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Ann Thorac Surg 2000;70:1839-1846
© 2000 The Society of Thoracic Surgeons

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Original article: general thoracic

Where is the boundary between N1 and N2 stations in lung cancer?

^a Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan

Address reprint requests to Dr Asamura, Division of Thoracic Surgery, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
e-mail: hasamura{at}gan2.ncc.go.jp

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
Background. The anatomical definition of N1 stations, its boundary to N2 stations, and its prognostic implication are yet to be defined in lung cancer. Metastasis in lymph nodes close to the pleural reflection has been classified differently as N1 or N2 according to the lymph node maps promulgated so far.

Methods. The pattern of lymphatic involvement and prognosis were retrospectively analyzed in 180 N1 patients who underwent at least lobectomy and complete hilar/mediastinal lymphadenectomy from 1987 through 1997. For comparison, the prognoses of 166 N2 patients were also analyzed.

Results. The overall 5-year survival of N1 and N2 patients was 67% and 37%, respectively, and the difference was statistically significant (p = 0.0000, log-rank test). The prognosis was compared between N1 without No. 10 involvement (N1^-, n = 145), N1 with No. 10 involvement (N1⁺, n = 35), and N2 (n = 166). Their 5-year survival was 70%, 54%, and 37%, respectively. A significant difference was observed only between N1⁺ and N2 (p = 0.04), and not observed between N1^- and N1⁺. However, survival curves of single-node N2 (n = 66) and N1⁺ were superimposed.

Conclusions. In terms of prognosis, a pleural reflection does not seem an appropriate anatomical boundary between N1 and N2 stations in lung cancer.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
N1 disease in non-small cell lung carcinoma represents a local spreading of tumor cells, which might be the cause of its less favorable prognosis compared with N0 disease [1]. For T1 to T3 tumors without distant disease, N1 consists of three different stage groups: stage IIA (T1N1), stage IIB (T2N1), and stage IIIA (T3N1), according to the 1997 revised version of the TNM classification [2]. In terms of treatment, histologically/cytologically proved N2 disease no longer indicates resection, and chemoradiotherapy is the standard treatment of choice. An induction therapy with surgery for N2 disease is under active investigation. Surgical resection, however, is selected for N1 disease, and therapeutic strategy is essentially the same as with N0 disease. N1 disease is a heterogeneous group in terms of survival. Martini and coworkers suggested that when tumor metastasis is limited to within one node (single-node N1) and the tumor is less than 3 cm in diameter, a favorable prognosis could be expected with a 5-year survival rate of 48% [3]. Sawyer and associates reported that N1 disease with positive bronchoscopic findings and a nonsquamous histology is associated with a poor prognosis [4]. The prognostic significance of N1 disease and its clinicopathological characteristics have not yet been defined.

The anatomical definition of each N1 station and the N1-N2 boundary is another important problem in N1 disease. To describe the lymph node location where metastasis was confirmed pathologically, the concept of a lymph node map was introduced by Naruke and coworkers in 1979 [5]. Thereafter, three lymph node maps have been promulgated in the US [6–8]. However, lymph node stations close to the pleural reflection have been treated differently in the different maps. The recent revision by Mountain and Dresler [8] and the former American Joint Committee map [6] set an N1-N2 boundary at the pleural reflection. However, the Naruke-Japanese map [5] and the American Thoracic Society map [7] did not mention pleural reflections. In the Naruke-Japanese map, the lymph node station was defined in relation to the bronchial tree and mediastinal structures.

The purpose of our study was to evaluate the prognostic significance of N1 disease, especially N1 disease at the main bronchial node (No. 10), as compared with N2 disease. This information should help to explain whether main bronchial node metastasis is N1 disease or N2 disease, and whether the pleural reflection can be considered an N1-N2 boundary.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
During the 10-year period from 1988 to 1997, 1,610 patients underwent pulmonary resections for lung cancer at the National Cancer Center Hospital, Tokyo. Among these, we retrospectively analyzed the pattern of lymph node metastasis and the prognosis in 180 patients with a non-small cell histology as a lung carcinoma and histologically proved lymph node metastasis in the N1 region (pN1) after a careful pathological examination of all of the lymph nodes dissected. All of the tumors were resected by pulmonary resection (at least lobectomy) and systematic hilar/mediastinal lymph node dissection as described elsewhere [9], and categorized as either T1, T2, or T3 [10]. Patients with the following tumors or conditions were excluded from this study: tumors with small-cell or low-grade malignant histology; T4 tumors, including those with malignant effusion and pleural dissemination; tumors with distant metastatic disease; patients who underwent less than lobectomy for the primary tumor (segmentectomy or wedge resection); and patients who did not undergo hilar/mediastinal lymphadenectomy. These patients comprised 11% of the total. The patients ranged in age from 37 to 81 years (median 62 years). One hundred fifty patients (83%) were male and 30 (17%) were female. Most of the patients underwent a physical examination, chest roentgenography, chest computed tomography scan, bone scintigraphy, and abdominal ultrasonography for staging and the evaluation of resectability before the operation. However, all patients did not always undergo mediastinoscopy before surgery to exclude N2 disease. The clinical characteristics of these 180 patients are presented in Table 1. Resected specimens were examined histologically, and their histologic type was determined according to the World Health Organization classification [11] as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or adenosquamous carcinoma. For comparing survival rates, 166 patients with documented N2 disease were analyzed as well. They were operated on during the same period and selected according to the same criteria as N1 patients.

