National utilization patterns of Mohs micrographic surgery for invasive melanoma and melanoma in situ Kate V. Viola, MD, MHS,a Kameron S. Rezzadeh, BS,b Lou Gonsalves, PhD,c Payal Patel, MD,a Cary P. Gross, MD, MPH,d Jane Yoo, MD, MPP,a Emily Stamell, MD,a and Ryan B. Turner, MDa Bronx, New York; New Brunswick, New Jersey; and Hartford and New Haven, Connecticut Background: Although wide local excision continues to be commonly used for melanoma treatment, Mohs micrographic surgery (MMS) for the treatment of melanomas remains controversial. Objective: We sought to determine national utilization patterns for MMS in the treatment of invasive melanoma and melanoma in situ. Methods: A retrospective analysis of patients receiving surgical excision (MMS or wide local excision) for the treatment of invasive melanoma and melanoma in situ was performed using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. Results: A total of 195,768 melanomas were diagnosed from 2003 through 2009 from the 17 SEER registries. Utilization of MMS for invasive melanoma and melanoma in situ increased by 60% from 2003 to 2008. Of all SEER-captured lesions treated by surgical excision in this time period, 3.5% (6872) were excised by MMS. Limitations: Patient insurance status, physician reimbursement practices, and health care provider type were not addressed in this article. Conclusion: Use of MMS for melanoma appears to be increasing. Future studies should explore whether this is associated with better outcomes. ( J Am Acad Dermatol 2015;72:1060-5.) Key words: disparities; melanoma; Mohs micrographic surgery; population-based; surgical excision; Surveillance, Epidemiology, and End Results; utilization rates.
ach year more than 3 million nonmelanoma skin cancers are diagnosed in the United States with 1000 associated deaths. By contrast, 76,250 new cases of invasive melanoma arise annually with 9180 related deaths.1,2 Whereas the incidence of other cancers has declined, the number of melanoma cases is rising.3-7 The estimated occurrence within Caucasian populations shows a 3% to 7% increase with a doubling of the number of cases every 10 to 20 years.8 Americans lose 20.4 years of potential life secondary to melanoma mortality, compared with 16.6 years of potential life from all other malignancies.9-11
Melanoma prognosis is dependent on tumor parameters including ulceration, dermal mitosis, and Breslow thickness.8 The overall survival of melanoma has increased substantially since the mid-twentieth century. This improvement may be
From the Albert E. Einstein College of Medicine, Bronxa; Rutgers University-Robert Wood Johnson Medical School, New Brunswickb; Connecticut Tumor Registry, State of Connecticut Department of Public Health, Hartfordc; and Cancer Outcomes Policy and Effectiveness Research Center, Yale University School of Medicine, New Haven.d The Connecticut Tumor Registry is supported by a contract (no. HHSN261201000024C) between the National Cancer Institute and the State of Connecticut Department of Public Health.
