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Melanoma Recurrence Patterns After Negative Sentinel Lymphadenectomy
Theresa G. Zogakis, MD;
Richard Essner, MD;
He-jing Wang, MD;
Roderick R. Turner, MD;
Yuki T. Takasumi, MD;
Robin L. Gaffney, MD;
Jonathan H. Lee, MD;
Donald L. Morton, MD
Arch Surg. 2005;140:865-872.
ABSTRACT
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Hypothesis A tumor-negative sentinel node (SN) does not eliminate the chance of melanoma recurrence. Patterns of metastasis can be identified and characterized in patients with tumor-negative SNs.
Design Retrospective review.
Setting Melanoma referral center.
Patients Patients who underwent lymphatic mapping and sentinel lymphadenectomy between 1995 and 2002 and whose SNs were negative for metastasis by hematoxylin-eosin and immunohistochemistry staining were included in the study. The SN specimens from patients with recurrent disease were reexamined for missed metastasis.
Main Outcome Measures Differences in survival related to sites of recurrence and the rate of false-negative histopathologic SN diagnosis were determined.
Results At a median follow-up of 36.7 months, 69 (8.9%) of 773 patients with tumor-negative SNs had recurrent disease. Three-year survival after first recurrence was 17.1% in the 37 patients with distant recurrence, 48.7% in the 19 patients with local or in-transit recurrence, and 63.5% in the 13 patients with regional basin recurrence; the difference in survival between patients with local or regional and distant recurrences was statistically significant (P<.001). Histopathologic reexamination of SNs from the 69 patients identified 9 patients with false-negative SNs; 2 of these had same-basin recurrences.
Conclusions The SN is a valuable prognostic indicator because only 8.9% of patients with tumor-negative SNs will develop recurrence. The low incidence (1.7%) of regional basin recurrence in patients with negative SNs supports the accuracy of our current method of lymphatic mapping and sentinel lymphadenectomy to identify occult regional nodal basin metastasis.
INTRODUCTION
Before the introduction of lymphatic mapping and sentinel lymphadenectomy (LM/SL), surgeons advocated elective lymph node dissection (ELND) to identify and treat patients with melanoma who had occult regional node metastasis. Unfortunately, ELND is associated with several problems. Pathologic analysis of multiple nodes for the presence of tumor cells is time-consuming, costly, and prone to sampling error. Patients with tumor-negative regional nodes are subjected to an unnecessary operation, with its potential for the long-term risks of nerve injury and lymphedema. Furthermore, it is not clear whether ELND improves survival. Multiple prospective randomized trials of ELND have been performed, with some suggesting an improvement of survival in particular patient subgroups.1-4
In 1990, Morton et al5 first introduced the concept that a single node, the sentinel node (SN), could be identified, harvested, and examined to determine the presence of regional nodal metastasis in patients with clinical stage I/II melanoma. In their original report that used vital blue dye for intraoperative lymphatic mapping, the SN was successfully identified in 82% of 223 patients.6 Since this first published report, LM/SL has proved to be a less invasive technique that accurately assesses the tumor status of the regional lymph node basin compared with ELND, and during the past decade, it has been used routinely.7
Spread of melanoma to the SN is one of the most important determinants of prognosis in patients with early-stage cutaneous melanoma.8-9 Three-year disease-free survival rates of 88.5% for patients with tumor-negative vs 55.8% for tumor-positive SNs have been reported.8
Although a tumor-negative SN imparts a survival advantage, it does not eliminate the risk of recurrence. Several studies9-17 have examined melanoma recurrence patterns and outcome in patients with tumor-negative SNs. However, many of these studies are limited by small numbers of patients, short follow-up times, and/or histopathologic assessments based only on hematoxylin-eosin (H&E) staining.