View larger version (28K): [in this window] [in a new window]   Fig 1. Lymph node stations in the N1 region (A, right side; B, left side). The location of each station is defined in relation to the bronchial structure as main bronchial (No. 10), interlobar (No. 11), lobar (No. 12), segmental bronchial (No. 13), and intrapulmonary (No. 14), regardless of the pleural reflection. For the right side, No. 11s(superior, between the upper and intermediate bronchi) and No. 11i (inferior, between the middle and lower bronchi) are distinguished.

Recurrence and prognosis
Cancer recurrence was carefully divided into two categories according to the site of initial relapse: locoregional or distant. Locoregional recurrence was defined as any recurrent disease within the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes. All other sites of recurrence were considered distant metastases. The cause of death was recorded as either cancer related, other diseases, or unknown. Survival rates were calculated by the Kaplan-Meier life-table method [12] and comparisons were made by a log-rank test [13], in which the initial day of treatment was the day of surgery. Deaths that were not because of cancer were considered a censored case. A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
Lymph node metastasis according to the location of the primary tumor
The prevalence of metastasis at each lymph node station was determined according to the site of the primary tumors by lobe (Fig 2). There was no characteristic difference in the pattern of N1 lymph node metastasis according to the primary site by lobe. Intrapulmonary and extrapulmonary N1 stations were both involved regardless of tumor location. However, interlobar tumor involvement was seen only at No. 11s and not at No. 11i for tumors of the right upper lobe (n = 44). On the other hand, both the No. 11s and No. 11i interlobar stations were involved for tumors the right middle (n = 5) and lower lobes (n = 35).

View larger version (23K): [in this window] [in a new window]   Fig 2. Lymph node metastasis according to the site of the primary tumor by lobe. (A) Tumors of the right upper lobe (n = 44); (B) tumors of the right middle lobe (n = 5); (C) tumors of the right lower lobe (n = 35); (D) tumors of the left upper lobe (n = 66); (E) tumors of the left lower lobe (n = 30). Numbers (%) of patients with metastasis in each lymph node station are indicated in the circle.

View larger version (22K): [in this window] [in a new window]   Fig 3. Survival curves of patients with N1 (n = 180) and N2 (n = 166) metastases. Five-year survival rates for patients with N1 and N2 metastases are 67% and 37%, respectively. A statistically significant difference is observed (p = 0.0000, log-rank test).

View larger version (24K): [in this window] [in a new window]   Fig 4. Survival curves of patients with N1- (n = 145), N1+ (n = 35), and N2 (n = 166) metastasis. There is no statistically significant difference between N1- and N1+ (log-rank test, p = 0.97). However, patients with N1+ show significantly better survival than N2 patients (p = 0.04, log-rank test).

View larger version (30K): [in this window] [in a new window]   Fig 5. Survival curves of patients with N1- (n = 145), N1+ (n = 35), single-node N2 (n = 66), and multiple-node N2 (n = 100) metastases. Their 5-year survival rates are 70%, 54%, 53%, and 24%, respectively. N1+ and single-node N2 are superimposed.

View larger version (30K): [in this window] [in a new window]   Fig 6. Survival curves of patients with N1- (n = 145), N1+ (n = 35), single-station N2 (n = 94), and multiple-station N2 (n = 72) metastases. Their 5-year survival rates are 70%, 54%, 48%, and 22%, respectively. N1+ and single-station N2 are superimposed.

Prognosis by histology
Survival was compared according to tumor histology, ie, squamous cell carcinoma (n = 76), adenocarcinoma (n = 76), large cell carcinoma (n = 12), and adenosquamous carcinoma (n = 5). Their 5-year survival rates were 73%, 61%, 76%, and 40%, respectively. Although squamous cell carcinoma tended to show a better prognosis, there was no significant difference between the four different histologic types.

