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Minimally Invasive Techniques for Diagnosing and Staging Lung Cancer

PCCSU Volume 25, Lesson 17

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Jonathan T. Puchalski, MD, MEd

Dr. Puchalski is Director, Thoracic Interventional Program, Yale University, New Haven, Connecticut.

Dr. Puchalski has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Understand advances in bronchoscopic biopsy techniques used to diagnose lung cancer, including endobronchial ultrasound (EBUS) and electromagnetic navigation.
  2. Describe the clinical utility of convex-probe EBUS compared with peripheral EBUS.
  3. Understand the complications of bronchoscopic biopsies compared with those of transthoracic biopsies.
  4. List five techniques for diagnosing lung cancer in order of invasiveness.
  5. Understand that new diagnostic bronchoscopic modalities have a higher yield than conventional techniques for diagnosing lung cancer.

Key words: bronchoscopy; electromagnetic navigation; endobronchial ultrasound; lung biopsy; lung cancer; lung nodule

Abbreviations: CXR = chest radiograph; EBUS = endobronchial ultrasound; EMN = electromagnetic navigation; EUS = esophageal ultrasound; FNA = fine-needle aspiration; pEBUS = peripheral endobronchial ultrasound

The diagnosis and staging of lung cancer has improved with technology that enables the physician to visualize lesions that are not apparent to the unaided eye. Approximately 70% of patients with lung cancer present with locally advanced or metastatic disease.1 The least invasive diagnostic modality is the preferred approach when pathologic confirmation is necessary. When adenopathy or masses are not palpable, bronchoscopic or image-guided procedures are typically used. Ultrasound, virtual navigation, advanced bronchoscopes, and other developments have significantly improved the yield and accuracy when diagnosing lesions bronchoscopically, making bronchoscopy the preferred initial test in many circumstances. It is critical to understand all available options for the initial evaluation of intrathoracic malignancies.

The current standard of care incorporates fine-needle aspiration (FNA) or core needle biopsy for metastatic extrathoracic lesions, as well as conventional bronchoscopic techniques, such as transbronchial biopsy and transbronchial needle aspiration, for intrathoracic disease. Techniques such as endobronchial ultrasound (EBUS) will likely evolve into the new standard of care sometime in the next decade. Other techniques, such as electromagnetic navigation (EMN), are currently available only in specialized centers and this limited availability is likely to continueas a result of cost and training issues. Other potential diagnostic modalities (eg, optical coherence tomography) are only in the early stages of development.

Early Detection of Endobronchial Lung Cancer

Lung cancer is the leading cause of cancer death worldwide, and it accounted for approximately 157,300 deaths in the United States in 2010.2 Unfortunately, lung cancer is often in an advanced stage when detected. It is anticipated that CT scans will be beneficial for early detection, but to date there is an absence of good screening tests for lung cancer. Sputum cytology is the least invasive technique when lung cancer is suspected, but it is also the test with the lowest yield. Combining chest radiograph (CXR) and sputum cytology has not shown any survival advantage in screening studies3 and a Cochrane Database analysis4 concluded that screening for lung cancer with CXR or sputum cytology is not indicated. The majority of lung cancer cases are first detected through imaging techniques used in patients who have risk factors and symptoms.

