Single-cell sequencing on CD8+ TILs revealed the nature of exhausted T cells recognizing neoantigen and cancer/testis antigen in non-small cell lung cancer.

BACKGROUND: CD8+tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8+ TILs, especially T-cell populations specific for tumor antigens, remain poorly understood. METHODS: High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8+ TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8+ TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells. RESULTS: A total of 6998 CD8+ T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX, PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1. CONCLUSIONS: Our approach focusing on T cells with an exhausted phenotype among CD8+ TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC.

Relationship of urinary liver-type fatty acid-binding protein with cardiovascular risk factors in the Japanese population without chronic kidney disease: Sasayama study.

BACKGROUND: Urinary liver-type fatty acid-binding protein (L-FABP) is a well-known marker of proximal tubular impairment. We evaluated the relationship between cardiovascular disease (CVD) risk factors and levels of L-FABP in a cross-sectional community-based study. Participants with normoalbuminuria and normal estimated glomerular filtration rate (eGFR), that is, non-chronic kidney disease (non-CKD), were enrolled in this study. To the best of our knowledge, this is the first study to focus on the association between CVD risk factors and a proximal tubular marker in the Japanese general population with normoalbuminuria and normal eGFR. METHODS: The present study is part of the Sasayama study. The participants included 1000 community residents (447 men and 553 women) aged 40-64 years without a history of CVD or renal dysfunction. Out of these participants 375 men and 477 women, defined as non-CKD, were included for further analysis. In each sex, the highest quintile group was considered to have high-normal L-FABP levels. A multiple logistic regression model was used to evaluate the relationship between risk factors for CVD and high-normal L-FABP levels in the non-CKD participants. We performed a similar analysis using the high-normal urinary albumin to creatinine ratio (UACR) as a dependent variable instead of L-FABP. RESULTS: Among the non-CKD participants, in the highest quintile group (Q5, top 20%), L-FABP was ≥2.17 µg/gCre in men and ≥ 2.83 µg/gCre in women. In women, the multivariate odds ratio was 3.62 (1.45-9.00) for high-normal L-FABP in the presence of diabetes mellitus (DM) compared with that in the group without DM. However, the relationship between DM and the UACR level was not significant. In men, DM was significantly associated with high-normal UACR. However, the relationship with L-FABP levels was not significant. CONCLUSIONS: The presence of DM was more strongly related to high-normal L-FABP levels than to high-normal UACR in women even at the stage of normoalbuminuria and normal eGFR. Our results were also consistent with the findings of a previous study where women were more prone to nonalbuminuric renal impairment compared to men, although further studies are required to confirm the results.

Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL.

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.

Automated histological classification of whole-slide images of gastric biopsy specimens.

BACKGROUND: Automated image analysis has been developed currently in the field of surgical pathology. The aim of the present study was to evaluate the classification accuracy of the e-Pathologist image analysis software. METHODS: A total of 3062 gastric biopsy specimens were consecutively obtained and stained. The specimen slides were anonymized and digitized. At least two experienced gastrointestinal pathologists evaluated each slide for pathological diagnosis. We compared the three-tier (positive for carcinoma or suspicion of carcinoma; caution for adenoma or suspicion of a neoplastic lesion; or negative for a neoplastic lesion) or two-tier (negative or non-negative) classification results of human pathologists and of the e-Pathologist. RESULTS: Of 3062 cases, 33.4% showed an abnormal finding. For the three-tier classification, the overall concordance rate was 55.6% (1702/3062). The kappa coefficient was 0.28 (95% CI, 0.26-0.30; fair agreement). For the negative biopsy specimens, the concordance rate was 90.6% (1033/1140), but for the positive biopsy specimens, the concordance rate was less than 50%. For the two-tier classification, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.5% (95% CI, 87.5-91.4%), 50.7% (95% CI, 48.5-52.9%), 47.7% (95% CI, 45.4-49.9%), and 90.6% (95% CI, 88.8-92.2%), respectively. CONCLUSIONS: Although there are limitations and requirements for applying automated histopathological classification of gastric biopsy specimens in the clinical setting, the results of the present study are promising.

Automated histological classification of whole slide images of colorectal biopsy specimens.

