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Original Research: LUNG CANCER |

PET Scan 18F-Fluorodeoxyglucose Uptake and Prognosis in Patients With Resected Clinical Stage IA Non-small Cell Lung Cancer FREE TO VIEW

Viswam S. Nair, MD; Paul G. Barnett, PhD; Lakshmi Ananth, MS; Michael K. Gould, MD, MS, FCCP; for the Veterans Affairs Solitary Nodule Accuracy Project Cooperative Studies Group
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Nair and Gould), Stanford University School of Medicine, and the Department of Health Research and Policy (Drs Barnett and Gould), Stanford University, Stanford; the Health Economics Resource Center (Dr Barnett and Ms Ananth), VA Palo Alto Health Care System, Menlo Park; and the VA Palo Alto Health Care System (Dr Gould), Palo Alto, CA.

Correspondence to: Viswam S. Nair, MD, Stanford University School of Medicine, Division of Pulmonary and Critical Care Medicine, 300 Pasteur Dr, A283, Stanford, CA 94305; e-mail: viswamnair@stanford.edu


Funding/Support: This study was supported by the VA Cooperative Studies Program, Office of Research and Development (VA Cooperative Study 027).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(5):1150-1156. doi:10.1378/chest.09-2356
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Objective:  Our objective was to examine the association between 18F-fluorodeoxyglucose (FDG) uptake on PET scan and prognosis in patients with surgically treated, clinical stage IA non-small cell lung cancer (NSCLC).

Methods:  We reviewed data collection forms and Veterans Affairs administrative records of 75 patients with surgically treated, stage IA NSCLC who were enrolled in a prospective study of PET imaging from 1999 to 2001. We used Cox proportional hazards analysis to examine the association between FDG uptake and survival 4 years following enrollment.

Results:  Most patients were men (97%), and the mean age was 68 ± 9 years. Almost half of the patients (44%) had adenocarcinoma, and 35% underwent a sublobar resection. The mean maximum standardized uptake value (SUVmax) was 4.9 ± 2.5 in survivors and 7.1 ± 3.9 in nonsurvivors (P = .045). Before and after adjustment for age, tumor size, histology, and type of resection, the hazard of death was significantly higher in patients with squamous cell histology (adjusted hazard ratio [HR], 4.54; 95% CI, 1.09-18.9) and those with higher degrees of FDG uptake (adjusted HR, 1.21 per 1 unit increment; 95% CI, 1.01-1.45). At a threshold value of 5 for SUVmax, 34 of 39 patients (87%) with low FDG uptake survived, compared with only 24 of 36 patients (67%) with high FDG uptake (P = .04). Visual assessment of FDG uptake was not associated with an increased hazard of death (HR 0.66; 95% CI, 0.19-2.29).

Conclusions:  High FDG uptake as measured by SUVmax identifies individuals with clinical stage IA NSCLC who are at increased risk of death following surgery. Such high-risk patients may be good candidates for participation in future trials of adjuvant therapy.

Figures in this Article

Lung cancer remains the number one cancer-related cause of death worldwide.1 Non-small cell lung cancer (NSCLC) accounts for the majority of these cases, and, to date, prognosis and therapy have been guided chiefly by the TNM staging system.24 Although operable patients with localized disease have the best prognosis, only 60% of patients with pathologic stage I and 75% with stage IA disease are alive 5 years after resection.46

Recent studies have established that adjuvant chemotherapy is beneficial following resection in patients with stage II NSCLC.7 It is not clear whether adjuvant therapy should be given to those with stage Ib NSCLC, and a metaanalysis has shown a trend toward harm when adjuvant chemotherapy was administered to patients with resected stage IA NSCLC.8,9

18F-fluorodeoxyglucose (FDG) PET imaging provides information about both a tumor’s metabolic activity and the extent of disease burden. Because metabolically active cells selectively take up and trap fluoridated glucose, the intensity of FDG uptake correlates with tumor growth rates.10,11 Several investigators have examined tumor FDG uptake as a prognostic marker in patients with NSCLC. The majority of retrospective, cross-sectional studies performed in patients with all stages of NSCLC indicate that FDG uptake provides prognostic information beyond that of TNM staging alone.12,13 However, no studies have examined tumor FDG uptake and survival in prospectively enrolled patients with malignant nodules that are currently classified as stage IA NSCLC. Given that prognosis is uncertain following resection, we examined the association between tumor FDG uptake and survival in patients with resected, clinical stage IA NSCLC.