Early lung cancer, and particularly that which is limited to mucosa in the central airways, is usually not detected by available imaging techniques. Bronchoscopy may be beneficial for visualizing central lung cancer in very early stages or in a premalignant state, such as carcinoma in situ. Bronchoscopic advances beyond traditional white-light bronchoscopy include the use of autofluorescence, narrow-band imaging, and optical coherence tomography. White-light bronchoscopy is often not sensitive enough to accurately detect premalignant lesions. Autofluorescence bronchoscopy uses blue light (520 nm) rather than white light to detect dysplasia and carcinoma in situ. Unfortunately, this technique has significant inter-rater variability5 and the evolution of central airway dysplasia remains in question.6 Narrow-band imaging enhances vessels in bronchial mucosa by using the light absorption characteristics of hemoglobin at a specific wavelength,7 and it may have a greater specificity for abnormal lesions with aberrant angiogenesis.5,6 Narrow-band imaging is readily available on some bronchoscopy processors. Optical coherence tomography uses infrared light to obtain cross-sectional images and may provide information regarding the depth of invasion of endobronchial lesions. It does not require direct contact and has recently been adapted for use within the airways.5 Miniaturized EBUS probes fitted with a catheter that carries a water-inflatable balloon at its tip (different from other more peripheral EBUS probes) improve bronchial wall contact to allow detailed images of the bronchial wall structure. EBUS findings have correlated with histologic specimens when patients are being examined to identify invasion of the tracheobronchial wall.7 Confocal endomicroscopy, high-magnification bronchoscopy, and multimodality fluorescein imaging are additional techniques that may become useful in the future.8 However, there is currently no gold standard for the bronchoscopic diagnosis of early-stage central-airway-limited lung cancer.

Conventional Techniques for Diagnosing Lung Cancer

For most patients, the lung nodule or mass is discovered by CXR or CT. Surgical resection is considered 100% sensitive and specific, but is also the most invasive means of diagnosing lung cancer. Confirmation of the malignant process is not always necessary preoperatively for lung cancer, as patients with the appropriate risk factors, characteristic imaging findings, and early-stage disease may be suited for surgical resection and cure without additional diagnostic testing. In the presence of obvious metastatic disease, the least invasive diagnostic approach should be used to make the diagnosis. Most patients with lung cancer should undergo PET-CT scanning to look for metastatic disease. Integrated PET-CT is more accurate than CT alone, PET alone, or visually correlated PET-CT scanning for predicting tumor, node, metastasis, and staging of lung cancer.9

Assuming that disease is isolated to the chest and a diagnosis is needed, bronchoscopy is often the first test of choice. For central lesions, the mean diagnostic yield of bronchial washing is 68%; bronchial brushing, 72%; endobronchial biopsy, 80%; and endobronchial needle aspiration, 80%. When these techniques are combined for visible tumors, especially endobronchial biopsy and endobronchial needle aspiration, the overall sensitivity for detecting lung cancer is 89% to 95%.10 When the abnormality is beyond the bronchoscopic field of view, the diagnostic accuracy diminishes. The pooled sensitivity for conventional transbronchial needle aspiration in diagnosing lymph node involvement with cancer is 39%.11 The sensitivity increases with higher prevalence and larger lymph nodes, but remains lower than desired.12 Table 1 reports the diagnostic accuracy of these and other tests discussed in this article.

 


Table 1Minimally Invasive Evaluation of Lung Cancer

Location of Lesion Modality Yield Comments and References
Endobronchial visible lesions Wash 68% Using combined bronchoscopic techniques, the sensitivity of diagnosing endobronchial lesions is 89%-95%10
Brush 72 % Using combined bronchoscopic techniques, the sensitivity of diagnosing endobronchial lesions is 89%-95%10
Endobronchial biopsy 80% Using combined bronchoscopic techniques, the sensitivity of diagnosing endobronchial lesions is 89%-95%10
Endobronchial needle aspiration 80% Using combined bronchoscopic techniques, the sensitivity of diagnosing endobronchial lesions is 89%-95%10
Parenchymal Conventional 43%-65% Techniques include BAL, transbronchial lung biopsy, brush, and aspiration23
pEBUS 73% pEBUS is more sensitive than conventional techniques23,25
EMN 59%-77% Yield improved with combined pEBUS and EMN23,30
Ultrathin bronchoscope 69% No randomized trials23
CT fluoroscopy 62%-71% May not improve sensitivity compared with fluoroscopy only23
Virtual bronchoscopy 63%-86% Combining pEBUS or CT-fluoroscopy plus virtual bronchoscopy results in the highest yield32
Transthoracic Up to 95% Pneumothorax rate 20%-25%23,34
Mediastinal Conventional TBNA 39% Increases with prevalence and larger lymph node size11
EBUS 93% Results from meta-analysis11
EUS 83% Results from meta-analysis14
EBUS + EUS 93% Higher sensitivity than for either technique in isolation16
CT-guided 75%-90% Cannot access as many nodes during one procedure as with EUS/EBUS

