- Email: [email protected]
4886595 Process of both flotation using a methylene bisxanthate as a collector reagent
RESEARCH Association of 25-hydroxyvitamin D levels and cutaneous melanoma: A nested case-control study of the Women’s Health Initiative Observation Study To the Editor: Exposure to ultraviolet radiation is an important risk factor for melanoma but is also the principal means by which the body synthesizes vitamin D in the skin. Prior studies on the association between 25-OH-D levels and melanoma occurrence and prognosis have shown conflicting results.1,2 To gain further insight into the relationship between serum 25-OH-D levels and later development of melanoma, we conducted a nested case-control study in postmenopausal white women in the Women’s Health Initiative Observation Study and the Population Architecture using Genomics and Epidemiology study, which selected 718 melanoma cases and 718 controls without melanoma.3,4 The protocol was approved by each participating institution’s review board and all women provided written informed consent. 25-OH-D levels were measured by using liquid chromatographyemass spectrometry from stored serum samples taken at baseline. Multivariable conditional logistic regression models were used to evaluate the association between 25-OH-D levels and risk for melanoma. Cox proportional hazards regression was used to estimate hazard ratios for melanoma-specific mortality, which was adjudicated with medial records. Table I shows the baseline characteristics of the Women’s Health Initiative participants. Women with higher 25-OH-D concentrations resided in geographic areas of higher sun exposure (in langleys) (P ¼ .003). On average, women who developed melanoma had a 2-ng/mL higher mean 25-OH-D level at baseline than the controls (27.2 ng/mL vs 25.1 ng/mL, P \ .0001). At the time of diagnosis, 53.5% of melanoma cases (n ¼ 381) were invasive and 46.5% (n ¼ 331) were in situ. In multivariable models (Table II), women with 25-OH-D levels of 30 ng/mL or higher had a 1.59-fold higher risk for development of invasive and in situ melanoma compared with women with 25-OH-D levels of 20 ng/mL or lower (95% confidence interval [CI], 1.04-2.42; P \ .01). Women with 25-OH-D levels between 20.1 and 29.9 ng/mL had a 1.79-fold higher risk for development of melanoma compared with women with 25-OH-D levels of 20 ng/mL or lower (95% CI, 1.22-2.62). J AM ACAD DERMATOL
LETTERS
Women with melanoma and 25-OH-D levels of 20 ng/mL or lower at baseline were 2.75 times more likely to die of melanoma than women with 25-OH-D levels between 20.1 and 29.9 ng/mL (95% CI 1.14-6.65; P ¼.025), but there was no significant relationship in death by melanoma when comparing women with 25-OH-D levels of 20 ng/mL or lower at baseline to women with 25-OH-D levels of 30 ng/mL or higher (hazard ratio, 1.43; 95% CI, 0.66-3.12; P ¼ .396). The lack of significant association in the 30 ng/mL or higher strata could be due to the smaller sample size in this group (Table I). In our study, higher serum 25-OH-D levels were associated with a greater risk for development of melanoma, which may be related to higher ultraviolet radiation exposure. In contrast, low 25-OH-D levels before melanoma diagnosis were associated with a higher risk for melanoma-related death. Because 25-OH-D levels are higher in more physically active, healthier individuals, it is possible that these levels are serving as a marker for overall health.5 It is important to note, however, that the difference in 25-OH-D levels between the melanoma and control group was small (2 ng/mL) and of unclear physiologic significance. Our data