Conflicts of interest: None declared. Accepted for publication February 14, 2015. Reprint requests: Kate V. Viola, MD, MHS, Division of Dermatology, Albert E. Einstein College of Medicine, 3411 Wayne Ave, Bronx, NY 10467. E-mail: [email protected]
Published online March 30, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.02.1122
Abbreviations used: ACMS: MIS: MMS: SEER:
American College of Mohs Surgery melanoma in situ Mohs micrographic surgery Surveillance, Epidemiology, and End Results
J AM ACAD DERMATOL
Viola et al 1061
VOLUME 72, NUMBER 6
attributed to more aggressive screening programs determine and may not be easily visible with with an emphasis on prevention and early diagnosis, conventional staining on frozen sections.22 rather than the development of novel therapeutic There remains a paucity of data examining modalities.12-14 The National Comprehensive Cancer patterns of MMS in the treatment of invasive melanoma and MIS. We therefore examined MMS Network 2013 treatment guidelines for melanoma and wide local excision for the treatment of invasive recommend surgical excision with margins of 0.5 cm melanoma and MIS. In addition, we identified for melanoma in situ (MIS), although this may be patient and lesion characinsufficient for the lentigo teristics within different maligna subtype, and 1 cm CAPSULE SUMMARY geographic regions associfor invasive melanoma less ated with these lesions. This than 1 mm in depth.15-17 A total of 195,768 melanomas were study represents, to our Mohs micrographic surgery diagnosed from 2003 through 2009 from knowledge, the first longi(MMS) is a tissue-preserving the National Cancer Institute tudinal population-based surgical procedure that is used Surveillance, Epidemiology, and End analysis of surgical excision for the treatment of recurrent, Results (SEER) program. and MMS utilization for infiltrative, and high-risk Mohs micrographic surgery utilization in the treatment of invasive anatomical site (face) nonmethe treatment of melanomas increased melanoma and MIS in the lanoma skin cancers.18-20 by 60% between the years of 2003 and United States. Wide local excision is the 2008; of all SEER-captured lesions treated most frequently utilized by surgery, 3.5% (6872) were excised by surgical treatment modality METHODS Mohs micrographic surgery. for melanoma with survival Data source prognosis associated with We performed a retroIt is uncertain whether this increased several variables including spective analysis of primary utilization is associated with better tumor thickness, presence of melanoma lesions from outcomes. ulceration, advanced age, patients receiving surgical male gender, tumor location excision (MMS or wide local) (trunk, head, or neck has worse prognosis), and for the treatment of invasive melanoma and MIS from metastases. January 1, 2003, through December 31, 2009. This In recent years, MMS has become a more was performed using data from the National Cancer prevalent surgical alternative.17 However, the Institute Surveillance, Epidemiology, and End utilization of this therapy for the treatment of Results (SEER) program. SEER collects populationmelanomas remains controversial, in part, because based data on cancer incidence, treatment, and of the questionable reliability of detecting atypical survival for approximately 28% of the US population melanocytes in frozen sections.21 Opponents of through 17 SEER cancer registries throughout the MMS for melanoma raise concerns over inconsiscountry. Our data set in this study captured 195,768 tencies associated with the use of frozen sections, a melanomas diagnosed from 2003 through 2009, of hallmark of the MMS technique, in the examination which 60.2% (n = 117,764) were invasive melanoma. of atypical melanocytes.22 Frozen sections, which To clarify, some patients may have had more than 1 simultaneously sample peripheral and deep margins, primary melanoma diagnosed within the study have their own limitations. These include the period; therefore our study is based on the presence of artifacts within sections, difficulty in quantification of melanomas, rather than patients, discerning between melanocytes and keratinocytes, with respect to intervention type. In addition, we and demonstrated lack of reproducibility with only captured lesions that were newly diagnosed multiple observers.23 Studies of dermatopathologist with no medical or surgical treatment history. margin reading have shown low concordance Current Procedural Terminology codes were between frozen and permanent section margin used for type of surgical treatment including MMS interpretation for melanocytic lesions.22,24 The (17304-17310), wide excision (26117), and simple recent rise in MMS for the treatment of invasive excision (11600-11646) of malignant lesion. Simple melanoma and MIS may in part be a result of the and wide excision coding were combined to development of novel, highly specific stains for delineate between MMS and other types of surgical atypical melanocytes. Melanoma-associated antigen excision (wide and simple). Our dependent variable recognized by T cells is used by many Mohs surgeons of interest was surgical procedure type, which was to detect melanocytes, particularly in lentigo categorized into MMS versus all other surgery types. maligna melanoma, where margins are difficult to Our analysis focus is on melanomas that have been d
J AM ACAD DERMATOL
1062 Viola et al
treated with surgery (surgical excision and MMS); the melanomas not treated by surgical measures may represent medically treated, nontreated, or metastatic skin cancers. Variables were characterized into patient (age, sex, and race/Hispanic ethnicity), lesion (ulceration status and Breslow thickness), and regional (area of country where melanoma was diagnosed, as determined by SEER region) characteristics. Statistical analysis The unit of analysis was procedure type. A bivariate comparison between our dependent variable (surgical procedure type) and our independent variables (age, race/ethnicity, lesion Breslow thickness, and ulceration status) was performed using x2 analyses. A logistic regression to assess odds ratios was also performed to assess the likelihood of each of these independent variables associated with MMS treatment. Statistical analyses were performed using SPSS Statistics, Version 19 (IBM Corp, Armonk, NY) and SYSTAT, Version 13 (Systat Software Inc, Chicago, IL).