BACKGROUND: An automated image analysis system, e-Pathologist, was developed to improve the quality of colorectal biopsy diagnostics in routine pathology practice. OBJECTIVE: The aim of the study was to evaluate the classification accuracy of the e-Pathologist image analysis software in the setting of routine pathology practice in two institutions. MATERIALS AND METHODS: In total, 1328 colorectal tissue specimens were consecutively obtained from two hospitals (1077 tissues from Tokyo hospital, and 251 tissues from East hospital) and the stained specimen slides were anonymized and digitized. At least two experienced gastrointestinal pathologists evaluated each slide for pathological diagnosis. We compared the 3-tier classification results (carcinoma or suspicion of carcinoma, adenoma, and lastly negative for a neoplastic lesion) between the human pathologists and that of e-Pathologist. RESULTS: For the Tokyo hospital specimens, all carcinoma tissues were correctly classified (n=112), and 9.9% (80/810) of the adenoma tissues were incorrectly classified as negative. For the East hospital specimens, 0 out of the 51 adenoma tissues were incorrectly classified as negative while 9.3% (11/118) of the carcinoma tissues were incorrectly classified as either adenoma, or negative. For the Tokyo and East hospital datasets, the undetected rate of carcinoma, undetected rate of adenoma, and over-detected proportion were 0% and 9.3%, 9.9% and 0%, and 36.1% and 27.1%, respectively. CONCLUSIONS: This image analysis system requires some improvements; however, it has the potential to assist pathologists in quality improvement of routine pathological practice in the not too distant future.

Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index After Exercise: Sasayama Study.

We investigated the relationship between smoking and the risk of nonnormal (≤0.99) ankle-brachial index (ABI) at rest and after ankle plantar flexion exercise in healthy male community dwellers. A cross-sectional study was performed including 228 Japanese men aged 40 to 64 years without a history of cardiovascular diseases. Participants were classified as never, ex-, and current smokers. We estimated the multivariate-adjusted odds ratios (ORs) for nonnormal ABI of ex- and current smokers in relation to never smokers after adjusting for age and other confounding factors. At rest, the prevalence of nonnormal ABI was not significantly different by smoking status. After exercise, the prevalence of nonnormal ABI increased from 1.8% to 11.5% in ex-smokers and from 3.8% to 17.0% in current smokers, while the prevalence did not significantly change in never smokers. The multivariate-adjusted OR for nonnormal ABI after ankle plantar flexion exercise, in relation to never smokers, was 3.85 (95% confidence interval [CI]: 0.79-18.9) for ex-smokers and 6.97 (95% CI: 1.32-36.7) for current smokers. Our results suggest that ABI after ankle plantar flexion exercise is useful for early detection of subclinical peripheral artery ischemia in male smokers without typical symptoms.

Relationship between PK/PD of Cefepime and Clinical Outcome in Febrile Neutropenic Patients with Normal Renal Function.

The efficacy of cefepime (CFPM) is known to depend on the ratio of the time that the serum levels exceed the minimum inhibitory concentration (MIC) to the dosing interval (%T>MIC). The objective of this study was to clarify the relation between %T>MIC and clinical outcome of CFPM, and to identify the optimal dosage regimen. We investigated the outcome of CFPM treatment for febrile neutropenia (FN) patients with normal renal function. Treatment success was defined as the completion of FN therapy with CFPM only. And we calculated %T>MIC for each case based on population pharmacokinetic parameters. The MIC value for simulation was set as 8 µg/mL. In logistic regression analysis, treatment success was significantly associated with the elevation of %T>MIC in the group with persistent neutropenia, yielding a receiver operating characteristic curve with an optimal cutoff value of 73.1%. Next, we simulated %T>MIC for each case under various dosing regimens. For patients whose creatinine clearance (CLcr) exceeded 100 mL/min, it was found to be difficult to attain the objective under the current regimen. In contrast, it was calculated that treatment with 2 g three times a day (t.i.d.) could attain the objective for most of the patients with 3 h of infusion. These results suggest that CFPM treatment under the current regimen is ineffective for FN patients with normal or augmented renal function, and that 2 g t.i.d. is necessary in quite a lot cases, although such use is off-label.

Automatic quantification of morphological features for hepatic trabeculae analysis in stained liver specimens.