Immunohistochemistry (IHC) can increase the sensitivity of SN histopathologic analysis by identifying individual cells and small clusters of melanoma cells that might be missed by H&E staining.18 In their original study on LM/SL, Morton et al6 used IHC for SN evaluation and achieved a low false-negative rate. Despite this, some groups chose to perform SN histopathologic analysis using only H&E staining. Gershenwald et al10 reported melanoma recurrence patterns in patients with tumor-negative SNs by H&E staining. Reanalysis of the SNs in patients with same-basin recurrences by serial sectioning and/or IHC demonstrated evidence of missed occult metastases in 80%.
In this study, we retrospectively evaluated the recurrence patterns of patients whose SNs were negative for melanoma by a standardized pathologic technique that included IHC staining with antibodies to S100 and HMB-45. We investigated differences in survival based on sites of recurrence. The SNs from patients with recurrence were reevaluated by further sectioning and IHC staining. The goals of the study were to gain an understanding of the natural history of disease in patients with tumor-negative SNs as well as the accuracy of LM/SL.
METHODS
We performed a retrospective review of a prospectively acquired database to identify all patients with stage I and II melanoma who underwent successful LM/SL between January 1995 and December 2002 at our melanoma referral center. The database contained each patient’s clinical characteristics, pathologic findings, and follow-up records. Excluded from this study were patients with a history of melanoma or other malignancy (other than skin cancers such as squamous cell or basal cell), those with more than 1 primary melanoma at presentation, those with tumor-positive margins after wide excision of the primary tumor, and those who underwent LM/SL more than 3 months after primary melanoma diagnosis. Also excluded were patients enrolled in the phase 3 randomized Multicenter Selective Lymphadenectomy Trial.7 Our study population comprised the subgroup of patients with tumor-negative SNs. The joint institutional review board of the John Wayne Cancer Institute and Saint John’s Health Center approved this study.
In each case, LM/SL was undertaken after preoperative lymphoscintigraphy to identify the nodal drainage basin and the location of the SN within this basin. Our protocol for mapping and histologic assessment of the SN is detailed elsewhere.7, 18-21 In brief, approximately 1 to 4 hours before operation, 500 µCi (18.5 MBq) of filtered technetium Tc 99m–labeled sulfur colloid is injected intradermally into the melanoma site. After localization with a scintillation camera and a handheld gamma probe (Neoprobe 2000; Neoprobe Corporation, Dublin, Ohio), the site of the SN is marked on the skin. In the operating room, after the induction of anesthesia, 1 to 2 mL of blue dye (1% Lymphazurin; Tyco, Norwalk, Conn) is injected intradermally into the melanoma site. Five to 10 minutes after injection, an incision is made within the lymphatic basin over the site marked preoperatively. Sentinel nodes are defined as blue-stained lymph nodes or radioactive and non–blue-stained lymph nodes. The handheld gamma probe is used to identify each radioactive node and measure its radioactivity (counts per second) before (in vivo) and after (ex vivo) excision in triplicate. These radioactive nodes are removed as SNs until the counts approach measured background levels. Background counts are obtained from 3 neutral body sites (10 to 20 cm away from the primary injection site and lymph node basin).
Each SN was removed and sent to the pathology department, where it was sectioned at 2-mm intervals, fixed in 10% buffered formalin, and embedded in paraffin (the block). Histologic sections were prepared at 2 levels from the block, separated by 200 µm, and each level was evaluated with H&E and IHC staining (antibodies to HMB-45 and S100)18 for the presence of tumor cells.
Postoperative follow-up generally included a physical examination every 3 months for the first 2 years, every 4 months for the third year, and every 6 months subsequently to the end of the fifth year. After 5 years, patients were examined on an annual basis. Laboratory tests, including complete blood cell counts, liver function tests, lactate dehydrogenase measurement, and chest radiographs, were obtained at each clinic visit. Other radiographic studies, such as computed tomography, magnetic resonance imaging, and positron emission tomography, were performed as indicated by symptoms or physical findings.
For this study, SN slides from all patients with recurrence were retrieved and reviewed by 1 of 3 experienced pathologists (R.R.T., Y.T.T, or R.L.G.) not involved in the original assessment. If the slide review was negative for tumor, the SN specimen was further sectioned at 2 additional levels separated by 200 µm and stained with H&E and IHC (antibodies to HMB-45, S100, and melan-A). A second pathologist (R.R.T., Y.T.T., or R.L.G.) confirmed tumor-positive results.