Prognosis by mode of operation
Survival was compared according to the operative mode, ie, lobectomy (n = 117), bilobectomy (n = 10), and pneumonectomy (n = 53). Their 5-year survival rates were 72%, 74%, and 50%, respectively. Although patients undergoing lobectomy tended to have a better prognosis, there was no significant difference.

Recurrence
Eighty patients (44%) had cancer recurrence after surgery. Detailed data regarding recurrence was not available in 5 patients. The initial relapse site was analyzed in the remaining 75 patients: 55 patients (69%) had distant relapse, 20 (25%) had locoregional relapse. The initial site of recurrence is presented in Table 2. Mediastinal lymph nodes were the most common local site for recurrence, followed by the bronchial stump. Lung was the most common site for distant recurrence, followed by bone. As for the tumor histology of 6 patients with recurrence at the bronchial stump, squamous cell histology was seen in 5 patients and adenocarcinoma was seen in only 1 patient.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

Defining the anatomical extent of each nodal station is indispensable for the accurate categorization of nodal status as N0, N1, N2, and N3, which serves as a basis for stage groupings. However, the lymph node map that defines the anatomical location of each lymph node station has been revised, and a universal map is not yet available. Without a clear definition of the boundary between N1 and N2 stations as well as between N2 and N3 stations, there cannot be an accurate description of nodal status. Furthermore, because of the different therapeutic strategy for N1 and N2 tumors, their distinction is important.

The concept of lymph node mapping was first introduced by Naruke and coworkers in 1977. In Japan, this map has been adopted for nodal classification with only slight modification as the Naruke-Japanese map. On the other hand, US maps originated with the AJC map in 1973, and two maps were promulgated in 1983 (ATS map) and 1997 (Mountain’s map). In the Naruke-Japanese map, the boundary between N1 and N2 stations is not clearly defined: No. 10 station (N1 node) is defined simply as "nodes around the main bronchus" and adjacent No. 4 and No. 7 (N2 node) were defined as "nodes at the tracheobronchial angle" and "nodes below tracheal carina," respectively. In the AJC map, the pleural reflection was set as a clear boundary for N1-N2 stations. Mediastinal nodes were defined as those within the pleural envelope. However, this was abandoned in the ATS map, in which No. 10 (tracheobronchial and peribronchial nodes) and No. 4 (paratracheal nodes) stations were defined according to anatomical structures such as the azygos vein and upper lobe bronchus. These No. 4 and No. 10 stations were not clearly designated as N2 nodes: "prospective data will determine how each of these nodal stations should be staged; i.e. N1, N2, or some intermediate designator." In Mountain’s map, the pleural reflection was revived as an N1-N2 boundary, and No. 10 station was moved distally. Furthermore, No. 10 station was designated as an N1 node and No. 4 station was designated as N2. Because of this uncertainty regarding the N1-N2 boundary, metastatic nodes around the main bronchi have been designated as either N1 or N2 according to the map used; for example, metastatic nodes around the right main stem bronchus are No. 10 (N1) nodes by the Naruke-Japanese map, No. 4 (N2) by the AJC map, No. 10R (N1 or N2) by the ATS map, and No. 4R (N2) by Mountain’s map, because most of the right main bronchus is located beneath the mediastinal pleura. This difference in nodal diagnosis might be a cause of stage migration, which makes uniform and consistent staging difficult.

Indeed, it is indispensable for consistent accurate staging to have an unequivocal anatomical landmark dividing N1 and N2 lymph node stations. However, should the pleural reflection be used for this purpose? This is a very important question. Where is the pleural reflection? Is the reflection recognized on imaging diagnosis? Even during thoracotomy, the pleural reflection is recognized as a "plane" rather than as a "line." Furthermore, the "reflecting line" can be easily moved simply by retracting the lung anteriorly or posteriorly. Furthermore, it is very difficult to define the reflection by imaging such as computed tomography or magnetic resonance. When we consider these anatomical characteristics of pleural reflection, we conclude that it is not a good landmark as a boundary. In addition to such anatomical problems, the present study demonstrated that patients with No. 10 metastasis had a significantly better prognosis than those with N2. Considering these two issues, we think that it is imprudent to set an N1-N2 boundary at the pleural reflection and to incorporate nodes around the main bronchus in N2.

However, the limitations of the present study should also be addressed. Nodes around the main bronchus were designated as No. 10-N1 nodes in this study. However, some of them should have been categorized as No. 7-N2, because no clear boundary had been indicated. Therefore, for future studies, the survival data of N1 patients based on a detailed and well-defined station map must be collected. Furthermore, it must be stressed that the current study is based on surgical and pathologic data, and that actual staging for selection of therapeutic modality must be derived from the clinical assessment of disease extent.