demonstrate the challenge of studying the association of vitamin D levels with melanoma risk, because the measurement of 25-OH-D level is confounded by sunlight exposure, which is a major risk factor for the development of melanoma. The cause-and-effect relationship between serum 25-OH-D level and melanoma incidence and prognosis is important to explore, and carefully designed clinical trials are needed. Gina P. Kwon, MD,a,b Christina S. Gamba, MD,a Marcia L. Stefanick, PhD,c Susan M. Swetter, MD,a,d Shufeng Li, MS,a Run Zhang Shi, MD, PhD,e Christina A. Clarke, PhD, MPH,f,g David Feldman, MD,h Amy E. Millen, PhD,i Catherine Messina, PhD,j James M. Shikany, DrPH,k JoAnn E. Manson, MD, DrPH,l Rowan T. Chlebowski, MD, PhD,m and Jean Y. Tang, MD, PhDa Department of Dermatology, Stanford University School of Medicine, Redwood City, Californiaa; University of Washington Medical Center, Dermatology Division, Seattle, Washingtonb; Department of Medicine, Stanford Prevention Research Center,c Department of Pathology,e Division of Epidemiology, Department of Health Research and Policy,g and Department of Medicine, Stanford University School of
JULY 2018 145
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Table I. Baseline characteristics of women with serum 25-OH-D levels by clinically defined limits 25-OH-D level, ng/mL Characteristic
Age, y 50-59 60-69 $70 Education None-HS Diploma-GED certificate School after HS $College degree Vitamin D intake, IU/d \400 $400 Regional solar irradiance, Ly 300-325 350 375-380 400-430 475-500 Summer season of blood draw Smoking Never smoked Past smoker Current smoker History of NMSC Skin type (skin reaction to sun) No change in skin color Tans but does not burn Burns, then tans Burns, then tans a minimal amount Burns but does not tan Sun exposure Time outdoors during summer/youth \30 min 30 min to 2 h [2 h Time outdoors during summer/this year \30 min 30 min to 2 h [2 h Usually use sunscreen outside No Yes
#20.0 ng/mL (n = 341)
20.1-29.9 ng/mL (n = 545)
$30.0 ng/mL (n = 455)
109 (32.0) 153 (44.9) 79 (23.2)
184 (33.8) 236 (43.3) 125 (22.9)
160 (35.2) 210 (46.2) 85 (18.7)
21 56 111 149
29 81 227 202
17 84 175 178
P value*
.45
.08 (6.2) (16.6) (32.9) (44.2)
(5.4) (15.0) (42.1) (37.5)
(3.7) (18.5) (38.6) (39.2) .60
193 (56.0) 148 (43.4)
327 (60.0) 218 (40.0)
266 (58.5) 189 (41.5)
126 72 44 51 48 75
(36.95) (21.1) (12.9) (15.0) (14.1) (23.0)
189 110 61 81 104 142
(34.7) (20.2) (11.2) (14.9) (19.1) (26.1)
125 89 49 71 121 109
(27.5) (19.6) (10.8) (15.6) (26.6) (24.0)
176 141 18 38
(52.5) (42.1) (5.4) (11.2)
291 215 33 65
(54.0) (39.9) (6.1) (12.0)
207 208 32 63
(46.3) (46.5) (7.2) (13.9)
26 107 88 87 21
(7.9) (32.5) (26.8) (26.4) (6.4)
50 168 132 126 54
(9.4) (31.7) (24.9) (23.8) (10.2)
43 140 100 106 51
(9.8) (31.8) (22.7) (24.1) (11.6)
.003
.32 .16
.48 .41
.51 4 (0.01) 63 (18.8) 268 (80)
8 (1.5) 121 (22.6) 407 (75.9)
10 (2.2) 98 (21.7) 344 (76.1)
115 (34.3) 155 (46.3) 65 (19.4)
172 (32.1) 270 (50.4) 94 (17.5)
146 (32.2) 224 (49.5) 83 (18.3)
163 (48.5) 173 (51.5)
253 (47.6) 279 (52.4)
206 (46.5) 237 (53.5)
.83
.86
Information on age, daily vitamin D intake, history of NMSC, and other variables were obtained by questionnaire at baseline. Sun exposure variables were collected in a questionnaire administered at year 4. Baseline characteristics and melanoma risk factors were compared between 3 groups of 25-OH-D levels (#20 ng/mL, 20-29 ng/mL, and $30 ng/mL). Not all adjusted variables are shown. GED, General Educational Development; HS, high school; Ly, langley; NMSC, nonmelanoma skin cancer; 25-OH-D, 25-hydroxyvitamin D. *Boldface indicates statistical significance.