Statistically significant differences (P<.05) in patient- and tumor-related characteristics according to the presence or absence of recurrence were evaluated by  2 or Wilcoxon rank sum tests. Sites of recurrence were defined as local (within 2 cm of the primary tumor excision site), in transit (>2 cm from the primary site but proximal to the lymphatic drainage basin), regional lymphatic basin, or distant (beyond the regional lymphatic basin). Duration of survival after local, regional, or distant first recurrence was determined using the Kaplan-Meier product method.22 Survival curves were analyzed for statistical difference by log-rank analysis.
RESULTS
Of the 915 patients identified from the database who met the study inclusion criteria, 773 (84.5%) had a histologically tumor-negative SN. These patients had a mean age of 54 years (range, 8-91 years) and a mean primary tumor thickness of 1.56 mm (range, 0.15-14.0 mm); other clinical and pathologic characteristics are listed in Table 1 and Table 2. Most primary melanomas were nonulcerated (83%) and superficial spreading (63%) lesions, predominantly on the trunk and extremities. Eighty percent were less than 2 mm thick.
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Table 1. Clinical Characteristics of Patients Who Had Melanoma With Tumor-Negative Sentinel Nodes and Patients Whose Melanoma Recurred
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Table 2. Pathologic Characteristics of Patients Who Had Melanoma With Tumor-Negative Sentinel Nodes and Patients Whose Melanoma Recurred
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Most SNs were harvested from the axillary or inguinal basins (Table 1). Forty-five patients (5.8%) had SNs in more than 1 lymphatic drainage basin; most of these patients had a primary melanoma on the trunk, head, or neck. The mean number of SNs harvested from patients with tumor-negative SNs was 2.3 (range, 1-8); this finding did not differ significantly from the mean number of SNs harvested from the 142 patients with tumor-positive SNs (2.2; range, 1-8).
PATTERNS OF RECURRENCE
At a median follow-up of 36.7 months, melanoma had recurred in 69 (8.9%) of the 773 patients (Table 1 and Table 2). The 69 patients had a mean age of 58.8 years (range, 25-90 years) and a mean primary tumor thickness of 2.79 mm (range, 0.77-14.0 mm). Because 1 patient had simultaneous local and distant recurrences and 3 patients had simultaneous in-transit and nodal recurrences, 73 sites of first recurrence were found. First recurrences were local in 9 patients, in transit in 14 patients, nodal in 13 patients, and distant in 37 patients. Figure 1 shows the distribution of first recurrences for all patients based on the most distant site of recurrence. For example, simultaneous local and distant first recurrences are categorized as a distant recurrence.
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Figure 1. Sites of first recurrence in 773 patients with tumor-negative sentinel nodes (SNs). Median follow-up was 36.7 months (range, 1-106 months).
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Approximately half (50.6%) of first recurrences were at distant sites. Twenty-eight of the 37 patients with a distant site of first recurrence died of melanoma during follow-up. Of the 32 patients who did not have a distant site of first recurrence, 15 eventually developed distant recurrences, 11 of which were fatal.
All nodal first recurrences (17.8% of all first recurrences) were in the SN basin. Thus, the incidence of same-basin recurrence was 1.7% for the total population. Same-basin recurrence was followed by distant recurrence in 9 cases, 4 of which were fatal.
Approximately one third of all recurrences were local or regional in transit. Of 14 patients who developed in-transit first recurrences, 3 had synchronous nodal recurrences and 1 developed nodal recurrence after treatment for the in-transit recurrence. The time to development of local or in-transit (median, 23 months; range, 2.5-91.8 months) vs nodal (median, 17.6 months; range, 1.1-46.3 months) vs distant (median, 25.9 months; range, 1.4-88.8 months) first recurrence was not significantly different.