This paper proposes a digital image analysis method to support quantitative pathology by automatically segmenting the hepatocyte structure and quantifying its morphological features. To structurally analyze histopathological hepatic images, we isolate the trabeculae by extracting the sinusoids, fat droplets, and stromata. We then measure the morphological features of the extracted trabeculae, divide the image into cords, and calculate the feature values of the local cords. We propose a method of calculating the nuclear-cytoplasmic ratio, nuclear density, and number of layers using the local cords. Furthermore, we evaluate the effectiveness of the proposed method using surgical specimens. The proposed method was found to be an effective method for the quantification of the Edmondson grade.

Does flat epithelial atypia have rounder nuclei than columnar cell change/hyperplasia? A morphometric approach to columnar cell lesions of the breast.

Columnar cell lesions of the breast encompass columnar cell change/hyperplasia (CCC/CCH) and flat epithelial atypia (FEA). These have attracted researchers because emerging data suggest that FEA may represent the earliest histologically detectable non-obligate precursor of breast cancer. However, it is occasionally difficult to distinguish FEA from CCC/CCH because of similar histology. Although the nuclei of FEA are frequently described as relatively round compared with those of CCC/CCH, there are few morphometric studies to support this statement. The aim of this study was to provide objective data as to the nuclear shape in columnar cell lesions. As a shape descriptor, we adopted ellipticity that is defined by the formula 2b/2a, where a is the length of the long axis of the ellipse and b is the length of the short axis. Contrary to circularity, ellipticity reflects the overall configuration of an ellipse irrespective of surface irregularity. Our image analysis included generating whole slide images, extracting glandular cell nuclei, measuring nuclear ellipticity, and superimposing graded colors based on execution of results on the captured images. A total of 7917 nuclei extracted from 22 FEA images and 5010 nuclei extracted from 13 CCC/CCH images were analyzed. There was a significant difference in nuclear roundness between FEA and CCC/CCH with mean ellipticity values of 0.723 and 0.679, respectively (p < 0.001, Welch's t test). Furthermore, FEA with malignancy had significantly rounder nuclei than FEA without malignancy (p < 0.001). Our preliminary results suggest that nuclear ellipticity is a key parameter in reproducibly classifying columnar cell lesions of the breast.

Enhancing automatic classification of hepatocellular carcinoma images through image masking, tissue changes and trabecular features.

BACKGROUND: Recent breakthroughs in computer vision and digital microscopy have prompted the application of such technologies in cancer diagnosis, especially in histopathological image analysis. Earlier, an attempt to classify hepatocellular carcinoma images based on nuclear and structural features has been carried out on a set of surgical resected samples. Here, we proposed methods to enhance the process and improve the classification performance. METHODS: First, we segmented the histological components of the liver tissues and generated several masked images. By utilizing the masked images, some set of new features were introduced, producing three sets of features consisting nuclei, trabecular and tissue changes features. Furthermore, we extended the classification process by using biopsy resected samples in addition to the surgical samples. RESULTS: Experiments by using support vector machine (SVM) classifier with combinations of features and sample types showed that the proposed methods improve the classification rate in HCC detection for about 1-3%. Moreover, detection rate of low-grades cancer increased when the new features were appended in the classification process, although the rate was worsen in the case of undifferentiated tumors. CONCLUSIONS: The masking process increased the reliability of extracted nuclei features. The additional of new features improved the system especially for early HCC detection. Likewise, the combination of surgical and biopsy samples as training data could also improve the classification rates. Therefore, the methods will extend the support for pathologists in the HCC diagnosis.

Association between serum long-chain n-3 and n-6 polyunsaturated fatty acid profiles and glomerular filtration rate assessed by serum creatinine and cystatin C levels in Japanese community-dwellers.

BACKGROUND: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived long-chain n-3 PUFA intake. METHODS: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. RESULTS: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had non-significantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73 m(2), T2+T3: 91 ml/min/1.73 m(2); P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. CONCLUSIONS: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers.

Tomosynthesis of the wrist and hand in patients with rheumatoid arthritis: comparison with radiography and MRI.

