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Classification of the Thoroughness of Mediastinal Staging of Lung Cancer FREE TO VIEW

Frank Detterbeck, MD, FCCP; Jonathan Puchalski, MD; Ami Rubinowitz, MD; David Cheng, MD
Author and Funding Information

Section of Thoracic Surgery (Dr Detterbeck), Section of Internal Medicine—Pulmonary (Dr Puchalski), Section of Diagnostic Radiology (Drs Rubinowitz and Cheng), Yale University School of Medicine, Yale Thoracic Oncology Program, New Haven, CT.

Correspondence to: Frank Detterbeck, MD, FCCP, Yale University School of Medicine, Section of Thoracic Surgery, Yale Thoracic Oncology Program, PO Box 208057, New Haven, CT 06520-8062; e-mail: frank.detterbeck@yale.edu


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


© 2010 American College of Chest Physicians


Chest. 2010;137(2):436-442. doi:10.1378/chest.09-1378
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There are many complementary techniques for mediastinal staging of lung cancer. It is increasingly apparent that the accuracy of mediastinal staging depends not only on which test is used but also on technical factors of how the procedure is performed. This article reviews data regarding such technical factors and proposes a classification schema of the thoroughness of execution of mediastinal staging tests. Such a schema is needed for a thoughtful discussion of how mediastinal staging tests should be integrated and for the development of standards of good quality care for patients with non-small cell lung cancer.

Accurate mediastinal staging is crucial in lung cancer when determining the best curative treatment approach.1,2 Mediastinal staging techniques include CT, PET scan, mediastinoscopy, and needle aspiration techniques such as endobronchial ultrasound (EBUS-NA), esophageal ultrasound (EUS-NA), transbronchial needle aspiration (TBNA) and transthoracic needle aspiration (TTNA).1,2 Despite many publications there is confusion about which technique is best. A simple comparison is inappropriate because the procedures are used in different patient cohorts, and they should be viewed as complementary rather than competitive techniques.3

Many population-based studies demonstrate that the quality of staging is generally quite poor.4-9 The vast majority of patients undergo only chest CT, although CT is notoriously inaccurate for mediastinal staging in many situations.1,2 A recent study poignantly underscores the impact of such poor staging: the benefit of better staging exceeds by severalfold the benefit seen from so-called “breakthrough” advances in treatment.9,10

Even when further mediastinal staging is undertaken, the thoroughness of these procedures in the broader community appears to be much lower than that of experts with a focused interest.5,11-14 For example, when mediastinoscopy was performed, not even a single lymph node was biopsied in more than half of the patients in a 2001 US patterns-of-care study.5 Therefore, the reported accuracy of staging tests probably represents optimal results, and not what is typically achieved. It is not just the selection of a staging test but also the manner in which it is executed and interpreted that matters.

It is clear that the thoroughness of pretreatment staging must receive significant attention if we are to improve outcomes for patients with non-small cell lung cancer (NSCLC). However, metrics of the thoroughness of staging interventions have received little attention. Definition of what constitutes appropriate staging in a particular situation requires that we have a system for classification of the thoroughness of mediastinal staging. We have reviewed data relevant to this topic, and in this article we propose such a system for mediastinal staging procedures. We hope this will provide an initial platform for discussion and will facilitate development of standards of good quality care for patients with NSCLC.

We think it is more appropriate to refer to this schema as one that addresses the level of thoroughness, rather than quality, for several reasons. First, the system is based primarily on levels of thoroughness. Second, the term “quality” creates an implication that the highest level is what should be done, but the top level of thoroughness is probably not justified in many situations because of the amount of benefit relative to the increase in complexity, time, and cost. Finally, definition of metrics of quality of care should include many factors that are beyond the scope of this schema (ie, specialty certification, demonstrated experience, outcomes, definition of what level of thoroughness of clinical mediastinal staging is actually appropriate).

