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Original Investigation | Clinical Sciences

Cutaneous Vitiligo Following Management of Uveal Melanoma in 6 Patients FREE

Pukhraj Rishi, MD1,2; Carol L. Shields, MD1; Kaitlin Patrick, BS1; Jerry A. Shields, MD1
[+] Author Affiliations
1Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
2On sabbatical from Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralya, Chennai, India
JAMA Ophthalmol. 2013;131(9):1174-1178. doi:10.1001/jamaophthalmol.2013.4254.
Text Size: A A A
Published online

Importance  The relationship of vitiligo to cutaneous melanoma is believed to be due to an immune response generated to melanoma antigens that cross-react with normal skin. There is little in the literature on the relationship between cutaneous vitiligo and uveal melanoma.

Objective  To describe the clinical profile, treatment, and outcome in patients with uveal melanoma who subsequently developed cutaneous vitiligo.

Design, Setting, and Participants  Retrospective case series of 6 patients with uveal melanoma who had developed cutaneous vitiligo and were examined at a tertiary eye care institution.

Main Outcome and Measure  Development of cutaneous vitiligo.

Results  The mean age at presentation was 62 years (range, 39-85 years). No patient had a personal history of cutaneous melanoma, autoimmune disease, or cutaneous vitiligo. The mean tumor basal diameter was 12.9 mm (median, 12.7 mm; range, 7-19 mm), with a mean thickness of 9.5 mm (median, 8.4 mm; range, 3-19 mm). Treatment included plaque radiotherapy in 4 patients and enucleation in 1 patient; 1 patient refused therapy. No patient had local tumor recurrence at the 71-month mean follow-up, but of the 3 patients who developed metastases at the 52-month mean follow-up, 2 were treated with a melanoma vaccine. The mean interval from initial presentation to onset of vitiligo was 77 months (range, 5-168 months). The vitiligo developed bilaterally with multiple well-defined lesions, affecting 5% to 40% of the cutaneous surface, generally in the upper body. During the 71-month mean follow-up (range, 4-205 months), there was 1 death.

Conclusions and Relevance  Patients with uveal melanoma can develop vitiligo spontaneously or following vaccine therapy. Involvement is multiple and bilateral, predominantly affecting the upper body.

Figures in this Article

Vitiligo is an acquired chronic pigmentary disorder of the skin characterized by depigmented patches, often symmetrically distributed, and with a propensity to increase in size over time. The depigmented regions correspond to a loss of melanocytes within epidermal and sometimes hair follicle melanocytes.1 This condition affects approximately 0.5% of the population.2 Vitiligo is generally a sporadic autoimmune disease. However, vitiligo-like depigmentation can occur due to posttraumatic, postinflammatory, postinfectious, drug-induced situations and rare causes such as hypomelanosis from piebaldism and tuberous sclerosis.1 A rare cause of vitiligo is previously treated or spontaneously regressed cutaneous melanoma.

The relationship between vitiligo and cutaneous melanoma is believed to be due to an immune response generated to melanoma antigens that cross-react with normal skin. Melanoma-related vitiligo occurs in 1% to 5% of patients with cutaneous melanoma.25 There is little in the literature on the relationship between cutaneous vitiligo and uveal melanoma.610 Herein, we describe 6 patients with uveal melanoma who developed cutaneous vitiligo.

Of approximately 4760 patients with uveal melanoma examined at the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, between July 1, 2003, and September 30, 2012, 6 patients had developed cutaneous vitiligo. The institutional review board at the Wills Eye Institute approved this study. The study and data collection conformed to local laws and were compliant with the principles of the Declaration of Helsinki.

Data were reviewed regarding patient demographic information such as age, race, sex, and past personal or family history of cutaneous melanoma, autoimmune disorder, or cutaneous vitiligo. A detailed systemic and ocular history was obtained from the medical records, including best-corrected visual acuity, slitlamp biomicroscopy, intraocular pressure measurement, indirect ophthalmoscopy, and transillumination findings. B-scan ultrasonography was performed in all patients to quantify tumor dimensions. Additional imaging with computed tomography or magnetic resonance imaging was done when needed. Details of the uveal melanoma were recorded regarding tumor size (base and thickness in millimeters), location, related features, and treatment. Outcomes of therapy were recorded, including melanoma control, metastasis, and death.

Details on the development of cutaneous vitiligo with regard to the extent, location, time to onset, progression, and treatment were noted. Vitiligo outcomes included progression of disease and relationship to the primary uveal melanoma.