 


Endoultrasonography for Adenopathy and Central Lesions

EBUS and esophageal ultrasound (EUS) are highly accurate techniques for the diagnosis and staging of advanced lung cancer. EUS was initially developed for GI disease in the 1970s. The utility of EBUS advanced in the 1990s with the addition of a saline-filled balloon to overcome the limitations of ultrasound transmission within airways. The combined use of EUS and EBUS in this decade promises to significantly advance minimally invasive strategies in lung cancer evaluation.

EUS endoscopes have channels that are 2.0 to 3.7 mm in diameter and are capable of using 19- to 25-gauge needles for biopsies. For the evaluation of lung cancer, the 22-gauge needle is typically used.13 Because of the anatomic location of the esophagus, the most readily accessed areas include the 1L, 2L, 4L, 7, 8, and 9 lymph node stations, as well as the left adrenal gland.11 The lymph node stations accessed by EUS and EBUS are depicted in Figure 1. A recent meta-analysis described the ability of EUS to stage lung cancer. A pooled sensitivity of 88% and specificity of 97% was found for patients with enlarged mediastinal lymph nodes. The sensitivity was 58% in the absence of mediastinal adenopathy. There were no major complications with the use of EUS.14


L17Fig1

Figure 1. Lymph node stations accessed by EBUS, EUS, and mediastinoscopy. Reprinted with permission from Yasufuku et al.39


The EBUS scope is 6.9 mm wide at its tip and can accommodate a 21- or 22-gauge biopsy needle. This convex probe bronchoscope is limited to the central airways and thus distinct from peripheral EBUS, discussed below. It may be used to sample lymph node stations 1, 2R, 2L, 4R, 4L, 7, 10, and 11.11 It is also useful for centrally located parenchymal lesions and its yield may surpass that of transbronchial biopsies.15 A meta-analysis of studies in which EBUS was used for these lesions reported a 93% sensitivity with a 9% false-negative rate.11

EUS and EBUS are complementary techniques that, when used together, further increase the diagnostic yield. This may be accomplished with different specialists using different scopes.16 The EBUS scope may also be passed into the esophagus, enabling both procedures to be accomplished by one operator in the same setting. The combined approach has been shown to increase the diagnostic accuracy as well as increase the number of lymph node stations biopsied.17,18

Finally, lymph nodes may be biopsied using mediastinoscopy or video-assisted thoracoscopic surgery. Thoracotomy may, of course, be used but rarely is for this reason. Although morbidity and mortality are low, these are considered to be the most invasive diagnostic strategies and the complication rates are higher than with the minimally invasive strategies mentioned above. The invasive techniques are more expensive and require use of the operating room and general anesthesia. Surprisingly, a large study revealed that only 46% of mediastinoscopies performed in the United States had documented evidence of lymph node material.19 EBUS has also been shown to have a higher diagnostic yield compared with mediastinoscopy at stations 4R and 7.20 That said, mediastinoscopy is still the current gold standard and it should be performed in the setting of negative EBUS findings in cases in which the clinical suspicion for malignancy is high. The yield of endoscopic evaluation (EUS/EBUS) plus mediastinoscopy is higher than for either modality alone.21

Ultrasonography for Peripheral Lesions

Patients undergoing resection for suspicious pulmonary lesions have up to a 55% benign rate. There are validated prediction models, such as the Mayo model and solitary pulmonary nodule model, for the general population. However, it has recently been suggested that these models perform poorly when attempting to isolate malignant lesions in the surgical population.22 CT-guided biopsy has a high yield but is associated with an inherently higher risk of pneumothorax (20%-25%) than bronchoscopic biopsies. Increased distance from the pleura, the presence of obstructive airway disease, and small size affects the yield. Reports of diagnostic yield for benign lesions have been highly variable, and bronchoscopy instruments may provide more tissue in addition to enabling the biopsy of more than one location.23 Because of the high yield and lower complication rates compared with transthoracic biopsies, endobronchial approaches may be preferred for peripheral lesions.