RESULTS A total of 195,768 melanomas were diagnosed from 2003 through 2009 (Table I). Of these, 45.0% (88,010) were in patients aged 40 to 64 years old at the time of diagnosis. The majority of melanomas were diagnosed in males (112,374, 57.4%). Among all melanomas diagnosed from 2003 through 2009, 91.0% (178,112) were in non-Hispanic Caucasian patients whereas 2.6% were in Hispanic patients and 0.3% (671) of patients were in African American patients. Of the melanomas included in this study, 39.8% (78,004) were MIS, whereas 60.2% (117,764) were invasive melanoma. MMS was performed on 3.5% (6872) of melanomas whereas 90.3% (176,763) were treated by other surgery types and 5.9% (11,529) received no surgical treatment. Among melanomas treated with MMS, 64.5% (4432) were MIS whereas 35.5% (2440) were invasive melanoma. Of all melanomas, 38.9% (75,420) had a Breslow thickness of less than 1 mm. Nonulcerated lesions accounted for 84.3% (165,030) of melanoma diagnoses. Patient characteristics by intervention type Patient and tumor characteristics delineated by surgical type (MMS vs wide local excision) are summarized in Table II. When examining MMS for melanoma by age, percent utilization was similar between MMS cohort groups aged 40 to 64 and 65 to 79 years (37.8% and 37.6%, respectively); a decrease in MMS use was observed in the treatment of patients age 80 years and older (19.5%) as compared with the other
Table I. Patient and lesion characteristics Patient characteristics
Age, y \40 40-64 65-79 $80 Gender Female Male Race/ethnicity Caucasian African American Hispanic Other Unspecified/unknown Tumor and treatment characteristics
Cancer type Melanoma in situ Invasive melanoma Treatment type No surgical intervention Mohs micrographic surgery Wide local excision Unknown Melanoma type receiving Mohs micrographic surgery (N = 6872) Melanoma in situ Invasive melanoma Breslow thickness, mm #1 1.01-2 2.10-4 [4 Not stated Ulceration present No ulceration Ulceration present Unknown
10.6% 45.0% 30.1% 14.3%
(20,782) (88,010) (58,904) (27,952)
42.6% (83,394) 57.4% (112,374) 91.0% 0.3% 2.6% 0.7% 5.4%
(178,112) (671) (4998) (1373) (10,614)
39.8% (78,004) 60.2% (117,764) 5.9% 3.5% 90.3% 0.3%
(11,529) (6872) (176,763) (604)
64.5% (4432) 35.5% (2440) 38.9% 7.9% 4.6% 3.3% 44.5%
(75,420) (15,479) (9036) (6398) (87,180)
84.3% (165,030) 6.8% (13,242) 8.9% (17,496)
age groups. Approximately 20% of all MMS procedures were performed on patients age 80 years or older, as compared with 13.4% of patients in this age group receiving wide local excision for melanoma. Conversely, 1 in every 20 MMS procedures were performed on patients younger than 40 years, whereas 11% of wide local excision were observed in this age group. Of all MMS procedures, 6361 (97.4%) were performed on Caucasian patients. Relatively fewer (0.2%) MMS procedures were performed on African American patients and on those patients who identified as Hispanic (1.9%). In our bivariate analysis, age, Breslow thickness, and ulceration status were significantly associated with MMS for the treatment of invasive melanoma and MIS (all P \.001) (Table II).