Surgical Staging Tests

Surgical staging of the mediastinum refers to mediastinoscopy, variations thereof such as video-assisted mediastinal lymphadenectomy (VAMLA) and transcervical extended mediastinal lymphadenectomy (TEMLA), and thoracoscopic or other surgical approaches. It is important to note that these techniques are all part of clinical staging; the term pathologic staging refers to the staging after a surgical resection is performed.15

Clinical guidelines by the American College of Chest Physicians and European Society of Thoracic Surgeons2,16 recommend that mediastinoscopy include exploration and biopsy of representative nodes in five mediastinal node stations: right and left superior and inferior paratracheal (stations 2R, 2L, 4R, and 4L) and subcarinal nodes (station 7). Evaluation of fewer stations is regarded as selective or poor (Table 1). Assessment of a node station requires that the pretracheal fascia is opened and an exploration reveals either no nodes or a representative node biopsy.2 The most thorough surgical mediastinal staging involves mediastinal lymphadenectomy.

Table Graphic Jump Location
Table 1 —Classification of Type and Thoroughness of Clinical Mediastinal Staging of Lung Cancer

EBUS-NA = endobronchial ultrasound with needle aspiration; EUS-NA = esophageal ultrasound with needle aspiration; LUL = left upper lobe tumor; ROSE = rapid on-site evaluation; TBNA = transbronchial needle aspiration; TTNA = transthoracic needle aspiration; TEMLA = transcervical mediastinal lymphadenectomy; VAMLA = video-assisted mediastinal lymphadenectomy; VATS = video-assisted thoracic surgery.

a 

If immediate cytology or frozen section examination demonstrates malignant involvement, further biopsies of nodes in that category (ie, N3 or N2) is not required, but N3 nodes should be assessed if only N2 involvement is demonstrated.

b 

ROSE should document either malignant cells or lymphatic tissue on ≥ 1 aspirate per node.

c 

In short-axis dimension on transverse slice.

A lymphadenectomy (removal of all mediastinal node-bearing tissue) can be accomplished by TEMLA and VAMLA (either with or without, respectively, the highest mediastinal and lower cervical nodes).17-19 The sampling of Level 5 and 6 nodes for left upper lobe (LUL) tumors is possible via TEMLA but not VAMLA.17 However, TEMLA and VAMLA are grouped together because the differences between them are relatively minor in contrast to other surgical staging procedures.

The impact of the thoroughness of preoperative surgical staging has not been defined. A reasonable extrapolation is from data regarding intraoperative staging at the time of resection (see pathologic staging section). Systematic sampling consistently yields more accurate staging compared with selective nodal sampling.3 Lymphadenectomy compared with systematic sampling detects more multistation involvement, but does not change the stage classification (ie, stage II, IIIa, or IIIb).3

Needle-Based Staging Tests

Needle-based staging techniques include EUS-NA, EBUS-NA, TBNA, and TTNA. These are grouped together, despite some differences among them. A major factor is visual confirmation of the site of the needle (integral to EUS-NA and EBUS-NA but not TBNA). Additionally, it is rather impractical to aspirate multiple sites with some techniques (ie, TTNA). Finally, there are differences in the ability to reach specific nodal stations.

Intuitively, the number of nodes sampled should correlate with the thoroughness of the mediastinal assessment, although this has not been well studied for needle-based techniques. It seems reasonable to extrapolate to needle-based staging techniques the data from preoperative surgical staging and intraoperative pathologic staging,3 showing superiority of systematic sampling of all accessible nodes vs selective sampling of abnormal nodes. This suggests that the most thorough level of needle-based staging should involve sampling of at least one node per station (if accessible and present) and sampling of several nodes in a station if they are suspicious.

