting for PGD of single gene disorders (PGD-SG) and group B consisted of 48 subjects undertaking PGD for aneuploidy screening (PGD-AS). A control group consisted of 32 subjects that were about to commence their first IVF cycle. Results and discussion All groups found PGD to be a highly acceptable treatment. They expressed little concern about its extension to testing non-disease states such as sex and they were strongly in favour of a shared decision-making model in which couples have considerable autonomy over decisions about the embryo(s) to transfer. Differences between the groups included issues surrounding the transfer of embryos, restrictions to PGD and the destruction of embryos. Copyright © 2002 John Wiley & Sons, Ltd.

Introduction Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. Methods An international database of 94,708 patients with lung cancer diagnosed in 1999–2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. Results Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. Conclusions An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.