The demographic features and clinical characteristics of the 6 patients are listed in Table 1. The mean age at presentation was 62 years (median, 62 years; range, 39-85 years). Five patients were white and 1 was African American. There was no personal or family history of cutaneous melanoma, autoimmune disease, or cutaneous vitiligo. No patient received treatment before referral to our department.

The most common ocular symptom was reduction of vision, with visual acuity ranging from 20/20 to no light perception. The mean tumor basal diameter was 12.9 mm (median, 12.7 mm; range, 7-19 mm), with a mean thickness of 9.5 mm (median, 8.4 mm; range, 3-19 mm).

The treatment outcomes are listed in Table 2. There was no local tumor recurrence during the 71-month mean follow-up. Three patients (patients 2, 4, and 6) developed metastases. The mean interval from treatment of the melanoma to onset of metastasis was 52 months (median, 33 months; range, 28-96 months). Patient 4 refused therapy because of poor general health.

The vitiligo outcomes are listed in Table 3. The mean interval from presentation to onset of vitiligo was 77 months (median, 74 months; range, 5-168 months). The vitiligo developed bilaterally with multiple well-defined lesions, affecting 5% to 40% of the cutaneous surface, generally on the upper body (Figure 1, patient without metastasis; Figure 2, patient with metastasis). During the total 71-month mean follow-up (median, 50 months; range, 4-205 months), there was 1 death from metastatic melanoma. None of the patients sought treatment for vitiligo.

Table Graphic Jump LocationTable 3.  Details of Cutaneous Vitiligo Following Uveal Melanoma in 6 Patients
Place holder to copy figure label and caption
Figure 1.
Vitiligo in a Patient Treated With Plaque Radiotherapy

A 39-year-old man (patient 5) with an amelanotic melanoma (A) 9.9 mm in thickness on ultrasonography (B) was treated with plaque radiotherapy. Seventeen years later, the right eye displayed cataract (C) and regressed melanoma (D). Cutaneous vitiligo was found on both arms (E and F), and there was no evidence of metastatic disease.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Vitiligo in a Patient Treated With Enucleation and Immunotherapy

A 65-year-old woman (patient 2) with eyelid edema, chemosis, and total hyphema (A) of the left eye had an ill-defined large intraocular mass filling the globe on ultrasonography (B), necessitating enucleation. At the 28-month follow-up, with a prosthesis in place (C), systemic metastases were detected and immunotherapy with vaccination was provided (D). Fifty-nine months later, cutaneous vitiligo of the periocular region (E) and arms (F) was detected.

Graphic Jump Location

Cutaneous vitiligo is a common skin disorder, recognized as patchy depigmentation and occurs in approximately 0.5% to 1% of the world population.2 There is no apparent predilection for sex, race, or skin type, and nearly half of affected patients manifest vitiligo by the third decade of life.1

The cutaneous surface of the body is endowed with complex adaptive immune mechanisms. In the past 50 years, studies on tumor immunology have revealed a link between tumor immunity and autoimmunity,11 with an extensive overlap between normally expressed antigens and those expressed by malignant neoplasms, such as melanoma.1 Spontaneous regression of cutaneous nevi is recognized in children and adolescents, probably reflecting an active and robust immunosurveillance that eliminates normal and neoplastic melanocytes, thus preventing tumor development.12 Conversely, it also has been shown that immunodeficiency is associated with a higher incidence of melanocytic nevi.13 Furthermore, medication-related immunosuppression in transplant recipients can cause eruption of cutaneous nevi.14 Such nevi are reported to involute after discontinuation of immunosuppressive therapy. These observations directly support the theory of skin immunosurveillance against melanocytic proliferation.15 An important finding to further confirm this observation is the fact that cutaneous melanoma increases 4 to 7 times in immunosuppressed populations compared with age- and sex-matched controls.16

Melanoma cells express a family of differentiation antigens that are shared by normal melanocytes.11 This family of proteins includes tyrosinase and related proteins TRP-1 (gp75), TRP-2 (dopachrome tautomerase), gp100, and MART-1 (Melan-A). Each of these proteins plays a crucial role in melanin synthesis. Two major mechanisms of vitiligo pathogenesis in patients with cutaneous melanoma have been proposed by the antibody-based theory and the T-cell–based theory. In the antibody-based theory, the host antibodies lyse melanocytes and melanoma cells. Studies have detected the presence of autoantibodies recognizing tyrosinase, TRP-1, and TRP-2 from the serum samples of patients with melanoma and those with vitiligo.17 In the T-cell–based theory, the host CD8+ T cells react with host melanoma and cross-react with benign melanocytes, leading to destruction. Clonotypically, identical T cells have been found in cutaneous melanoma and vitiligo patches.18 Furthermore, most cells infiltrating vitiligo are CD8+ T cells that recognize melanocytes and melanoma cells.19