Historically, bronchoscopy has been hindered by an inability to identify or navigate to peripheral lesions. Although the literature is skewed by studies that address lesions of all sizes, transbronchial biopsy (sensitivity, 57%), transbronchial needle aspiration (65%), brush (54%) and BAL (43%) have traditionally been used, with or without fluoroscopy. The yield increases when these techniques are used in combination.23

The advent of EBUS has improved the yield for diagnosing peripheral lesions compared with historic reports. Peripheral EBUS (pEBUS) may be used with or without a guide sheath. The sheath is passed through the working channel of the bronchoscope and a 20-MHz radial-type probe with a 360° image is advanced into the lung parenchyma. A typical “snowstorm” seen in the parenchyma will convert to a more homogeneous image when the lesion in question is approached. The probe is withdrawn while the guide sheath remains in place and the biopsy tools are advanced to the location identified by pEBUS. The image seen by pEBUS is shown in Figure 2. The yield is higher for central lesions, for larger lesions, in cases where the probe is within rather than adjacent to the lesion.24 A recent meta-analysis reviewed 16 studies including 1,420 patients and found a point sensitivity of 0.73 for the detection of lung cancer, with a positive likelihood ratio of 26.84 and a negative likelihood ratio of 0.28. The sensitivity for diagnosing malignant lesions <2 cm in size is increased with the use of pEBUS.25 The addition of transbronchial needle aspiration to conventional techniques, such as biopsy forceps, brush biopsy, and BAL. increased the yield when using pEBUS.26 A prototype 3.4-mm ultrathin bronchoscope used with a 1.4-mm peripheral ultrasound probe and biopsy forceps has been shown to have a diagnostic yield of 69% for peripheral lesions with a mean size of 34 mm.27 The benefit of the smaller bronchoscope is its ability to initially navigate further into the bronchial tree for better localization of subsegmental airways.


L17Fig2A

L17Fig2B

L17Fig2C

Figure 2. The use of ultrasound in three settings. A, Convex-probe EBUS. B, pEBUS. C, Transthoracic ultrasound of a pleural effusion.


 

Navigational Bronchoscopy

Electromagnetic navigation (EMN) combines real-time 3-dimensional CT images with virtual bronchoscopy and a locatable guide that has active 360° steering capability in order to route the guide sheath more readily and accurately to peripheral lung lesions. The steps of the process have been well summarized and include planning, mapping, navigation, and then the biopsies.28 An extended working channel is similar to a guide sheath that remains in place endobronchially after the target has been identified. The various biopsy tools and a radial EBUS probe can be passed through the sheath. The sensor is 1 mm in diameter and the guide sheath is 1.9 mm, limiting the utility of EMN to bronchoscopes with larger suction channels. Its use has increased since 2003 and the overall diagnostic yield has ranged from 59% to 77%.23 Diagnostic yield is not necessarily affected by the size of the lesion, with several studies demonstrating a similar diagnostic accuracy for lesions that are <2 cm or >2 cm.23 The use of rapid on-site evaluation by cytology has been shown to increase the yield.29 In a randomized controlled trial, combining EMN and pEBUS improved the diagnostic yield to 88%, compared with 69% for pEBUS and 59% for EMN alone.30 Lesions in which a bronchus leads to the abnormality in question (“bronchus sign”) have a significantly higher diagnostic yield than lesions without a visible airway to the lesion.31