J AM ACAD DERMATOL
Viola et al 1063
VOLUME 72, NUMBER 6
Table II. Bivariate analysis by surgery type Variable
Age, y \40 5.1% 40-64 37.8% 65-79 37.6% $80 19.5% Race Caucasian 97.4% African American 0.2% Hispanic 1.9% Other 0.5% Breslow thickness, mm #1 83.1% 1.01-2 9.6% 2.10-4 4.3% [4 3.0% Ulceration present No ulceration 97.6% Ulceration present 2.4%
Wide local excision
(352) (2596) (2581) (1341)
11.0% 45.6% 29.8% 13.7%
(19,433) \.001 (80,543) (52,574) (24,136)
(6361) (11) (126) (32)
96.3% 0.3% 2.6% 0.7%
(161,857) \.001 (579) (4395) (1208)
(1947) (226) (100) (70)
70.4% 14.8% 8.7% 6.1%
(71,265) \.001 (14,997) (8760) (6174)
(6258) 92.2% (151,326) \.001 (155) 7.8% (12,720)
Percentages represent column percentages by surgery type. MMS, Mohs micrographic surgery.
Lesion characteristics by intervention type Of all MMS procedures, 83.1% (1947) were for melanomas with Breslow thickness of 1 mm or less. Nearly 10% (9.6%) of MMS procedures were performed on lesions with Breslow thickness of 1.01 to 2 mm. The remaining MMS procedures (7.3%) were performed on melanomas with Breslow thickness of greater than 2 mm. A lower proportion of melanomas treated with MMS were ulcerated on presentation compared with those treated by other surgery types (2.4% vs 7.8%, respectively). MMS utilization by SEER region Fig 1 represents the geographic distribution of MMS procedures by SEER region. For all SEER regions combined, 3.5% of all melanomas diagnosed were treated with MMS. There was considerable variation between SEER regions, ranging from 1% in metropolitan Detroit and Seattle Puget Sound to 10.5% in Utah. The utilization of MMS in the treatment of melanomas increased by 60% between the years of 2003 and 2008 (555 vs 1138 lesions, respectively, P \ .001) (Fig 2). A slight decline in MMS utilization was observed between 2008 and 2009 (1138 vs 1107 lesions, respectively). Logistic regression analyses Patients were more likely to receive MMS if they were age 65 years or older (Fig 3) (odds ratio 1.774; 95% confidence interval 1.688-1.876; P \.001). MMS
Fig 1. Percentage of surgical procedures performed by region (2003-2009). A = California; B = Connecticut; C = metropolitan Detroit; D = Georgia; E = Hawaii; F = Iowa; G = Kentucky; H = Louisiana; I = New Jersey; J = New Mexico; K = Seattle Puget Sound; L = Utah). SEER, Surveillance, Epidemiology, and End Results.
was more likely to be performed if the target lesion was less than 1 mm in Breslow thickness (odds ratio 1.985; 95% confidence interval 1.756-2.243; P \ .001); ulcerated lesions were less likely to be treated with MMS (odds ratio 0.294; 95% confidence interval 0.243-0.356; P \.001).
DISCUSSION A total of 195,768 melanomas were diagnosed from 2003 through 2009 of which 3.5% (6872) were treated with MMS. Appropriate use criteria for MMS jointly published by the American Academy of Dermatology and the American College of Mohs Surgery (ACMS) in 2012 indicate that MMS is an ‘‘uncertain’’ therapy option for the treatment of primary MIS located on the trunk or extremities.25,26 However, the appropriate use criteria deems MMS an ‘‘appropriate’’ treatment option when MIS is located in the mask area. The appropriate use criteria does not provide recommendations pertaining to the use of MMS for invasive melanoma. Our study demonstrates that, despite the lack of consensus on this therapeutic approach, the use of MMS for invasive melanoma and MIS increased by 60% from 2003 to 2008. MMS is frequently, and incorrectly, viewed as a more expensive surgical treatment than wide local excision.27 This misperception is often caused by the characteristic bundling of surgical and surgical pathology codes together into a single reimbursement for the Mohs surgeon.28,29 Studies addressing the cost-effectiveness of various treatments for skin cancer have shown that MMS is the least expensive surgical option when compared
1064 Viola et al
J AM ACAD DERMATOL
Fig 2. Use of Mohs micrographic surgery (MMS ) in melanoma, Surveillance, Epidemiology, and End Results Registries (SEER) (2003-2009).