Another important point in the present study is that there was no difference in survival between single-node (53%) (as well as single-station [48%]) N2 metastasis and No. 10 metastasis (54%). In our previous report, we used the term "early N2 disease" for single-node and single-station N2 diseases [14]. Riquet and coworkers reported similar results: survival curves of extralobar N1 disease (positive No. 10 and No. 11 nodes) and single-station N2 disease were superimposed, and their 5-year survival rates were 38.5% and 28.3%, respectively [15]. They concluded that N1 disease consists of two subgroups, and extralobar or hilar N1 disease behaves like an early stage of N2 disease. In this sense, such nodal status (main bronchial and interlobar N1, single-node [-station] N2 disease) can be designated as intermediate between N1 and N2. However, this information can be obtained only after meticulous intraoperative and postsurgical pathologic evaluation, and therefore, it is difficult to select among different therapeutic modalities based on this information.

For universal and consistent accurate staging, it is indispensable to define clearly the border of each lymph node station. For this purpose, at least, the pleural reflection does not seem appropriate. We think that the lymph node stations of the N1 region should be determined in relation to the anatomic structure of the bronchial tree independent of the pleural reflection [16].

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
This work was supported in part by a Grant-in-Aid for Cancer Research (11-19) from the Ministry of Health and Welfare, Japan.

	Discussion

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
DR GILBERT MASSARD (Strasbourg, France): It is my particular honor to be an invited discussant for this remarkable study, and I wish to thank the Society for this privilege. I also thank the authors for sending me the manuscript in advance of the meeting.

I am confident to say that Dr Asamura has convinced the audience that location of lymph nodes should refer to clearly defined anatomic landmarks that are not influenced by our dissection and that may be easily recognized on medical imaging. Therefore, the only reasonable references, as you suggested, are the bronchial tree and the major thoracic vessels. When we are dealing with the N1 category, we are facing a very disparate population. Reported 5-year survival rates range from 20% to 50%. Many authors have demonstrated a different prognosis for intralobar and extralobar N1 disease. I tell you with some pride that one of the first studies was made by Dr Roeslin and colleagues at our institution [1]. Dr Riquet and yourself further showed a similar prognosis for extralobar N1 (invasion of main bronchial nodes) and single station N2 disease [2]. In contrast, Dr Riquet and Dr Van Velzen and their coworkers showed that direct invasion of the lymph nodes heralds an improved prognosis when compared with lymph node metastasis [2, 3]. Dr Martini and colleagues nicely demonstrated an improved prognosis of single station N1 compared with multiple station N1 [4].

During the past two decades, the community dealing with lung cancer was upset by the Will Rogers phenomenon, ie, stage migration because of improved staging. We are currently entering a new era where we have extensively staged patients, and where we are trying to reset the boundaries between the different prognostic categories. I would like to refer to this process as the farmer phenomenon, insofar as it reminds me of the nocturnal fights of farmers in my home country, Luxembourg, where farmers used to move their fences overnight to increase their land.

The danger of this process is confusion. The currently used TN coding leads to 16 different formulas. If we split up N1 in intralobar and extralobar N1, and if we split up N2 in single station and multiple station N2, we will end up with 24 categories. However, in our daily practice, we need a simple stanging system, based on a low number of prognosis-related groups, which should help us to define the adequate treatment plan and to estimate prognosis of the individual patient.

Dr Asamura, I would like to ask you four questions. The first question addresses the dilemma about boundaries. You showed us that intralobar N1 has a fair prognosis, similar to N0. You further showed us that extralobar N1 and single station N2 have similar outcomes. Based on these findings, do you still accept the current AJCC staging system, or would you advocate the following revisions: reintegration of intralobar N1 into stage IB, and downstaging of single station N2 into stage IIB.

My second question refers to the adequate extent of resection for extralobar N1. In France, as in other European countries, some colleagues think that the optimal operation for such patients is pneumonectomy. In my opinion, routine pneumonectomy would dramatically increase operative mortality without any proved survival advantage; I consider that lobectomy and sleeve lobectomy are valuable alternatives provided that a complete resection is performed. What do you think about it?

My third question addresses the issue of multimodality management. Staging allows us to classify patients into subgroups with different prognoses. Ideally, this classification should lead to group-specific management. N1 patients have a risk of at least 40% of dying from metastatic disease. Should this fact open the way to some kind of adjuvant treatment?