Virtual bronchoscopic navigation has been described.32 In essence, virtual bronchoscopic images are constructed using CT scans with a slice thickness of <1 mm. An ultrathin bronchoscope (external diameter, 2.8 mm) is advocated. It is used in combination with CT bronchoscopy, fluoroscopy, or EBUS. Under CT bronchoscopy, the diagnostic yield approached 86% in all lesions and 80.8% in lesions <2 cm. Using x-ray fluoroscopy, the yield is reported to be 62.5% for all lesions and 54.5% for lesions <2 cm. Finally, when pEBUS, guide sheath, and virtual bronchoscopic navigation are combined, the diagnostic yield is reported to be as much as 84.4% for all lesions and 75.9% for lesions <2 cm.32 More studies are required to substantiate these findings in a broader context.

Nonendoscopic Techniques for Diagnosing Lung Cancer

Transthoracic image-guided biopsies are commonly performed. Prior to the emergence of EBUS, an algorithm for image-guided techniques focused on fluoroscopy, ultrasound-guided or CT-guided biopsies in the anterior mediastinum, CT-guided FNA for all nodal stations except station 7 (subcarinal) in the middle mediastinum, and fluoroscopic or CT-guided transthoracic FNA in the posterior mediastinum. Transthoracic approaches were classified as more invasive than bronchoscopy because of the higher complication rates. CT-guided windows of access have been established for all major lymph node stations in the chest and the diagnostic yield is 75% to 90%.33

The accuracy of CT-guided transthoracic lung biopsy reaches 95% for malignant nodules. The overall accuracy decreases for smaller lesions and for benign lesions. The most common complication is pneumothorax, and the rate of pneumothorax increases with increasing severity of emphysema, decreasing nodule size, and decreasing needle-to-skin angle. The reported effect of nodule depth on pneumothorax has been inconsistent. Pneumothoraces occur in 20% to 25% of patients with CT-guided transthoracic lung biopsies.34 Figures 3 and 4 are images obtained with EMN and CT-guided biopsies.


L17Fig3

Figure 3. EMN is a newer endobronchial technique used to approach peripheral lesions.


L17Fig4

Figure 4. CT-guided needle biopsies are accurate but have a higher incidence of pneumothorax than bronchoscopic techniques.


 

Image-guided techniques are also widely available for the diagnosis of metastatic disease. The most frequent sites of lung cancer metastases include bone, brain, liver, and adrenal glands. Most of these areas can be accessed with CT-, fluoroscopy- or ultrasound-guided techniques. Adequate samples are usually obtained (eg, 86% of bone aspirates).35 It is likely that clinician experience increases local accuracy when using fine-needle and core needle biopsy techniques and that, with time, smaller lesions will be accessed with even greater accuracy and minimal complications.36 EUS has emerged as an excellent technique, and possibly the preferred technique, for diagnosing adrenal metastases. Conventional ultrasound is commonly used for targeting FNA. A recent study37 found utility in performing ultrasound of the neck in patients in whom mediastinal adenopathy or enlarged supraclavicular lymph nodes were seen on CT scanning. Identified nodes were biopsied, as were pleural effusions or sites of metastatic disease in which the lesion was identified by ultrasound.37 The importance of ultrasound for performing thoracentesis is well established38 and thoracentesis for potential malignant pleural effusions may very well be among the least invasive strategies discussed. Medical pleuroscopy is another technique used for diagnosing and treating malignant pleural effusions. It is highly effective, but beyond the purview of this article.

Summary

Minimally invasive techniques for the evaluation of lung cancer have entered a new era. The diagnostic yield using EBUS and EMN for nodules, masses, and adenopathy has improved and exceeds the yield for conventional bronchoscopic modalities. Ultrasound is now recognized as a major tool for diagnosing lung cancer in pleural effusions, but also for guiding FNA and core needle biopsies of lymph nodes and metastatic disease. CT- or image-guided biopsies still have an important role, although the risk of pneumothorax remains higher than with bronchoscopic techniques. Minimally invasive diagnostic strategies for lung cancer are available and the least invasive modality for establishing the diagnosis is preferred.


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