with wide local excision with either frozen or permanent sections.27-30 When adjusted for inflation, the cost of solely MMS was lower in 2009 ($1378) than in 1998 ($1635).27 However, conclusions regarding the cost effectiveness of MMS are still the subject of debate.31 Importantly, none of the studies cited specifically examine the use of MMS for melanoma. Geographic variations in the frequency of MMS for invasive melanoma and MIS, including above-average rates of utilization in the Utah and Georgia registries, are worthy of further investigation. This variation may be a result of disparities between Mohs surgeon density in the registry area, number of fellowship positions available within the region, and mentor influence on MMS utilization tendencies. For example, there are currently 12 Mohs surgeons registered through the ACMS to practice within the city of Seattle and an equal number who are registered within the state of Utah. It is unclear whether individual or multiple practitioners are contributing to the number of MMS procedures within registry areas. Of all SEER-captured lesions treated by surgery, only 3.5% (6872) were excised by MMS. As the rate of skin cancer incidence continues to increase within the United States, MMS may become a more prevalent technique for the treatment of melanomas. A recent prospective study of 1120 MIS cases concluded that MMS with 9-mm margins resulted in complete removal of nearly 99% of lesions.32 Despite these findings, disparities currently exist in the treatments received for melanoma within different patient populations. Further research into the perceived benefits of MMS for invasive melanoma and MIS is necessary.
Fig 3. Odds of receiving Mohs micrographic surgery (MMS ). CI, Confidence interval.
Limitations Although our study used a large database to evaluate current trends in the treatment of invasive melanoma and MIS, it is limited in the scope of the SEER registries, which are only able to capture information from 17 states. As such, this cohort population does not include information from key states such as New York, Pennsylvania, or Florida where MMS is more routinely used for the treatment of melanoma. This limitation could underestimate the number of patients receiving MMS for invasive melanoma and MIS as it excludes regions with higher numbers of Mohs surgeons and cases of invasive melanoma and MIS. Patient insurance status, physician reimbursement practices, type of provider referring for MMS, ultraviolet light radiation differences by registry, specification of MMS and differences in MMS surgery coding by the provider (ie, ‘‘slow Mohs’’), and treatment setting were not addressed by this study, although most likely play a significant role in surgical treatment choice, and would be useful parameters in future analyses. Conclusions This study examined multistate patterns of MMS utilization for the treatment of melanoma. Patient age, race/Hispanic ethnicity, year of diagnosis, Breslow thickness, ulceration status, and location of lesion were all associated with MMS as a treatment option for invasive melanoma and MIS. Our study highlights disparities in treatment among populations with melanoma and elucidates the
J AM ACAD DERMATOL VOLUME 72, NUMBER 6
current state of MMS as a treatment for invasive melanoma and MIS. As the number of cases of invasive melanoma and MIS receiving MMS is increasing, large prospective studies are necessary to qualify treatment outcomes of MMS in the treatment of invasive melanoma and MIS. REFERENCES 1. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of non-melanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287. 2. The National Cancer Institute. Definition of skin cancer. Available from: URL:http://www.cancer.gov/cancerinfo/types/ Skin. Accessed February 4, 2012. 3. Simard EP, Ward EM, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999-2008. Cancer J Clin. 2012;62(2):118-128. 4. Jemal A, Saraiya M, Petal P, et al. Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006. J Am Acad Dermatol. 