Medicine, Stanford, Californiah; Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, Californiad; Cancer Prevention Institute of California, Fremont, Californiaf; Department of Epidemiology and Environmental Health, University of Buffalo,
Buffalo, New Yorki; Department of Preventive Medicine, Stony Brook University, Stony Brook, New Yorkj; Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabamak; Department of Medicine, Brigham and Women’s
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Table II. Multivariate model with key risk factors for incident melanoma in postmenopausal women in the Women’s Health Initiative Observational Study Variable
Age, y (ref, 50-59) 60-69 70-99 History of NMSC ( yes vs no) Calcium intake, mg/d (ref, \800) 800-1200 $1200 Regional solar irradiance, Ly (ref, 300-325) 350 375-380 400-430 475-500 Vitamin D intake \400 IU vs $400 IU 25-OH-D level, ng/mL (ref, #20.0 ng/mL)
Odds ratio* (95% CI)
P valuey
.50 1.20 (0.83-1.74) 0.98 (0.64-1.49) 4.10 (2.45-6.87) \.0001 .06 0.75 (0.45-1.25) 0.51 (0.28-0.93) .81 1.17 1.42 1.12 1.17 0.80
(0.75-1.81) (0.80-2.50) (0.68-1.84) (0.75-1.81) (0.47-1.38)
1.79 (1.22-2.62) $30.0 1.59 (1.04-2.42) Last medical visit within 1 year 1.65 (1.09-2.48)
Disclosure: Dr Manson receives funding from the National Institutes of Health ( grant CA138962) to conduct the Vitamin D and OmegA-3 Trial (VITAL), a randomized trial of vitamin D and omega-3 fatty acid supplementation in the prevention of cancer and cardiovascular disease. Dr Chlebowski is a consultant for Pfizer, Novartis, Amgen, Genentech, Genomic Health, and Novo Nordisk, and he is on the speaker’s bureau for Novartis and Genentech. Dr Clarke receives research support from Genentech outside the submitted work. Drs Kwon, Gamba, Stefanick, Swetter, Li, Shi, Feldman, Millen, Messina, Shikany, and Tang have no conflicts of interest to disclose. This work was presented in the Society for Investigational Dermatology in 2016.
.43 .01
.02
Women in the Women’s Health Initiative Observational Study were mailed annual questionnaires to report health outcomes, including diagnosis with melanoma, which was confirmed by review of medical records and pathology reports. Our multivariate model was adjusted for all the factors listed in this table. Not all variables are shown. CI, Confidence interval; Ly, langley; NMSC, nonmelanoma skin cancer; 25-OH-D, 25-hydroxyvitamin D; ref, reference. *Odds ratios are for each covariate in a multivariable model adjusted for age, BMI, education, multivitamin and calcium intake, sun exposure history, history of skin cancer, physical activity, season of blood draw, smoking, time spent outdoors in the summer both in childhood and in adulthood, use of sunscreen, regional solar irradiance (in langleys), and having a medical visit in the last year. y Boldface indicates statistical significance.
Hospital, Harvard Medical School, Boston, Massachusettsl; and Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, Californiam Supported by the National Heart, Lung, and Blood Institute (National Clinical Trial identifier NCT00000611) and the American Skin Association Medical Student Grant. The Population Architecture Using Genomics and Epidemiology program is funded by the National Human Genome Research Institute, which is supported by grants U01HG004790, U01HG007376 (Women’s Health Initiative), and U01HG004801 (Coordinating Center).