OBJECTIVE: The purpose of this article is to compare tomosynthesis with radiography and MRI of the wrist and hand for evaluating bone erosion in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Twenty consecutive patients with an established diagnosis of RA and five control patients were included in this study. They underwent radiography, tomosynthesis, and MRI of the bilateral hand and wrist within a week. The mean total dose of radiography and tomosynthesis was 0.13 and 0.25 mGy, respectively. MRI evaluation was performed according to the Outcome Measures in Rheumatology Clinical Trials recommendations. Bone erosion on images from the three modalities was independently reviewed by two certificated radiologists with a 4-point scale (0, normal; 1, discrete erosion; 2, < 50% of the joint surface; and 3, ≥ 50% of the joint surface). RESULTS: The detection rates of bone erosion for radiography, tomosynthesis, and MRI were 26.5%, 36.1%, and 36.7%, respectively. Significantly more bone erosions were revealed with tomosynthesis and MRI than with radiography (p < 0.01). When MRI was used as the reference standard, the sensitivity, specificity, and accuracy were 68.1%, 97.5%, and 86.7%, respectively, for radiography and 94.8%, 97.8%, and 96.7%, respectively, for tomosynthesis. Interobserver agreement (kappa value) for bone erosion was good to excellent on tomosynthesis and MRI for all joints (0.65-1.00 and 0.68-1.00, respectively), whereas it was slight to fair on radiography for some carpal bones and bases of metacarpal bones (0.22-0.56). CONCLUSION: Tomosynthesis is superior to radiography and almost comparable to MRI for the detection of bone erosion in patients with RA.

High-resolution MRI predicts steroid injection response in carpal tunnel syndrome patients.

OBJECTIVES: To correlate median nerve T2 signal and shape at the carpal tunnel with steroid injection (SI) response in carpal tunnel syndrome (CTS) patients. METHODS: One hundred and sixty-three CTS wrists of 92 consecutive patients who were scheduled to undergo SI were prospectively evaluated with 3-T magnetic resonance imaging (MRI) and a nerve conduction study. All patients underwent axial high-resolution T2-weighted MRI (in-plane resolution of 0.25 × 0.25 mm). The CTS wrists were classified into three groups according to the nerve T2 signal and the flattening ratio at the hook of hamate level: group 1, high and oval; group 2, high and flat; group 3, low and flat. Clinical response to SI was evaluated at 6 months after injection. RESULTS: One hundred and thirteen of the 163 wrists (69.3%) responded well to SI. The percentage of improvement was 81.7% (49/60) in group 1, 69.9% (51/73) in group 2, and 43.3% (13/30) in group 3 (P < 0.01). On stepwise logistic regression analysis high-resolution MRI was the only significant independent factor for SI response in CTS patients (P < 0.01). CONCLUSIONS: High-resolution MRI correlates well with SI response in CTS patients and seems useful for predicting SI response. KEY POINTS: • MRI may help determine appropriate care in carpal tunnel syndrome. • MRI helps in therapeutic decision-making whenever steroid injection is considered. • T2 signal decrease of the median nerve correlates with poor outcome. • T2 signal decrease of median nerve may reflect fibrosis and amyloid deposition.

Diagnosis of early-stage rheumatoid arthritis: usefulness of unenhanced and gadolinium-enhanced MR images at 3 T.

Forty-one consecutive unclassified arthritis patients with polyarthralgia including wrist joint were evaluated with 3-T MRI as possible early-stage rheumatoid arthritis (RA). After prospective follow-up, 21 of 41 patients fulfilled the American College of Rheumatology (ACR) criteria. Synovitis was detected in all 21 RA patients (sensitivity=100%) with postcontrast MRI and in 14 patients (67%) with unenhanced MRI when none of them fulfilled ACR diagnostic criteria. Fat-suppressed intermediate-weighted fast spin-echo (FSE) image showed high detection rate of synovitis and bone erosion, whereas FIESTA image clearly delineated joint fluid and bone trabeculae. MRI at 3 T is a potentially powerful tool for discriminating and managing early-stage RA patients.

Computer-aided detection of lung nodules on multidetector CT in concurrent-reader and second-reader modes: a comparative study.