This study was a retrospective analysis of data from the Veterans Affairs (VA) Solitary Nodule Accuracy Project (SNAP), which examined the accuracy of CT scans and PET scans for characterizing solitary pulmonary nodules (SPNs). Subjects were enrolled prospectively from 10 geographically diverse VA hospitals between 1999 and 2001, and details of the study design and methods have been published elsewhere.14 Ethical conduct of this study and participant safety were approved and monitored by the Institutional Review Board at each of the study sites.

Patient Selection

The primary inclusion criterion for patients in the SNAP study was evidence of a new, untreated SPN measuring between 7 and 30 mm in size on posterior-anterior and lateral view chest radiographs. The SPN was surrounded completely by aerated lung, without associated atelectasis, postobstructive pneumonia, mediastinal widening, or pleural effusion. Exclusion criteria included age < 21 years; pregnancy or lactation; weight > 350 to 400 lb; intercurrent pulmonary infection; thoracic surgery in the past 6 months; radiotherapy to the chest in the past year; refusal to undergo biopsy, surgery, or a 2-year clinical follow-up; and life expectancy < 2 years if biopsy or surgery was not expected to be performed.

For our substudy, we included SNAP participants with pathologically confirmed NSCLC who underwent FDG-PET imaging prior to surgical resection. Information about pathologic staging was not recorded in available data sources. We therefore excluded patients with increased, nonphysiologic FDG uptake on PET imaging beyond the tumor (ie, nodal and/or extrathoracic uptake) and patients who received postoperative chemotherapy within 90 days.

CT Scan and PET Scan Acquisition

All participants underwent CT scanning of the chest and FDG PET imaging. All centers from the SNAP study followed a protocol for acquisition and processing of the image data for both PET and CT scanning. CT scans were performed according to the standards of the American College of Radiology (1998). High-speed spiral CT scanning was used with a requirement that slices be no wider than 3 mm through the area in which the target nodule was located. Prior to initiation of the study, the performance and minimal resolution requirements (7 mm full width at half maximum) of the PET scan cameras at the 10 sites were validated by use of a standard phantom (CTI; Knoxville, TN). Participants fasted for a minimum of 4 h. Prior to injection, a fasting blood sugar was taken, and participants with a blood sugar > 200 mg/dL were rescheduled. An injection of FDG ranging from 10 to 20 MCi was given, and local investigators had the option to provide a dosage not to exceed 140 µCi/kg of body weight if that was local practice. PET scan acquisition was initiated 45 to 60 min after injection.

FDG Uptake

The initial SNAP study from which we abstracted data for this substudy contained both quantitative and qualitative measures of FDG uptake. FDG uptake was quantified by selecting the imaging slice with the greatest lesion activity. This image was circumscribed with the manufacturer’s region-of-interest (ROI) application and activity was measured to calculate average uptake within the nodule. Maximum pixel intensity within the ROI was recorded as well. Both measures of FDG uptake were subsequently adjusted for dose administered and body weight to calculate mean standardized uptake value (SUVmean) and maximum standard uptake value (SUVmax). PET scan readers at each site also provided a qualitative visual estimate on an integer scale from 1 to 5 (visual score). For further analyses, we dichotomized visual score as being indicative of either low (1-3) or high (4-5) FDG uptake. This threshold roughly corresponds to the metabolic activity of the mediastinal blood pool.14 All PET images were interpreted by a single nuclear medicine specialist at each of the individual study sites.

Data Sources and Variables

From SNAP data collection forms, we obtained information about age, gender, tumor size (measured at the time of CT scan), histology, type of resection (lobar vs sublobar) and FDG uptake. We obtained information about past history of cancer by examining diagnosis codes contained in VA administrative files of inpatient stays and outpatient visits. We examined procedure codes from the VA Patient Treatment File to categorize the type of resection when not specified in the SNAP data collection forms. Postoperative pathologic stage and the reason for type of resection were not available from SNAP data sources.