Correspondence to: Gina Kwon, MD, Department of Dermatology, Stanford University, 450 Broadway St, Redwood City, CA 94063 E-mail: [email protected] Reprint requests: Jean Y. Tang, MD, PhD, Department of Dermatology, Stanford University, 450 Broadway St, Redwood City, CA 94063 E-mail: [email protected] REFERENCES 1. Afzal S, Nordestgaard BG, Bojesen SE. Plasma 25-hydroxyvitamin D and risk of non-melanoma and melanoma skin cancer: a prospective cohort study. J Invest Dermatol. 2013;133:629-636. 2. Newton-Bishop JA, Beswick S, Randerson-Moor J, et al. Serum 25-hydroxyvitamin D3 levels are associated with Breslow thickness at presentation and survival from melanoma. J Clin Oncol. 2009;27:5439-5444. 3. Design of the Women’s Health Initiative Clinical Trial and Observational Study. The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:61-109. 4. Matise TC, Ambite JL, Buyske S, et al. The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. Am J Epidemiol. 2011;174:849-859. 5. Brock K, Huang WY, Fraser DR, et al. Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women. J Steroid Biochem Mol Biol. 2010;121:462-466. https://doi.org/10.1016/j.jaad.2017.05.037
Descriptive survival study of nail melanoma patients treated with functional surgery versus distal amputation To the Editor: Nail melanoma, a variant of acral lentiginous melanoma, accounts for about 0.7%-3.5% of all types of melanomas.1,2 Phalangeal amputation can be performed to excise the tumor, a practice with
LETTERS
Women with melanoma and 25-OH-D levels of 20 ng/mL or lower at baseline were 2.75 times more likely to die of melanoma than women with 25-OH-D levels between 20.1 and 29.9 ng/mL (95% CI 1.14-6.65; P ¼.025), but there was no significant relationship in death by melanoma when comparing women with 25-OH-D levels of 20 ng/mL or lower at baseline to women with 25-OH-D levels of 30 ng/mL or higher (hazard ratio, 1.43; 95% CI, 0.66-3.12; P ¼ .396). The lack of significant association in the 30 ng/mL or higher strata could be due to the smaller sample size in this group (Table I). In our study, higher serum 25-OH-D levels were associated with a greater risk for development of melanoma, which may be related to higher ultraviolet radiation exposure. In contrast, low 25-OH-D levels before melanoma diagnosis were associated with a higher risk for melanoma-related death. Because 25-OH-D levels are higher in more physically active, healthier individuals, it is possible that these levels are serving as a marker for overall health.5 It is important to note, however, that the difference in 25-OH-D levels between the melanoma and control group was small (2 ng/mL) and of unclear physiologic significance. Our data demonstrate the challenge of studying the association of vitamin D levels with melanoma risk, because the measurement of 25-OH-D level is confounded by sunlight exposure, which is a major risk factor for the development of melanoma. The cause-and-effect relationship between serum 25-OH-D level and melanoma incidence and prognosis is important to explore, and carefully designed clinical trials are needed. Gina P. Kwon, MD,a,b Christina S. Gamba, MD,a Marcia L. Stefanick, PhD,c