Multiple studies have demonstrated improved accuracy with a higher number of aspirations per node.20-22 We propose that for the most thorough assessment three aspirates be obtained, because this is optimal for EBUS (without rapid on-site evaluation [ROSE]),20 although for TBNA (without visualization) five or more aspirates was best.21,22

ROSE improves the performance of needle-based mediastinal staging tests.22-26 If ROSE demonstrates nodal involvement, additional passes at that site are not required. Other potential factors include the node size,2,27 needle size, and perhaps obtaining a tissue core,20,27 but these are less well studied. Therefore, we propose that either ROSE or three or more aspirates be obtained for the most thorough level of assessment.

If ROSE demonstrates malignant involvement, sampling of additional nodes may not be worthwhile. More detailed characterization of stage III NSCLC may permit more optimal (smaller) radiation therapy treatment fields, and definition of patient cohorts suitable for a particular treatment strategy (ie, multistation vs single-station involvement). However, the benefit of complete staging may be overshadowed by the risk and practical downsides of a longer procedure. The highest station node should be evaluated first (ie, a high cervical, contralateral node) if the procedure will be aborted once a positive node is identified.

Metabolic Mediastinal Staging

Metabolic staging refers to fluorodeoxyglucose-PET imaging (the role of other isotopes and other methods of metabolic assessment is insufficiently defined). The quality of a PET study is influenced by many factors, such as scanner technology, the criterion for node positivity, intensity of uptake in the primary tumor, reader experience, and availability of clinical correlation. This provides a basis for the proposed classification scheme, although the impact of each these factors has not been fully defined.

Dual camera coincidence imaging is inferior to dedicated PET.28 Furthermore, interpretation of PET studies without a CT yields inferior results29,30 because of the poor anatomic definition of PET imaging. Integrated machines combining CT and PET detectors in the same gantry allow better metabolic and anatomic correlation and improved resolution because of better attenuation correction. Several studies consistently demonstrate significantly better mediastinal staging of lung cancer with integrated CT/PET compared with correlation of CT and PET images obtained separately.31-33

The quality of the PET interpretation is important, although this has not been studied in detail. Significant interobserver variability occurs even with integrated CT/PET.34 Experienced readers (prior experience with > 100 PET scans) exhibit less variability and better localization of involved nodes, but still provide correct management recommendations in only 80% of cases.34 Improvement probably requires frequent review of final pathologic findings in a joint conference involving radiologists, nuclear medicine physicians, surgeons, and other clinicians.34,35 Additionally, how the standard uptake value of a lesion is established is important; simply using a software package may yield erroneous results.

The most thorough metabolic staging involves integrated CT/PET, with clear definition of increased or normal uptake in each node station. Markedly elevated glucose levels preclude interpretation, although variations within the normal range have little impact.36 The next level of thoroughness involves a dedicated PET interpreted together with a CT scan (either using visual correlation or coregistered fusion images), with clear identification of positive (and negative) node stations. A vague description of node positivity or location corresponds to a level C study, as does PET interpretation without CT correlation. A thoroughness level of D is assigned to studies not involving a dedicated PET scanner with low fluorodeoxyglucose uptake in the tumor (Table 1).

Radiographic Mediastinal Staging

Radiographic staging refers to the use of CT, as MRI has little role.1,37 Many aspects of CT imaging may affect the quality of this modality, including scanner generation, multidetector technology, slice thickness, IV contrast, criterion to classify a node as malignant, and reader experience. The proposed classification of radiographic staging is based primarily on the thoroughness of mediastinal evaluation, because most factors have not been well studied. For example, a vague reference to “lymphadenopathy” or “enlarged nodes” without defining the criteria for “abnormal” or the node location constitutes a level D assessment.