Follow-up

All SNAP participants were followed for at least 2 years. Survival for this substudy was measured from the time of chest radiograph or CT scan acquisition, whichever came first. We extended the period of follow-up to 4 years and confirmed vital status by using the Beneficiary Identification Records Locator System (BIRLS) registry, which is a Department of VA database containing records of all beneficiaries, including veterans whose survivors applied for death benefits. An extract of the BIRLS database is the BIRLS Death File, which contains information on veterans known to be deceased. Patients who were not listed as deceased in this database were assumed to be alive at 4 years of follow-up.

Statistical Analysis

We compared characteristics of survivors and nonsurvivors by using a two-sided Student t test for continuous variables and a χ2 test for categorical variables. We performed linear regression analysis to determine the association between histology and FDG uptake. We used Cox proportional hazards analysis to examine the association between survival and each of the following covariates: age, previous history of lung cancer, history of other cancer, tumor size, histology, type of resection, and FDG uptake as measured by SUVmean, SUVmax, and visual score. Subsequently, we performed a prespecified multivariate analysis to examine the association between FDG uptake and survival after controlling for age, tumor size, histology, and type of resection (lobar or sublobar). Post hoc we also tested a model that included only statistically significant predictors of survival in the bivariate analyses.

We calculated the sensitivity and specificity of SUVmax for identifying nonsurvivors at threshold values ranging from 1 to 15 (representing the full spectrum of FDG uptake in our study sample). In performing these calculations, we chose to use SUVmax rather than SUVmean for this purpose because it was more strongly associated with survival, and it is generally considered to be a more reproducible measure that is commonly reported in the literature.15 We used the Kaplan-Meier method to compare survival between patients with low vs high FDG uptake at each threshold value. Analyses were performed with SAS (v. 9.1.3; SAS Institute Inc.; Cary, NC). Survival curves were generated using STATA (v.10; StataCorp LP; College Station, TX).

Of 532 SNAP participants, we identified 75 patients with biopsy-proven, clinical stage IA NSCLC who did not have suspected metastasis on PET scan and who were treated by surgical resection without adjuvant chemotherapy (Fig 1). Mean age for these patients was 68 years, and 97% were men. Twenty-eight percent of patients had a previous history of cancer, and one-third of patients had a sublobar resection. Tumor subtypes included adenocarcinoma in 44%, squamous cell carcinoma in 39%, non-small cell carcinoma in 16%, and bronchioloalveolar cell carcinoma in 1%. Mean tumor size was 19 ± 7 mm. Mean SUVmax was 5.4 ± 3.0 and mean SUVmean was 3.9 ± 2.2. Mean follow-up was 48 months for survivors and 27 months for nonsurvivors (Table 1).

Figure Jump LinkFigure 1. Flowchart for cohort assembly. NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer; SNAP = Solitary Nodule Accuracy Project; SUV = standard uptake value.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Patient and Tumor Characteristics

SDs or percentages are provided in parentheses. FDG = 18F-fluorodeoxyglucose; NSCLC = non-small cell lung cancer; ROI = region of interest; SUVmax = maximum standard uptake value; SUVmean = mean standard uptake value.

a 

Maximum FDG uptake of nodule within ROI.

b 

Average FDG uptake of nodule within ROI.

c 

Defined as visual score of 1-3 for low and 4-5 for high on a scale from 1-5.

Seventeen participants died within 4 years of followup (23%) and none died within the postoperative period (30 days). Survivors were more likely to have adenocarcinoma than nonsurvivors (P = .044). SUVmax for survivors was 4.9 ± 2.5 compared with 7.1 ± 3.9 for nonsurvivors (P = .045), and SUVmean for survivors was 3.6 ± 2.2 compared with 4.9 ± 3.6 for nonsurvivors, which was not significant (P = .18). Visual score was similar in survivors and nonsurvivors, and it correlated poorly with SUVmax (r2 = 0.11). Notably, tumor size was larger in nonsurvivors, but this difference was not significant between groups (18 mm vs 21 mm; P = .14). FDG uptake was significantly lower in patients with adenocarcinoma (P = .01) (Fig 2) and the majority of patients with adenocarcinoma had lobectomy performed (78%; P = .10).