PURPOSE: To compare the reading times and detection performances of radiologists in concurrent-reader and second-reader modes of computer-aided detection (CAD) for lung nodules on multidetector computed tomography (CT). MATERIALS AND METHODS: Fifty clinical multidetector CT datasets containing nodules up to 20mm in diameter were retrospectively collected. For the detection and rating of non-calcified nodules larger than 4mm in diameter, 6 radiologists (3 experienced radiologists and 3 resident radiologists) independently interpreted these datasets twice, once with concurrent-reader CAD and once with second-reader CAD. The reference standard of nodules in the datasets was determined by the consensus of two experienced chest radiologists. The reading times and detection performances in the two modes of CAD were statistically compared, where jackknife free-response receiver operating characteristic (JAFROC) analysis was used for the comparison of detection performances. RESULTS: Two hundreds and seven nodules constituted the reference standard. Reading time was significantly shorter in the concurrent-reader mode than in the second-reader mode, with the mean reading time for the 6 radiologists being 132s with concurrent-reader CAD and 210s with second-reader CAD (p<0.01). JAFROC analysis revealed no significant difference between the detection performances in the two modes, with the average figure-of-merit value for the 6 radiologists being 0.70 with concurrent-reader CAD and 0.72 with second-reader CAD (p=0.35). CONCLUSION: In CAD for lung nodules on multidetector CT, the concurrent-reader mode is more time-efficient than the second-reader mode, and there can be no significant difference between the two modes in terms of detection performance of radiologists.

Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) of the wrist and finger at 3T: comparison with chemical shift selective fat suppression images.

PURPOSE: To compare fat-suppressed magnetic resonance imaging (MRI) quality using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with that using chemical shift selective fat-suppressed T1-weighted spin-echo (CHESS) images for evaluating rheumatoid arthritis (RA) lesions of the hand and finger at 3T. MATERIALS AND METHODS: MRI was performed in eight healthy volunteers and eight RA patients with a 3.0T MR system (Signa HDxt GE healthcare) using an eight-channel knee coil. FS-CHESS-T1-SE and IDEAL imaging were acquired in the coronal planes covering the entire structure of the bilateral hands with a slice thickness of 2 mm. In the RA patients both images were obtained after intravenous gadolinium administration. Image quality was evaluated on a five-point scale (1 = excellent to 5 = very poor). Synovitis and bone marrow contrast uptake on MR images were reviewed by two musculoskeletal radiologists using the Rheumatoid Arthritis MRI Scoring System (RAMRIS) of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) group. RESULTS: IDEAL showed uniform FS unaffected by magnetic field inhomogeneity and challenging geometry of hand and fingers, while CHESS-T1-SE often showed FS failure within the first metacarpal joint, tip of the finger, and ulnar aspect of the wrist joint. Overall image quality was significantly better with IDEAL than CHESS-T1-SE images (4.43 vs. 3.43, P < 0.01). Interobserver agreement (κ value) for synovitis and bone marrow contrast uptake was good to excellent with IDEAL (0.74-0.91, 0.62-0.89, respectively). CONCLUSION: IDEAL could compensate for the effects of field inhomogeneities, providing uniform FS of the hand and finger than did the CHESS-T1-SE sequence.

Adenocarcinomas with predominant ground-glass opacity: correlation of morphology and molecular biomarkers.

PURPOSE: To retrospectively identify successive changes in peripheral lung adenocarcinoma that feature dominant ground-glass opacity (GGO) at computed tomography (CT) and correlate with biomolecular markers. MATERIALS AND METHODS: The institutional review board approved this retrospective study, and all 25 patients provided informed consent. Patients with lung adenocarcinomas smaller than 3 cm in diameter in whom tumor growth could be evaluated with CT before surgery were included. Two thoracic radiologists evaluated tumor growth by analyzing GGO type (pure or mixed) and size increases. Immunohistochemistry of the p53 protein and molecular analysis of the epidermal growth factor receptor (EGFR) and K-ras genes were performed. The Fisher exact test was used to assess statistical significance. RESULTS: Tumor size increased in 19 of 25 patients (76%) during the observation period. The CT changes in 19 patients were classified into four patterns: persistent pure GGO (n = 8), change from pure to mixed GGO (n = 3), mixed GGO with growth of solid component (n = 4), and mixed GGO with growth of GGO component (n = 4). The remaining six patients (24%) had pure GGO without any interval changes. Staining for p53 was negative in all 14 patients with pure GGO and positive in six of 11 patients (55%) with mixed GGO (P < .01). In these six patients appearance or growth of the solid component was seen. EGFR mutations were found in both pure (36%) and mixed (45%) GGO lesions (P = .70). CONCLUSION: Lung adenocarcinomas with a dominant GGO often possess EGFR mutations. Interval changes in the solid component may be related to p53 inactivation.