Of the 69 patients with recurrence, 40 (58%) died of melanoma during follow-up. The 3-year survival rate was significantly (P<.001) higher after a first recurrence in the regional lymphatic basin (63.5%) or at a local or in-transit site (48.7%) than after a first recurrence at a distant site (17.1%) (Figure 2).
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Figure 2. Kaplan-Meier estimates of survival after local or in-transit, nodal, or distant first disease recurrences in patients with tumor-negative sentinel nodes.
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HISTOPATHOLOGIC EVALUATION OF SNs
Histopathologic reevaluation of SN specimens identified tumor-positive findings in 9 (13%) of the 69 patients based on the presence of rare isolated tumor cells or clusters no greater than 0.2 mm in largest diameter on IHC stains (8 cases) or H&E stains (1 case). In 4 cases, review of the original SN slides identified isolated tumor cells or clusters (Figure 3); 1 patient had both local and distant first recurrences (recorded as distant recurrence in Figure 3), 2 had distant first recurrences, and 1 had an in-transit first recurrence. In the remaining 5 cases, deeper sections of SN blocks demonstrated a few isolated tumor cells or clusters; 2 patients had nodal first recurrences, 1 had an in-transit first recurrence, and 2 had distant first recurrences.
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Figure 3. Sites of first recurrence in 9 patients diagnosed as having missed tumor-positive sentinel nodes (SNs) on histopathologic reanalysis. H&E indicates hematoxylin-eosin; IHC, immunohistochemistry.
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The 9 patients with tumor-positive SNs included 5 women and 4 men, with ages ranging from 27 to 79 years. The mean thickness of the primary tumor for the group was 2.54 mm (range, 1.5-3.5 mm), and half of the patients had ulcerated (1 unknown) primary tumors. Five patients had distant, 2 same-basin nodal, and 2 local or in-transit first recurrences. The 2 cases of same-basin first recurrence were from thick truncal primary tumors (Breslow thickness of 2 and 3 mm) that initially metastasized to the axillary nodes and recurred in the same axillary basin 18 and 24 months after LM/SL, respectively. For these 9 patients, the mean time to recurrence was 24 months (range, 6.8-39.5 months). Five patients (55.5%) died of their disease, and 2 others were alive with disease at the time of this report.
COMMENT
For patients with melanoma, the tumor status of the SN is widely regarded as one of the most important prognostic indicators. By evaluating patients enrolled in the Sunbelt Melanoma Trial, Chao et al13 demonstrated a disease-free survival advantage in patients with tumor-negative SNs compared with patients with tumor-positive SNs. At a median follow-up of 16 months, rates of recurrence were 6% and 15.5%, respectively (P<.001). Multivariate analysis identified SN status as the most important predictor for recurrence of stage I/II melanoma (P<.001). Gershenwald et al8 retrospectively evaluated 612 patients with cutaneous melanoma who underwent LM/SL; rates of 3-year disease-specific survival were 96.8% and 69.9% for patients with tumor-negative and tumor-positive SNs, respectively. The SN status was again identified as the strongest predictor of disease-free survival.
The ability of the SN to predict outcome depends on how accurately LM/SL identifies the presence of occult regional nodal metastases. One way to assess how successfully the SN stages the regional nodal basin would be to monitor the incidence of recurrence in lymphatic basins with tumor-negative SNs. In this study of 773 patients with tumor-negative SNs, the 3-year rate of SN basin recurrence was only 1.7%, supporting the ability of LM/SL to accurately stage the regional nodal basin in patients with melanoma.
Same-basin recurrences after tumor-negative LM/SL may result from various failures, including an error in the technique of SN identification, an inaccurate histopathologic diagnosis of tumor-negative SN, or the biological features of the melanoma. Technical aspects of LM affect the accuracy of SN identification. By analyzing data acquired from the Multicenter Selective Lymphadenectomy Trial, Morton et al7 demonstrated a 95.2% rate of SN identification when blue dye alone was used to perform LM. The addition of radiocolloid increased the identification rate to 99.1%. Furthermore, preoperative lymphoscintigraphy is essential to identify unsuspected drainage pathways,23 particularly in patients with trunk or head and neck primary tumors that may drain to multiple sites. In the present study, all patients had at least 1 SN identified by preoperative lymphoscintigraphy and intraoperative blue dye and radiopharmaceutical-directed SN localization. All LM/SL procedures were performed at 1 institution by a stable group of surgeons and nuclear medicine staff skilled in the technique. This uniformity minimized the risk of technical error.