Susan M. Swetter, MD,a,d Shufeng Li, MS,a Run Zhang Shi, MD, PhD,e Christina A. Clarke, PhD, MPH,f,g David Feldman, MD,h Amy E. Millen, PhD,i Catherine Messina, PhD,j James M. Shikany, DrPH,k JoAnn E. Manson, MD, DrPH,l Rowan T. Chlebowski, MD, PhD,m and Jean Y. Tang, MD, PhDa Department of Dermatology, Stanford University School of Medicine, Redwood City, Californiaa; University of Washington Medical Center, Dermatology Division, Seattle, Washingtonb; Department of Medicine, Stanford Prevention Research Center,c Department of Pathology,e Division of Epidemiology, Department of Health Research and Policy,g and Department of Medicine, Stanford University School of
JULY 2018 145
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Table I. Baseline characteristics of women with serum 25-OH-D levels by clinically defined limits 25-OH-D level, ng/mL Characteristic
Age, y 50-59 60-69 $70 Education None-HS Diploma-GED certificate School after HS $College degree Vitamin D intake, IU/d \400 $400 Regional solar irradiance, Ly 300-325 350 375-380 400-430 475-500 Summer season of blood draw Smoking Never smoked Past smoker Current smoker History of NMSC Skin type (skin reaction to sun) No change in skin color Tans but does not burn Burns, then tans Burns, then tans a minimal amount Burns but does not tan Sun exposure Time outdoors during summer/youth \30 min 30 min to 2 h [2 h Time outdoors during summer/this year \30 min 30 min to 2 h [2 h Usually use sunscreen outside No Yes
#20.0 ng/mL (n = 341)
20.1-29.9 ng/mL (n = 545)
$30.0 ng/mL (n = 455)
109 (32.0) 153 (44.9) 79 (23.2)
184 (33.8) 236 (43.3) 125 (22.9)
160 (35.2) 210 (46.2) 85 (18.7)
21 56 111 149
29 81 227 202
17 84 175 178
P value*
.45
.08 (6.2) (16.6) (32.9) (44.2)
(5.4) (15.0) (42.1) (37.5)
(3.7) (18.5) (38.6) (39.2) .60
193 (56.0) 148 (43.4)
327 (60.0) 218 (40.0)
266 (58.5) 189 (41.5)
126 72 44 51 48 75
(36.95) (21.1) (12.9) (15.0) (14.1) (23.0)
189 110 61 81 104 142
(34.7) (20.2) (11.2) (14.9) (19.1) (26.1)
125 89 49 71 121 109
(27.5) (19.6) (10.8) (15.6) (26.6) (24.0)
176 141 18 38
(52.5) (42.1) (5.4) (11.2)
291 215 33 65
(54.0) (39.9) (6.1) (12.0)
207 208 32 63
(46.3) (46.5) (7.2) (13.9)
26 107 88 87 21
(7.9) (32.5) (26.8) (26.4) (6.4)
50 168 132 126 54
(9.4) (31.7) (24.9) (23.8) (10.2)
43 140 100 106 51
(9.8) (31.8) (22.7) (24.1) (11.6)
.003
.32 .16
.48 .41
.51 4 (0.01) 63 (18.8) 268 (80)
8 (1.5) 121 (22.6) 407 (75.9)
10 (2.2) 98 (21.7) 344 (76.1)
115 (34.3) 155 (46.3) 65 (19.4)
172 (32.1) 270 (50.4) 94 (17.5)
146 (32.2) 224 (49.5) 83 (18.3)
163 (48.5) 173 (51.5)
253 (47.6) 279 (52.4)
206 (46.5) 237 (53.5)
.83
.86
Information on age, daily vitamin D intake, history of NMSC, and other variables were obtained by questionnaire at baseline. Sun exposure variables were collected in a questionnaire administered at year 4. Baseline characteristics and melanoma risk factors were compared between 3 groups of 25-OH-D levels (#20 ng/mL, 20-29 ng/mL, and $30 ng/mL). Not all adjusted variables are shown. GED, General Educational Development; HS, high school; Ly, langley; NMSC, nonmelanoma skin cancer; 25-OH-D, 25-hydroxyvitamin D. *Boldface indicates statistical significance.