Figure Jump LinkFigure 2. Average values with standard deviations are shown for both SUVmax and SUVmean. SUVmax (P = .01) and SUVmean (P = .02) were both lower in patients with adenocarcinoma. SUVmax = maximum standard uptake value; SUVmean = mean standard uptake value. See Figure 1 for expansion of abbreviation.Grahic Jump Location

In bivariate survival analysis (Table 2), the hazard of death was significantly associated with both SUVmax (hazard ratio [HR] per 1 unit increment, 1.27; 95% CI, 1.09-1.48) and SUVmean (HR per 1 unit increment, 1.20; 95% CI, 1.01-1.43). Compared with patients with adenocarcinoma, the hazard of death was higher in patients with squamous cell histology (HR, 4.74; 95% CI, 1.3-17.2). Age, past history of cancer, tumor size, type of resection, and visual score were not associated with survival.

Table Graphic Jump Location
Table 2 —Results of Bivariate and Multivariate Survival Analyses

HR = hazard ratio. See Table 1 for expansion of other abbreviations.

a 

Reference category was low visual score. Therefore, the risk of death in the high visual score group was 0.66 compared with the low visual score group.

We developed two multivariate models to examine the effect of FDG uptake on survival (Table 2). After adjusting for prespecified potential confounders (age, tumor size, and type of resection), both squamous histology (HR, 4.54; 95% CI, 1.09-18.9) and SUVmax (HR, 1.21; 95% CI, 1.01-1.45) remained significant predictors of worse survival. In a model that included only squamous histology and SUVmax, only SUVmax was significantly associated with worse survival (HR, 1.24; 95% CI, 1.06-1.44). Although squamous histology and higher SUVmax were both predictive of worse survival in bivariate and multivariate survival models, the interaction between histology and SUVmax was not statistically significant (P = .84) indicating that the relationship between SUVmax and survival was similar across patients with different histologic subtypes.

We examined whether FDG uptake could provide a clinically useful threshold for clinical decision making by dichotomizing FDG uptake across the range of SUVmax values for patients in our sample (Table 3).16 The accuracy of FDG uptake for identifying nonsurvivors varied depending on the threshold value chosen. At an FDG threshold value of 5, 48% of patients had a positive test that was 71% sensitive and 59% specific for identifying nonsurvivors. At a threshold value of 10, 9% of patients had a positive test that was 95% specific but only 24% sensitive. FDG uptake was significantly associated with survival at both of these threshold values (Fig 3).

Table Graphic Jump Location
Table 3 —Accuracy of FDG Uptake for Predicting Nonsurvival at Varying Thresholds for SUVmax

See Tables 1 and 2 for expansion of abbreviations.

Figure Jump LinkFigure 3. Kaplan-Meier survival curves show that survival was better in patients with tumors that had lower 18F-fluorodeoxyglucose uptake at threshold values for SUVmax of 5 (A, P = .038) and 10 (B, P = .002). See Figure 2 for expansion of abbreviation.Grahic Jump Location

This study examined tumor FDG uptake and its association with survival in patients with resected, clinical stage IA NSCLC. We found that patients with higher FDG uptake had worse survival when FDG uptake was analyzed both as a continuous value (before and after adjusting for potential confounders) and dichotomized at various different threshold values. More specifically, the adjusted hazard of death was approximately 20% higher with each unit increment in FDG uptake, as measured by SUVmax. More strikingly, the hazard of death was almost three times higher in patients with tumor SUVmax > 5, who made up almost 50% of our sample.

We compared our results to previous retrospective studies of tumor FDG uptake and prognosis that performed subgroup analyses in patients with stage IA NSCLC (Table 4).1720 Two studies (both performed in Japan) found associations that were statistically significant. In contrast to our findings, FDG uptake was not associated with overall or disease-free survival in subgroups of patients with stage IA NSCLC in the two US studies, both of which used similar thresholds for SUVmax. It is not clear whether differences in the results of our study are related to patient selection, staging practices or other factors.