Step sectioning and IHC staining can improve the detection of SN micrometastases and reduce the chance of inaccurately determining the SN to be tumor negative when it is truly tumor positive. In their review of 243 patients whose SNs were tumor negative by H&E staining, Gershenwald et al10 discovered 10 patients who developed a nodal recurrence in a previously mapped basin. Serial sectioning and IHC staining of these patients’ SNs resulted in the identification of previously missed metastases in 80%. In contrast, all of our pathologists used a standardized technique in which sections of the SN were stained with H&E and antibodies to S100 and HMB-45. The 1.7% rate of same-basin recurrence for our study population is lower than that observed in other studies with similar follow-up in which the SN was evaluated only by H&E staining (Table 3). Thus, our study supports the routine use of IHC staining with antibodies to S100 and HMB-45 to aid the pathologist in identifying SN micrometastases that would otherwise be missed by H&E staining alone.
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Table 3. Reported Rates of Recurrence in Patients With Tumor-Negative SNs
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To determine the incidence and impact of errors in histopathologic SN diagnosis, we reevaluated the SNs from patients who developed recurrence. We found that 13% of all patients who developed recurrence had a tumor-positive SN that was originally misdiagnosed as tumor negative. However, 78% of the patients with missed tumor-positive SNs did not develop a recurrence within the SN basin. Our study focused on the subgroup of 69 patients who developed recurrence, and we hesitate to extrapolate these data to the parent population of 773 patients. However, if an inaccurate histopathologic SN diagnosis occurs in approximately 13% of the overall population of patients with tumor-negative SNs, then the 1.7% rate of same-basin recurrence is much lower than would be expected. One reason may be that SN removal becomes therapeutic if nodal metastasis is confined to isolated tumor deposits within the SN. Several recent studies24 have demonstrated the low rates of non-SN involvement in patients with SN metastases. Another reason is that the tumor status of the SN may only be a marker of systemic disease for some patients. These patients may have other sites of metastases that grow at a more rapid rate; therefore, they present with other sites of metastases before SN basin recurrence. Given the nature of our study, we are unable to report the false-negative rate of SN diagnosis because this would involve the pathologic reevaluation of all 773 patients’ SNs.
By evaluating additional SN sections, pathologists may improve their ability to detect micrometastases. Of the 69 patients with recurrence, 5 (7.2%) were diagnosed as having tumor-positive SNs after 2 additional 200-µm sections were stained with H&E and IHC. However, identification of more tumor-positive SNs with additional sectioning is unlikely to affect outcome given the already low nodal recurrence rate (1.7%). Furthermore, the cost-effectiveness of the additional processing of SNs does not seem reasonable.
Recently, several centers have reported the use of reverse transcription–polymerase chain reaction (RT-PCR) assay to detect subclinical melanoma metastasis in the SN. Typically, RT-PCR is performed on a portion of the SN to detect the melanoma and melanocyte-specific marker tyrosinase. Studies have shown that 48% to 65% of histologically melanoma-negative SNs will be RT-PCR positive for tyrosinase.25-27 Kammula et al28 examined the clinical impact of RT-PCR findings in patients with histologically negative SNs. At a median follow-up of 42 months, a significantly higher recurrence rate was apparent in 58 patients with positive RT-PCR results than in 39 patients with negative RT-PCR results (14% vs 0%). However, when the groups were followed up for 67 months, the rates of recurrence were not statistically different. In contrast to a single-marker RT-PCR assay based on tyrosinase, a multimarker RT-PCR that uses tyrosinase in conjunction with other markers has a lower false-negative rate and seems more promising. Kuo et al29 used a multimarker RT-PCR for tyrosinase, melanoma antigen recognized by T cells, tyrosinase-related protein 1, and tyrosinase-related protein to upstage 25% of histopathologically negative SNs in patients with melanoma. Eighty percent of these patients developed recurrence at a median follow-up of 55 months. Multimarker RT-PCR may be a way to eventually eliminate the need for SN histopathologic diagnosis. It also appears promising as a means of improving disease staging, and studies are under way to examine the clinical relevance of nodal micrometastases detected by molecular techniques.