Medicine, Stanford, Californiah; Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, Californiad; Cancer Prevention Institute of California, Fremont, Californiaf; Department of Epidemiology and Environmental Health, University of Buffalo,
Buffalo, New Yorki; Department of Preventive Medicine, Stony Brook University, Stony Brook, New Yorkj; Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabamak; Department of Medicine, Brigham and Women’s
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Table II. Multivariate model with key risk factors for incident melanoma in postmenopausal women in the Women’s Health Initiative Observational Study Variable
Age, y (ref, 50-59) 60-69 70-99 History of NMSC ( yes vs no) Calcium intake, mg/d (ref, \800) 800-1200 $1200 Regional solar irradiance, Ly (ref, 300-325) 350 375-380 400-430 475-500 Vitamin D intake \400 IU vs $400 IU 25-OH-D level, ng/mL (ref, #20.0 ng/mL)
Odds ratio* (95% CI)
P valuey
.50 1.20 (0.83-1.74) 0.98 (0.64-1.49) 4.10 (2.45-6.87) \.0001 .06 0.75 (0.45-1.25) 0.51 (0.28-0.93) .81 1.17 1.42 1.12 1.17 0.80
(0.75-1.81) (0.80-2.50) (0.68-1.84) (0.75-1.81) (0.47-1.38)
1.79 (1.22-2.62) $30.0 1.59 (1.04-2.42) Last medical visit within 1 year 1.65 (1.09-2.48)
Disclosure: Dr Manson receives funding from the National Institutes of Health ( grant CA138962) to conduct the Vitamin D and OmegA-3 Trial (VITAL), a randomized trial of vitamin D and omega-3 fatty acid supplementation in the prevention of cancer and cardiovascular disease. Dr Chlebowski is a consultant for Pfizer, Novartis, Amgen, Genentech, Genomic Health, and Novo Nordisk, and he is on the speaker’s bureau for Novartis and Genentech. Dr Clarke receives research support from Genentech outside the submitted work. Drs Kwon, Gamba, Stefanick, Swetter, Li, Shi, Feldman, Millen, Messina, Shikany, and Tang have no conflicts of interest to disclose. This work was presented in the Society for Investigational Dermatology in 2016.
.43 .01
.02
Women in the Women’s Health Initiative Observational Study were mailed annual questionnaires to report health outcomes, including diagnosis with melanoma, which was confirmed by review of medical records and pathology reports. Our multivariate model was adjusted for all the factors listed in this table. Not all variables are shown. CI, Confidence interval; Ly, langley; NMSC, nonmelanoma skin cancer; 25-OH-D, 25-hydroxyvitamin D; ref, reference. *Odds ratios are for each covariate in a multivariable model adjusted for age, BMI, education, multivitamin and calcium intake, sun exposure history, history of skin cancer, physical activity, season of blood draw, smoking, time spent outdoors in the summer both in childhood and in adulthood, use of sunscreen, regional solar irradiance (in langleys), and having a medical visit in the last year. y Boldface indicates statistical significance.
Hospital, Harvard Medical School, Boston, Massachusettsl; and Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, Californiam Supported by the National Heart, Lung, and Blood Institute (National Clinical Trial identifier NCT00000611) and the American Skin Association Medical Student Grant. The Population Architecture Using Genomics and Epidemiology program is funded by the National Human Genome Research Institute, which is supported by grants U01HG004790, U01HG007376 (Women’s Health Initiative), and U01HG004801 (Coordinating Center).
Correspondence to: Gina Kwon, MD, Department of Dermatology, Stanford University, 450 Broadway St, Redwood City, CA 94063 E-mail: [email protected] Reprint requests: Jean Y. Tang, MD, PhD, Department of Dermatology, Stanford University, 450 Broadway St, Redwood City, CA 94063 E-mail: [email protected] REFERENCES 1. Afzal S, Nordestgaard BG, Bojesen SE. Plasma 25-hydroxyvitamin D and risk of non-melanoma and melanoma skin cancer: a prospective cohort study. J Invest Dermatol. 2013;133:629-636. 2. Newton-Bishop JA, Beswick S, Randerson-Moor J, et al. Serum 25-hydroxyvitamin D3 levels are associated with Breslow thickness at presentation and survival from melanoma. J Clin Oncol. 2009;27:5439-5444. 3. Design of the Women’s Health Initiative Clinical Trial and Observational Study. The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:61-109. 4. Matise TC, Ambite JL, Buyske S, et al. The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. Am J Epidemiol. 2011;174:849-859. 5. Brock K, Huang WY, Fraser DR, et al. Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women. J Steroid Biochem Mol Biol. 2010;121:462-466. https://doi.org/10.1016/j.jaad.2017.05.037
Descriptive survival study of nail melanoma patients treated with functional surgery versus distal amputation To the Editor: Nail melanoma, a variant of acral lentiginous melanoma, accounts for about 0.7%-3.5% of all types of melanomas.1,2 Phalangeal amputation can be performed to excise the tumor, a practice with