Table Graphic Jump Location
Table 4 —Stage IA Subgroup Analysis of Previous Studies Examining FDG Uptake and Prognosis in NSCLC

DFS = disease-free survival; NS = not significant; OS = overall survival; SUV = standard uptake value. See Table 1 for expansion of other abbreviations.

a 

p = pathologic; c = clinical.

b 

SUVmax for stage IA patients.

c 

Survival curves were analyzed by the author in some cases to obtain data.

d 

Stated as not significant but further details were not specified.

We also found that FDG uptake was greater in patients with squamous cell histology and that squamous histology was significantly associated with an increased hazard of death, both before and after adjusting for age, tumor size, type of resection, and FDG uptake. Other studies have shown varying FDG uptake by histology,2022 but we did not expect to find that survival for patients with squamous cell cancer would be worse. One explanation is that SNAP recruitment procedures may have systematically excluded patients with more aggressive adenocarcinomas, leaving behind a subgroup with relatively more indolent tumors.23 A second possible explanation is that more patients with adenocarcinoma underwent lobectomy, conferring an undetected survival advantage to these patients.24 A recent retrospective analysis of stage IA and IB NSCLC indicated that there was an increased risk of death for patients with tumors > 3 cm who had adenocarcinoma compared with squamous cell carcinoma, but this difference was not significant for tumors < 3 cm. The authors noted that late recurrence of adenocarcinoma (> 2 years after diagnosis) was the primary factor responsible for differences in histology-related mortality.25

Many centers currently do not clinically use quantitative FDG uptake given the large variability inherent in this value. Dose of tracer, serum glucose, time to scan from injection, and type of scanner all are sources of imprecision when quantifying FDG uptake.15,26 However, we found that qualitative measurement of FDG uptake (visual score) correlated poorly with quantitative measurement, and that the visual score was not associated with survival. It seems likely that the visual score is too coarse an estimate to be clinically useful for predicting outcome. Given this, we believe that additional effort should be focused on standardizing quantitative measurement of FDG uptake for future research studies.

Strengths of our study include prospective enrollment of participants from 10 different centers, on-site reading of PET scans by practicing nuclear medicine specialists at each of the participating centers, review of regularly updated administrative files to confirm vital status, use of multivariate statistical models to adjust for potential confounders, and the clinical importance of findings that were statistically significant despite a relatively small sample size. Limitations include the small sample, use of dedicated PET scanners (as opposed to PET/CT scanners), absence of information about pathologic staging, and uncertain generalizability to non-veteran populations. Although PET/CT scanning is more accurate for staging in NSCLC,27 there is no reason to believe that it is more accurate for characterizing nodules or predicting outcome based on the FDG uptake of the primary tumor. Some of the patients that we excluded who had increased mediastinal and/or extranodular FDG uptake may have had false-positive findings, and some patients that we included may have had false-negative findings. Despite this shortcoming, 4-year survival in our cohort (77%) was comparable to that in much larger cohorts of patients with pathologic stage IA NSCLC.3,4 Finally, although our results apply most directly to populations of older men with clinical stage IA NSCLC, there is no compelling reason not to generalize to younger patients and women, although caution should be exercised when generalizing to nonsmokers with lung cancer.

Potentially, our results might be used to select patients for future trials of adjuvant therapy. To date, clinical trials of adjuvant chemotherapy have demonstrated a survival advantage for patients with stage IB (Cancer and Leukemia Group B 9633), IB-II (National Cancer Institute of Canada Clinical Trials Group JBr-10), I-IIIA (Adjuvant Lung Project Italy and Adjuvant Navelbine International Trialist Association), and I-III (Big Lung and International Adjuvant Lung Trial) NSCLC.7,9,2831 Cancer and Leukemia Group B 9633 showed a significant and beneficial chemotherapy treatment effect for patients with resected stage IB NSCLC, but this was subsequently shown to diminish over time. The results of the Lung Adjuvant Cisplatin Evaluation metaanalysis, which showed a trend toward harm for adjuvant therapy administration in patients with resected stage IA tumors, suggest that currently available chemotherapy regimens should not be used in unselected patients with stage IA NSCLC.8 In this study, we identified a subgroup of patients with resected, clinical stage IA NSCLC that has a relatively poor prognosis. Such patients might be ideal candidates for enrollment in future trials of currently available or novel adjuvant therapies.

