In the patient selection process, 388 patients with NSCLC who underwent pulmonary surgery in Shiga University of Medical Science between January 2011 and December 2016 were initially enrolled. Among them, 38 patients with NSCLC complicated with ILD who underwent 18F-FDG PET/CT before pulmonary surgery in our hospital or Oumikusatsu Tokushukai Hospital were identified. 2 patients with glucose metabolism abnormalities were excluded. Thus, finally, 36 patients with ILD were included.
To investigate the difference in 18F-FDG accumulation in the apparently normal or less-affected lung area between NSCLC patients with or without ILD, we additionally included 50 consecutive NSCLC patients without ILD who underwent both 18F-FDG PET/CT before pulmonary surgery and surgery in our hospital between August 2015 and December 2016.
Available patient characteristics, clinical laboratory data, and pulmonary functional tests, including age, sex, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, histology of NSCLC, surgical procedure, stage of NSCLC, lactate dehydrogenase, C-reactive protein, krebs von den lungen-6 (KL-6), and surfactant protein-D were obtained from medical records. Whether ILD was associated with NSCLC or not was estimated by chest HRCT underwent within 3 months before pulmonary surgery. Based on HRCT image findings the NSCLC patients with ILD were classified into having the usual interstitial pneumonia (UIP) pattern and non-UIP pattern. The UIP pattern was assigned when abnormal shadows, including subpleural basal predominance, reticular abnormalities, and honeycombing with or without traction bronchiectasis were present and features of an inconsistent UIP pattern were absent, according to the International Consensus Statement of IPF(21). Otherwise, patients were diagnosed as having a non-UIP pattern.
This study was approved by our institutional review board (approved number: 29-190, November 2, 2017). The need to obtain informed patient consent was waived because of the retrospective nature of this research.
Criteria for Postoperative Exacerbation of ILD
The diagnosis of postoperative AE of ILD was based on the definition of the International Working Group Report for AE of IPF (22). The diagnostic criteria were as follows: acute worsening or development of dyspnea, typically of < 1 month duration after pulmonary surgery; new bilateral ground-glass opacity and/or consolidation on computed tomography (CT); deterioration not fully explained by cardiac failure or fluid overload (22).
PET/CT Image Data Acquisition
18F-FDG PET scanning was performed using a combined PET/CT scanner (Discovery PET/CT 710, General Electronics, Fairfield, CT, USA) in our institution, or a Discovery PET/CT ST (General Electronics) in Oumikusatsu Tokushukai Hospital). All patients were instructed to fast for 5 hours or longer before 18F-FDG administration. Blood glucose level was measured before 18F-FDG injection to confirm a level of less than 150 mg/dL (23). Since the blood glucose level influenced 18F-FDG accumulation in brain (24, 25), patients with unknown blood glucose level were excluded if accumulation of 18F-FDG in their brains was judged to be insufficient. There were no cases whose blood glucose level before 18F-FDG-PET imaging exceeded 150 mg/dl. However, among 10 patients for whom blood glucose level values were unavailable, 2 patients were excluded from analysis because of faint 18F-FDG accumulation demonstrated in the brain. Three-dimensional PET data were acquired from the head to the thigh 60 min after the injection of a dose of 185–330 MBq/kg of 18F-FDG.
High Resolution CT Image Data Acquisition
All patients underwent enhanced or un-enhanced chest HRCT by 64-row helical mode using 320-row multidetector CT scanners (Aquilion ONE, Canon Medical Systems, Otawara, Tochigi, Japan) or 16-row helical scan mode (Sensation Cardiac, Siemens, Munich, Germany) within 3 months after 18F-FDG PET/CT. Other scanning parameters were as follows: tube voltage = 120 kVp, tube current; 180–320 mA (for 64-row mode) or 340–400 mA (for 16-row mode), slice thickness = 0.5 mm (for 64-row mode) and 0.75 mm (for 16-row mode), rotation time; 0.5 s (for 64-row mode) or 0.375 s (for 16-row mode); helical pitch; 40 (for 64-row mode) and 15 (for 16-row mode). CT images were reconstructed with 1-mm slice thickness, 1-mm interval, and lung kernel.