A widely adopted definition of an abnormal node is a short-axis diameter of ≥ 1 cm on an axial image.1,38-41 There is a significant benefit to a fourth-generation CT scanner,41 whereas the benefit from a multidetector scanner using multiplanar reconstruction is controversial.42,43 A trend to better results has been noted for thinner scan slices.41,44

IV contrast enhancement appears to be of marginal benefit in nodal staging. Several studies suggest no benefit with respect to mediastinal nodes,41,42,44-46 although this is questioned by some authors.43 However, most studies evaluated the ability to detect lymph nodes, not the accuracy of classifying nodes as malignant. Furthermore, some studies have suggested that the definition of N1 node size and involvement may be easier, more accurate, and faster when contrast enhancement is used.43,45 The status of N1 nodes affects how mediastinal staging should be approached.2 Therefore, we propose that highest level of radiologic staging include the use of IV contrast.

Intraoperative mediastinal staging at the time of resection can consist of a mediastinal lymph node dissection (MLND), a systematic sampling, or a selective sampling. A formal MLND involves removal of all node-bearing tissues, leaving only the skeletonized trachea, phrenic nerves, aorta, and superior vena cava.47 A systematic sampling requires opening the pleura, exploration, and biopsy of representative nodes in each accessible node station. Biopsy is performed on only selected nodes judged as abnormal in selective sampling. Some authors advocate a lobe-specific systematic node dissection, which consists of a complete dissection of those nodal regions most commonly involved by tumors in a particular lobe, and data suggest this is similar to complete MLND.48 A complete MLND is clearly safe with only a minor impact on operative times or morbidity.49-55

Diligent intraoperative mediastinal staging improves the accuracy of pathologic staging. Several controlled and randomized studies found that systematic sampling detects N2 involvement approximately twice as often as selective sampling.49,50,52,55 Systematic sampling and MLND define essentially the same number of patients with pN2 involvement.51,54,56 However, MLND detected more patients with multilevel N2 involvement than systematic sampling in two studies involving cI-IIIa patients (59% vs 17%, P < 0.01),51,56 but not in another study involving cIa patients.54 Whether there is a therapeutic value to MLND is a different (and controversial) question.49

The most thorough pathologic (intraoperative) mediastinal staging involves MLND (Table 2). A systematic sampling is classified as level B, whereas selective sampling is level C. Bilateral MLND has been proposed because of a potential therapeutic benefit but is omitted because it is rarely used and of unclear benefit.57 The classification scheme of intraoperative staging applies to both open and thoracoscopic resections: a metaanalysis demonstrates no difference between these approaches in either the number of nodes retrieved or the number of node stations accessed.58 Current clinical guidelines for intraoperative staging recommend either systematic sampling, complete MLND, or lobe-specific MLND (ie, level A or B).48,59,60

Table Graphic Jump Location
Table 2 —Classification of Thoroughness of Pathologic (Intraoperative) Mediastinal Staging of Lung Cancer

Assessment should include all ipsilateral node stations.

a 

Staging classified as class A+ if bilateral lymphadenectomy is performed.

Given the dramatic importance of diligent staging and the marked variability in how mediastinal staging tests are performed, a focus on the type and thoroughness of pretreatment staging is clearly needed. Confusion persists despite guidelines defining when tests are needed and how to integrate the various procedures.1-3 Conflicting data are partly to blame, arising from the variability in how staging interventions are carried out. Acceptable minimum standards of thoroughness must be defined. Furthermore, a regional organization of care is needed, based on the depth and experience, clinical organization, and expertise in specific interventions available at a particular institution.61,62

A system of classification of the thoroughness of mediastinal staging interventions is needed to make further progress in defining the appropriate extent and conduct of pretreatment staging of NSCLC. A classification system provides a definition of terms and concepts that allows discussion, further study, and analysis to occur. Without this, it is difficult to compare results of different studies, approaches, or centers.

The proposed classification system is somewhat speculative, because factors regarding the execution and interpretation of mediastinal staging techniques have only partially been defined. Nevertheless, the proposed system is based as much as possible on available data. We hope this system can serve as a starting point for further discussion and investigation.