The choice of an optimal threshold value for FDG uptake should balance tradeoffs between false-positive (unnecessary adjuvant treatment) and false-negative (missed opportunity for adjuvant treatment) test results. For example, by selecting a threshold value of 5 (rather than 10) for SUVmax, one obtains greater sensitivity for identifying nonsurvivors (fewer missed opportunities for adjuvant treatment) at the cost of lower specificity (more unnecessary treatment). Determination of the optimal threshold would require a formal decision analysis.

We found that higher tumor FDG uptake, as measured by SUVmax, is independently associated with worse survival in patients with resected clinical stage IA NSCLC, both before and after adjustment for age, prior history of cancer, tumor size, histology and type of resection. This information could be used to improve prognostication and to identify high-risk patients for inclusion in future trials of adjuvant therapy following surgical resection.

Author contributions:Dr Nair: contributed to study conception, design, manuscript writing, editing, and approval.

Dr Barnett: contributed to study design, critical appraisal, and approval.

Ms Ananth: contributed to data acquisition, statistical analysis, and critical appraisal.

Dr Gould: contributed to study design, manuscript writing, critical appraisal, and approval.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

BIRLS

Beneficiary Identification Records Locator System

FDG

18F-fluorodeoxyglucose

HR

hazard ratio

NSCLC

non-small cell lung cancer

ROI

region of interest

SNAP

Solitary Nodule Accuracy Project

SPN

solitary pulmonary nodule

SUV

standard uptake value

SUVmax

maximum standard uptake value

SUVmean

mean standard uptake value

VA

Veterans Affairs

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Figures

Figure Jump LinkFigure 1. Flowchart for cohort assembly. NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer; SNAP = Solitary Nodule Accuracy Project; SUV = standard uptake value.Grahic Jump Location
Figure Jump LinkFigure 2. Average values with standard deviations are shown for both SUVmax and SUVmean. SUVmax (P = .01) and SUVmean (P = .02) were both lower in patients with adenocarcinoma. SUVmax = maximum standard uptake value; SUVmean = mean standard uptake value. See Figure 1 for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3. Kaplan-Meier survival curves show that survival was better in patients with tumors that had lower 18F-fluorodeoxyglucose uptake at threshold values for SUVmax of 5 (A, P = .038) and 10 (B, P = .002). See Figure 2 for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Patient and Tumor Characteristics

SDs or percentages are provided in parentheses. FDG = 18F-fluorodeoxyglucose; NSCLC = non-small cell lung cancer; ROI = region of interest; SUVmax = maximum standard uptake value; SUVmean = mean standard uptake value.

a 

Maximum FDG uptake of nodule within ROI.

b 

Average FDG uptake of nodule within ROI.

c 

Defined as visual score of 1-3 for low and 4-5 for high on a scale from 1-5.

Table Graphic Jump Location
Table 2 —Results of Bivariate and Multivariate Survival Analyses

HR = hazard ratio. See Table 1 for expansion of other abbreviations.

a 

Reference category was low visual score. Therefore, the risk of death in the high visual score group was 0.66 compared with the low visual score group.

Table Graphic Jump Location
Table 3 —Accuracy of FDG Uptake for Predicting Nonsurvival at Varying Thresholds for SUVmax

See Tables 1 and 2 for expansion of abbreviations.

Table Graphic Jump Location
Table 4 —Stage IA Subgroup Analysis of Previous Studies Examining FDG Uptake and Prognosis in NSCLC

DFS = disease-free survival; NS = not significant; OS = overall survival; SUV = standard uptake value. See Table 1 for expansion of other abbreviations.

a 

p = pathologic; c = clinical.

b 

SUVmax for stage IA patients.

c 

Survival curves were analyzed by the author in some cases to obtain data.

d 

Stated as not significant but further details were not specified.

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