PET images were analyzed on a dedicated workstation (Advantage Workstation, version 2.0; General Electronics, Fairfield, CT, USA). On PET/CT images, a single cubic target volume-of-interest (VOI) of approximately 18 cm3 in volume (26 mm × 26 mm × 26 mm) was carefully placed to include normal-appearing regions while avoiding the mediastinum, chest wall, central bronchus, and blood vessels, in 12 areas (Figure 1): the ventral and dorsal locations in both lungs at each of the 3 predefined levels: aortic arch (AA), tracheal bifurcation (TB), and the orifice of the right lower pulmonary vein into the left atrium (RLPV), while referring to non-increased attenuation on HRCT images. Standardized uptake values (SUVs) were defined as follows: SUVmean was measured in a target VOI. SUVmax was measured as the highest SUV in ILD lesion (18, 19). SUVtissue fraction (TF) was analyzed to adjust for metabolic condition, regardless of differences in the degree of region-based aeration (26, 27). Mean CT density (CTDmean on PET/CT) as well as SUVmean was simultaneously obtained. CTDmean on HRCT were measured using Image J (Version 1.51. National Institutes of Health, Bethesda, ML, USA), by placing an identical-sized VOI at essentially the same location where the VOI was set on PET/CT.
SUVmean, SUVTF, SUVmax, and CTDmean on HRCT were independently assessed by 1 chest physician and 1 thoracic radiologist with 15 and 20 years of experience, respectively, to determine interobserver agreement.
Phantom Study for Adjustment of Measured Values between the Institutions The SUV values measured for images obtained at the 2 institutions were adjusted according to a method described in a previous study (28). Phantom experiments were performed with modification of the dedicated guideline issued by the Japan Nuclear Medicine Society, by using the National Electrical Manufacturers Association (NEMA) body phantom. The NEMA body phantom, with spherical containers of 6 different diameters: 10, 13, 17, 22, 28, and 37 mm, filled with 18F-FDG, for insertion into different body parts, was scanned for 30 minutes in list-mode. The radioactivity levels were 2.65 kBq/mL for spherical containers filled with 18F-FDG arranged and 0.66 KBq/mL for background parts, over 60 minutes at the time of data acquisition. SUVmax values of the image slice with the most highly integrated radio-isotope and the 2 antero-posterior neighboring image slices were averaged as the actual SUVmax for the spherical containers. The gauged mean SUV in the phantom background was determined as the mean of the SUVs of 12 ROIs of 37-mm diameter in the image slice with the most highly integrated radio-isotope and its 4 anteroposterior neighboring image slices for the 10-mm spherical container. The calibration factor was determined by dividing the actual SUVmax by the gauged mean SUV of the phantom background to reduce inconsistencies between 2 institutes. This adjustment for inter-institutional variability in SUV values shrunk the range from 0.69-0.89 to 0.74-0.97 when the SUVmax ratio was described as the SUVmax of the one institution to the SUVmax of the control institution. The original measured SUVmax values for both institutions were corrected by multiplication with the calibration factors derived from the phantom studies to minimize inter-institutional SUV variability; these values were defined as cSUV.
Univariate analyses were conducted to identify the difference in geographic data, physiological parameters, and laboratory data between patients with NSCLC with ILD and without ILD, and between the NSCLC patients with and without postoperative exacerbation of ILD. All continuous and categorical variables were analyzed with Wilcoxon’s test and the chi-square test. For locations with difference in cSUVmean, cSUVTF, and cSUVmax measured values based on PET/CT between NSCLC patients with and without postoperative exacerbation of ILD, receiver operating characteristic (ROC) curve analysis were performed. Two-sided P values of less than 0.05 were considered statistically significant. The normality of SUVmean, SUVTF, and CTDmean on HRCT measured by the 2 observers was evaluated with the Shapiro–Wilk test. Inter-observer variance was evaluated by Spearman’s correlation coefficient for the measured values. All statistical analyzes were performed using JMP 9.0 software (SAS Institute Inc., Cary, NC, USA).