There is a natural hierarchy of clinical staging interventions from radiologic through metabolic, needle-based, and finally surgical techniques. This follows a progression from a relatively simple, readily available test (CT) to more involved or more invasive tests. Furthermore, CT is notoriously inaccurate in many situations, whereas mediastinoscopy is considered the gold standard for clinical mediastinal staging. Nevertheless, one should not interpret this hierarchy to mean that a “higher” type of staging is necessarily better or more reliable. It is not only the type of test but also how it is executed that is important. For example, a very thorough EBUS may be correct more often than a low-level mediastinoscopy.

We hope the proposed classification provides a basis for further discussion and refinement of these definitions. It would be helpful if publications of staging techniques provided information about the level of thoroughness that was used. We must learn more about the impact of different levels of thoroughness. The highest level may not always be best: a small benefit may not offset extra risk or burden due to limited availability. Furthermore, what is eventually defined as an appropriate level of thoroughness may be different in different clinical scenarios (eg, a peripheral ground glass lesion vs a solid large mass with hilar node enlargement). Adoption of this classification scheme (or an improved version thereof) would greatly facilitate study of issues surrounding optimal mediastinal staging of NSCLC. This classification may also provide a nomenclature that facilitates definition of quality metrics for management of NSCLC, a task for which there is an acute need.

In conclusion, we have proposed a classification scheme for the type and thoroughness of mediastinal staging procedures. A system of classification is needed, given the importance of accurate staging and the variability in execution of mediastinal staging procedures that exists. A common language such as we have proposed is the first step in the process of refining how mediastinal staging should be conducted in patients with lung cancer.

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.

EBUS-NA

endobronchial ultrasound with needle aspiration

EUS-NA

esophageal ultrasound with needle aspiration

LUL

left upper lobe

MLND

mediastinal lymph node dissection

NSCLC

non-small cell lung cancer

ROSE

rapid on-site evaluation

TBNA

transbronchial needle aspiration

TEMLA

transcervical extended mediastinal lymphadenectomy

TTNA

transthoracic needle aspiration

VAMLA

video-assisted mediastinal lymphadenectomy

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Bollen ECM, van Duin CJ, Theunissen PHMH, vt Hof-Grootenboer BE, Blijham GH. Mediastinal lymph node dissection in resected lung cancer: morbidity and accuracy of staging. Ann Thorac Surg. 1993;554:961-966. [CrossRef] [PubMed]
 
Allen MS, Darling GE, Pechet TTV, et al. ACOSOG Z0030 Study Group Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg. 2006;813:1013-1019. [CrossRef] [PubMed]
 
Izbicki JR, Passlick B, Pantel K, et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg. 1998;2271:138-144. [CrossRef] [PubMed]
 
Sugi K, Nawata K, Fujita N, et al. Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg. 1998;223:290-294. [CrossRef] [PubMed]
 
Wu Y, Huang ZF, Wang SY, Yang XN, Ou W. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer. 2002;361:1-6. [CrossRef] [PubMed]
 
Izbicki JR, Passlick B, Karg O, et al. Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg. 1995;591:209-214. [CrossRef] [PubMed]
 
Sakao Y, Miyamoto H, Yamazaki A, et al. The spread of metastatic lymph nodes to the mediastinum from left upper lobe cancer: results of superior mediastinal nodal dissection through a median sternotomy. Eur J Cardiothorac Surg. 2006;303:543-547. [CrossRef] [PubMed]
 
Cheng D, Downey RJ, Kernstine K, et al. Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials. Innovations. 2007;26:261-292. [PubMed]
 
Robinson L, Ruckdeschel J, Wagner HJ, et al. American College of Chest Physicians. Treatment of non-small cell lung cancer – stage IIIA: ACCP evidence-based guidelines (2nd edition). Chest. 2007;1323Suppl:243S-265S. [CrossRef] [PubMed]
 
Scott WJ, Howington J, Feigenberg S, Movsas B, Pisters K. American College of Chest Physicians Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;1323suppl:234S-242S. [CrossRef] [PubMed]
 