2011;65: S17-S25. 5. Linos E, Swetter SM, Cockburn MG, Colditz GA, Clark CA. Increasing burden of melanoma in the United States. J Invest Dermatol. 2009;129:1666-1674. 6. Welch HG, Woloshin S, Schwartz LM. Skin biopsy rates and incidence of melanoma: population-based ecological study. BMJ. 2005;331:481. 7. Swerlick RA, Chen S. The melanoma epidemic: more apparent than real? Mayo Clin Proc. 1997;72:559-564. 8. Rutkowski P, Zdzienicki M, Nowecki ZI, et al. Surgery of primary melanomas. Cancers. 2010;2:824-841. 9. Guy GP, Ekwueme DU. Years of potential life lost and indirect costs of melanoma and non-melanoma skin cancer: a systemic review of literature. Pharmacoeconomics. 2011; 29(10):863-874. 10. Ekwueme DU, Guy GP, Li C, Rim SH, Parelkar P, Chen SC. The health burden and economic costs of cutaneous melanoma mortality by race/ethnicity- United States, 2000-2006. J Am Acad Dermatol. 2011;65(5 Suppl 1):S133-S143. 11. Yabroff KR, Bradley CJ, Mariotto AB, Brown ML, Feuer EJ. Estimates and projections of life lost from cancer deaths in the United States. J Natio Cancer Inst. 2008;100:1755-1762. 12. Eide MJ, Weinstock MA, Clark MA. The association of physician- specialty density and melanoma prognosis in the United States, 1988 to 1993. J Am Acad Dermatol. 2009;60: 51-58. 13. Durbec F, Vitry F, Granel-Brocard F, et al. The role of circumstances of diagnosis and access to dermatological care in early diagnosis of cutaneous melanoma. Arch Dermatol. 2010;146(3):240-246. 14. Epstein D, Lange J, Gruber S, Mofid M, Kock S. Is physician detection associated with thinner melanomas. JAMA. 1999; 281:640-643.
Viola et al 1065
15. Coit DG, Andtbacka R, Anker CJ, et al. Melanoma version 2.2013 featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013;11:395-407. 16. Raziano RM, Clark GS, Cherpelis BS, et al. Staged margin control techniques for surgical excision of lentigo maligna. G Ital Dermatol Venereol. 2009;144(3):259-270. 17. Campoli M, Freeman S, Brodland DG, Zitelli J. Mohs micrographic surgery for the treatment of cutaneous melanoma. In: Nouri K, ed. Mohs micrographic surgery. 1st ed. London (United Kingdom): Springer; 2012:211-223. 18. Nestle FO, Halpern AC. Melanoma. In: Bolognia JL, Jorizzo JL, Rapini RR, eds. Dermatology. 2nd ed. Philadelphia (PA): Elsevier; 2008:1745-1769. 19. Callahan EF, Otley CC, Roenigk RK. Mohs surgery. In: Bolognia JL, Jorizzo JL, Rapini RR, eds. Dermatology. 2nd ed. Philadelphia (PA): Elsevier; 2008:2269-2280. 20. Mosterd K, Krekels GA, Nieman FH, et al. Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomized controlled trial with 5 years’ follow-up. Lancet Oncol. 2008; 9(12):1149-1156. 21. Hui AM, Jacobson M, Markowitz O. Mohs micrographic surgery for the treatment of melanoma. Dermatol Clin. 2012;30(3): 503-515. 22. Trotter MJ. Melanoma margin assessment. Clin Lab Med. 2011; 31:289-300. 23. Prieto VG, Argenyi ZB, Barnhill RB, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003;120:203-208. 24. Levy RM, Hanke CW. Mohs micrographic surgery: facts and controversies. Clin Dermatol. 2010;3:269-274. 25. Connolly SM, Baker DR, Coldiron BM, et al. AAD/ACMS/ASDA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society of Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67: 531-550. 26. Cherpelis BS, Glass LF, Ladd S, Fenske NA. Mohs surgery for melanoma in situ: how we do it. J Drugs Dermatol. 2010;9: 786-788. 27. Ravitskiy L, Brodland DG, Zitelli JA. Cost analysis: Mohs micrographic surgery. Dermatol Surg. 2012;38:585-594. 28. Minton TJ. Contemporary Mohs applications. Curr Opin Otolaryngol Head Neck Surg. 2008;16(4):376-380. 29. Essers BA, Dirksen CD, Nieman FH, et al. Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol. 2006;142:187-194. 30. Bialy TL, Whalen J, Veledar E, et al. Mohs micrographic surgery vs traditional surgical excision: a cost comparison analysis. Arch Dermatol. 2004;140:736-742. 31. Stern RS. Cost effectiveness of Mohs micrographic surgery. J Invest Dermatol. 2013;133:1129-1131. 32. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66(3):438-444.