My fourth remark is not a question, but an offer. I am really impressed by the excellence of your 5-year survival rates. When reading your manuscript, I did not notice any difference in age or comorbidity when compared with our series. I therefore hypothesize that tumor biology and natural history of cancer might be different in the Eastern population. I wish to offer you a matched control group selected from our database and to invite you publicly for a comparative study. The substance could be submitted as an abstract for the coming STS meeting in New Orleans.

Dr Asamura, I compliment you and your coworkers for a remarkable study and thank you for your nice presentation.

References
1. Roeslin N, Chalkiadakis G, Dumont P, Witz JP. A better prognostic value from a modification of lung cancer staging. J Thorac Cardiovasc Surg 1987;94:504–9.

2. Riquet M, Manach D, Le Pimpec-Barthes F, Dujon A, Chehab A. Prognostic significance of surgical pathologic N1 disease in non-small cell cancer of the lung. Ann Thorac Surg 1999;67:1572–6.

3. Van Velzen E, Snijder RJ, Brutel de la Rivière A, Elbert HJ, Van den Bosch JM. Type of lymph node involvement influences survival rates in T1N1M0 non-small cell lung cancer. Chest 1996;110:1469–73.

4. Martini N, Burt ME, Bains MS, McCormack P, Rusch VW, Ginsberg RJ. Survival after resection of stage II non-small cell cancer. Ann Thorac Surg 1992;54:460–6.

	Discussion

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 
DR ASAMURA: Thank you Dr Massard for your comments. The first point of your questions is whether intralobar N1 should be reintegrated into category IB and whether single-node N2 disease should be moved to stage IIB. I think basically that this nodal information could be given only after intraoperative staging by meticulous lymph node dissection/sampling. Considering the inaccuracy of imaging diagnosis such as CT, I think it is difficult to diagnose this nodal status preoperatively. Although such reintegration of nodal grouping can be considered, I think it would be prudent to do so from a practical viewpoint. The second point regards the extent of resection for extralobar N1 cases. I agree with Dr Massard. I do not think that the proper extent of resection for extralobar N1 cases is always pneumonectomy. So far as metastatic nodes are encapsulated and removed completely, lobectomy should be preferred even if metastatic node is located extralobally. The third point regards an adjuvant treatment. So far as we know, little beneficial adjuvant treatment has ever been reported. Although I feel the necessity to develop an effective adjuvant treatment for such poor prognostic groups of patients with extranodal N1 and N2 diseases, it should be done only in a setting of clinical trials with novel effective regimens.

And finally, Dr Massard pointed out a better prognosis in our series for each staging category. One reason for this is related to the fact that patients in this present study were all staged by meticulous lymph node dissection of the hilum and mediastinum. In this sense, these patients were very, very purified in terms of prognosis by the assessment of all the lymph nodes removed. So, maybe most patients with occult N2 disease, which were overlooked with less complete lymph node dissection, were excluded from the N1 population. I think that the comparison between patients of different countries with matched age, gender, and prognostic indicators is a very good proposal, and I would like to accept it.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion Discussion  References

 

1. Naruke T., Goya T., Tsuchiya R., Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96:440-447.[Abstract]
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3. Martini N., Burt M.E., Bains M.S., McCormack P.M., Rusch V.W., Ginsberg R.J. Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 1992;54:460-466.[Abstract]
4. Sawyer T.E., Bonner J.A., Gould P.M., et al. Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma. Ann Thorac Surg 1999;68:1171-1176.[Abstract/Free Full Text]
5. Naruke T., Suemasu K., Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-839.[Abstract]
6. American Joint Committee on Cancer. Clinical Staging System for Carcinoma of the Lung. Chicago: American Join Committee for Cancer Staging and End Results Reporting, 1973.
7. American Thoracic Society. Clinical staging of primary lung cancer. Am Rev Resp Dis 1983;127:1-6.[Medline]
8. Mountain C.F., Dresler C.M. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718-1723.[Abstract/Free Full Text]
9. Naruke T. Mediastinal lymph node dissection. In: Shields T.W., ed. General thoracic surgery. Philadelphia: Lea & Febiger, 1995:469-480.
10. Sobin L.H., Wittekind C. UICC TNM classification on malignant tumours, 5th ed New York: Wiley-Liss, 1997.
11. World Health Organization. Histological typing of lung tumors, 2nd ed Geneva: World Health Organization, 1981.
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14. Asamura H., Nakayama H., Kondo H., Tsuchiya R., Naruke T. Extent of systematic lymph node dissection for non-small cell lung carcinomas based on a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg 1999;117:1102-1111.[Abstract/Free Full Text]
15. Riquet M., Manach D., Le Pimpec-Barthes F., Dujon A., Chehab A. Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 1999;67:1572-1576.[Abstract/Free Full Text]
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