Thin-section chest CT findings in systemic lupus erythematosus with antiphospholipid syndrome: a comparison with systemic lupus erythematosus without antiphospholipid syndrome.

PURPOSE: To assess thin-section chest CT findings in systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS), in comparison with SLE without APS. MATERIALS AND METHODS: We retrospectively reviewed the medical records and thin-section CT findings of 17 consecutive patients with an established diagnosis of SLE with APS, comparing with 37 consecutive SLE patients without APS, between 2004 and 2008, and patients who had other autoimmune disease, such as Sjögren syndrome, were excluded. No significant differences were seen between the two groups in age, gender, smoking habits, or history of steroid pulse and biological therapy. CT images of 2mm thickness obtained with a 16- or 64-detector row CT were retrospectively evaluated by two radiologists in consensus on ultra high-resolution gray-scale monitors. RESULTS: The frequency of thin-section CT abnormalities was higher in SLE with APS group (82%) than in SLE without APS group (43%). Ground-glass opacity (59%), architectural distortion (47%), reticulation (41%), enlarged peripheral pulmonary artery (29%), and mosaic attenuation (29%) were significantly more common in the SLE with APS group than in the SLE without APS group (Fisher's exact test, p<0.01). CONCLUSION: SLE patients with APS have increased prevalence of thin-section chest CT abnormalities than those without APS.

Frequency and significance of pulmonary nodules on thin-section CT in patients with extrapulmonary malignant neoplasms.

PURPOSE: To determine the frequency and significance of pulmonary nodules detected on thin-section CT in patients with extrapulmonary malignant neoplasms. MATERIALS AND METHODS: The institutional review board approved this study. This study retrospectively evaluated 308 patients with extrapulmonary carcinomas or sarcomas and had undergone thin-section chest CT (2mm slice thickness) for staging. Three radiologists identified non-calcified nodules and evaluated the size, the growth and the distance from the nearest pleural surface. The characteristics of the nodules were defined based on the results of either a diagnostic biopsy or nodule growth. RESULTS: One or more non-calcified pulmonary nodules were detected in 75% of the patients (233/308). One hundred and thirty-seven of these patients had nodules that met the criteria of either benign or malignant nodules. Nodules smaller than 10mm were more likely to be benign, whereas those 10mm or greater were more likely to be malignant (22/26, 85%; P<.0001). Most nodules less than 10mm from the pleura were benign (91%), whereas approximately half of the nodules 10mm or more away from the pleura were malignant (20/43, 47%; P<.0001). Patients with melanoma, sarcoma, or testicular carcinoma were more likely to have malignant nodules. A multivariable analysis demonstrated the nodule size (P<.0001) and distance from the pleura were predictive of malignancy. CONCLUSION: The nodule detection rate on thin-section CT in patients with extrapulmonary malignancy is high. Most of the nodules smaller than 10mm or less than 10mm from the pleura are benign.

Usefulness of computerized method for lung nodule detection on digital chest radiographs using similar subtraction images from different patients.

PURPOSE: The purpose of this study is to evaluate the usefulness of a novel computerized method to select automatically the similar chest radiograph for image subtraction in the patients who have no previous chest radiographs and to assist the radiologists' interpretation by presenting the "similar subtraction image" from different patients. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement for informed patient consent was waived. A large database of approximately 15,000 normal chest radiographs was used for searching similar images of different patients. One hundred images of candidates were selected according to two clinical parameters and similarity of the lung field in the target image. We used the correlation value of chest region in the 100 images for searching the most similar image. The similar subtraction images were obtained by subtracting the similar image selected from the target image. Thirty cases with lung nodules and 30 cases without lung nodules were used for an observer performance test. Four attending radiologists and four radiology residents participated in this observer performance test. RESULTS: The AUC for all radiologists increased significantly from 0.925 to 0.974 with the CAD (P=.004). When the computer output images were available, the average AUC for the residents was more improved (0.960 vs. 0.890) than for the attending radiologists (0.987 vs. 0.960). CONCLUSION: The novel computerized method for lung nodule detection using similar subtraction images from different patients would be useful to detect lung nodules on digital chest radiographs, especially for less experienced readers.