Same-basin recurrence may simply reflect the biological mechanism of the disease rather than an error in SN assessment. For example, some patients may have tumor cells located in the lymphatics that drain the primary melanoma. After wide local excision and SN biopsy, these tumor cells may remain. They then may travel to and present as a recurrence in the regional draining lymphatic basin, or they may result in in-transit recurrences. In our study, a review of SNs from the 13 patients with a regional nodal recurrence identified 2 patients who were misdiagnosed as having a tumor-negative SN. Three of the remaining 11 patients developed concurrent in-transit metastases, which suggests that tumor cells from the primary melanoma had already entered the dermal lymphatics at the time of wide local excision and SN biopsy and eventually spread to the regional nodal basin.
Most recurrences in patients with tumor-negative SNs were at distant sites, imparting a shortened survival compared with the other sites of recurrence (Figure 1). One reason for a distant recurrence is that some tumor cells may preferentially spread hematogenously. At the time of LM/SL, these cells may already have entered the bloodstream. Over time, they travel distantly and grow into a detectable metastasis. This possibility demonstrates the limitations of LM/SL for predicting outcome in a small subgroup of patients with tumor-negative SNs. Other known prognostic factors, such as Breslow level and primary tumor ulceration,30-31 may be more important in this small subgroup. In these patients, RT-PCR of blood or bone marrow for known melanoma tumor markers may also be useful.32-33
CONCLUSIONS
Tumor status of the SN has been used to predict outcome, direct treatment, and follow-up in patients with melanoma. Patients with tumor-positive SNs have a higher incidence of recurrence and a worse outcome and are more likely to receive adjuvant therapy and closer follow-up than those with tumor-negative SNs. This study’s 9% incidence of recurrence in patients with a tumor-negative SN supports the prognostic utility of LM/SL.
Accurate histopathologic examination of the SN is important to identify micrometastases. This study supports the use of a standardized histopathologic technique using both H&E and IHC (antibodies to HMB-45 and S100) to accurately evaluate the tumor status of the SN; only 1.7% of patients determined to have a tumor-negative SN with this technique experienced recurrence in the SN basin.
Independent, however, of how accurate we become in the identification and pathologic assessment of the SN, a small subgroup of patients with tumor-negative SNs will experience disease recurrence. The most common site of recurrence in these patients is distant rather than regional nodal (4.8% and 1.7%, respectively). Therefore, other prognostic factors, such as Breslow thickness and the presence of ulceration, should be kept in mind when trying to identify patients at high risk for recurrence. Furthermore, we must discover other methods to predict outcome, allowing us to better direct long-term follow-up and therapy for patients with melanoma.
AUTHOR INFORMATION
Correspondence: Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (essnerr{at}jwci.org).
Accepted for Publication: May 2, 2005.
Funding/Support: This study was supported by grant CA29605 from the National Cancer Institute (Bethesda, Md) and by funding from the Amyx Foundation Inc (Boise, Idaho), Alice Johnson McKinney, the Harold J. McAlister Charitable Foundation (Los Angeles, Calif), Nancy and Carroll O’Connor (Los Angeles), the George Hoag Family Foundation (Los Angeles [Dr Essner]), and the Saban Family Foundation (Los Angeles, [Dr Essner]).
Previous Presentations: This paper was presented at the 76th Annual Meeting of the Pacific Coast Surgical Association; February 21, 2005; Dana Point, Calif; and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.
Acknowledgment: We thank Hitoe Torisu Itakura, PhD, for her contributions to the manuscript and Gwen Berry, MPH, for her editorial assistance.
Author Affiliations: Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, Calif.
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