Frencher SK Jr, Ryoo JJ, Ko CY. Emerging importance of certification: volume, outcomes, and regionalization of care. J Surg Oncol. 2009;993:131-132. [CrossRef] [PubMed]
 
Sundaresan S, Langer B, Oliver T, Schwartz F, Brouwers M, Stern H. Expert Panel on Thoracic Surgical Oncology Standards for thoracic surgical oncology in a single-payer healthcare system. Ann Thorac Surg. 2007;842:693-701. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Classification of Type and Thoroughness of Clinical Mediastinal Staging of Lung Cancer

EBUS-NA = endobronchial ultrasound with needle aspiration; EUS-NA = esophageal ultrasound with needle aspiration; LUL = left upper lobe tumor; ROSE = rapid on-site evaluation; TBNA = transbronchial needle aspiration; TTNA = transthoracic needle aspiration; TEMLA = transcervical mediastinal lymphadenectomy; VAMLA = video-assisted mediastinal lymphadenectomy; VATS = video-assisted thoracic surgery.

a 

If immediate cytology or frozen section examination demonstrates malignant involvement, further biopsies of nodes in that category (ie, N3 or N2) is not required, but N3 nodes should be assessed if only N2 involvement is demonstrated.

b 

ROSE should document either malignant cells or lymphatic tissue on ≥ 1 aspirate per node.

c 

In short-axis dimension on transverse slice.

Table Graphic Jump Location
Table 2 —Classification of Thoroughness of Pathologic (Intraoperative) Mediastinal Staging of Lung Cancer

Assessment should include all ipsilateral node stations.

a 

Staging classified as class A+ if bilateral lymphadenectomy is performed.

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Allen MS, Darling GE, Pechet TTV, et al. ACOSOG Z0030 Study Group Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg. 2006;813:1013-1019. [CrossRef] [PubMed]
 
Izbicki JR, Passlick B, Pantel K, et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg. 1998;2271:138-144. [CrossRef] [PubMed]
 
Sugi K, Nawata K, Fujita N, et al. Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg. 1998;223:290-294. [CrossRef] [PubMed]
 
Wu Y, Huang ZF, Wang SY, Yang XN, Ou W. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer. 2002;361:1-6. [CrossRef] [PubMed]
 
Izbicki JR, Passlick B, Karg O, et al. Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg. 1995;591:209-214. [CrossRef] [PubMed]
 
Sakao Y, Miyamoto H, Yamazaki A, et al. The spread of metastatic lymph nodes to the mediastinum from left upper lobe cancer: results of superior mediastinal nodal dissection through a median sternotomy. Eur J Cardiothorac Surg. 2006;303:543-547. [CrossRef] [PubMed]
 
Cheng D, Downey RJ, Kernstine K, et al. Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials. Innovations. 2007;26:261-292. [PubMed]
 
Robinson L, Ruckdeschel J, Wagner HJ, et al. American College of Chest Physicians. Treatment of non-small cell lung cancer – stage IIIA: ACCP evidence-based guidelines (2nd edition). Chest. 2007;1323Suppl:243S-265S. [CrossRef] [PubMed]
 
Scott WJ, Howington J, Feigenberg S, Movsas B, Pisters K. American College of Chest Physicians Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;1323suppl:234S-242S. [CrossRef] [PubMed]
 
Frencher SK Jr, Ryoo JJ, Ko CY. Emerging importance of certification: volume, outcomes, and regionalization of care. J Surg Oncol. 2009;993:131-132. [CrossRef] [PubMed]
 
Sundaresan S, Langer B, Oliver T, Schwartz F, Brouwers M, Stern H. Expert Panel on Thoracic Surgical Oncology Standards for thoracic surgical oncology in a single-payer healthcare system. Ann Thorac Surg. 2007;842:693-701. [CrossRef] [PubMed]
 
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