The published incidence of melanoma-associated vitiligo has varied at 2.8%, 3.7%, 4.1%, and 5% and is higher than vitiligo in the general population.35,20 On the basis of age differences, lack of family history, and clinicopathologic findings, Koh et al21 have suggested that vitiligo associated with cutaneous melanoma may be different from autoimmune vitiligo unassociated with melanoma.

There is little in the literature on cutaneous vitiligo in patients with uveal melanoma. Individual observations of cutaneous vitiligo developing after enucleation7,8 or evisceration9 of eyes with uveal melanoma have been reported. In 1968, Nirankari et al9 described a 57-year-old man who underwent evisceration for panophthalmitis from undetected ocular melanoma, and cutaneous vitiligo was detected 7 years later with subsequent orbital melanoma recurrence thereafter. A similar phenomenon of depigmentation of the cutaneous nevus into the halo nevus has been observed following treatment of uveal melanoma.7,10

The development of vitiligo in patients with cutaneous melanoma has been associated with increased survival rates, attributed to activation of a systemic immune response.4 In 1983, Nordlund et al5 reported that the 5-year survival rate with patients who manifest melanoma-related vitiligo was significantly enhanced. In 1987, a more extensive study by Bystryn et al3 reached similar conclusions. However, these studies drew patients with stage I or II disease. Recently, in a cohort of patients with metastatic cutaneous melanoma, Quaglino et al4 reported that vitiligo was an independent positive prognostic factor correlated with significantly enhanced 5-year survival. In fact, vitiligo induction is recognized as a marker of effective melanoma tumor immunotherapy. Nordlund and Lerner22 suggested that vitiligo should be induced in patients after resection of primary melanoma. In a series of 374 patients with metastatic melanoma who were treated with high-dose interleukin 2, 22% developed treatment-related vitiligo.23

In conclusion, vitiligo can occur rarely in association with uveal melanoma. When present, it usually develops late in the clinical course with a predilection for bilateral, asymmetric involvement of the upper body. The potential prognostic benefit of this finding in these patients remains to be determined.

Submitted for Publication: October 30, 2012; final revision received December 29, 2012; accepted February 26, 2013.

Corresponding Author: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, 840 Walnut St, Ste 1440, Philadelphia, PA 19107 (carol.shields@shieldsoncology.com)

Published Online: July 25, 2013. doi:10.1001/jamaophthalmol.2013.4254.

Author Contributions: Drs Rishi and C. L. Shields had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rishi, Patrick.

Acquisition of data: All authors.

Analysis and interpretation of data: Rishi, C. L. Shields.

Drafting of the manuscript: Rishi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Rishi, C. L. Shields.

Administrative, technical, and material support: Rishi, Patrick, J. A. Shields.

Study supervision: C. L. Shields.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the Eye Tumor Research Foundation (Drs C. L. Shields and J. A. Shields).

Role of the Sponsor: The funders had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review or approval of the manuscript.

Taïeb  A, Picardo  M; VETF Members.  The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 2007;20(1):27-35.
Link to Article
Taïeb  A, Picardo  M.  Clinical practice: vitiligo. N Engl J Med. 2009;360(2):160-169.
PubMed   |  Link to Article
Bystryn  JC, Rigel  D, Friedman  RJ, Kopf  A.  Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol. 1987;123(8):1053-1055.
PubMed   |  Link to Article
Quaglino  P, Marenco  F, Osella-Abate  S,  et al.  Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol. 2010;21(2):409-414.
PubMed   |  Link to Article
Nordlund  JJ, Kirkwood  JM, Forget  BM, Milton  G, Albert  DM, Lerner  AB.  Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9(5):689-696.
PubMed   |  Link to Article
Shields  CL, Maktabi  AM, Jahnle  E, Mashayekhi  A, Lally  SE, Shields  JA.  Halo nevus of the choroid in 150 patients: the 2010 Henry van Dyke Lecture. Arch Ophthalmol. 2010;128(7):859-864.
PubMed   |  Link to Article
Albert  DM, Todes-Taylor  N, Wagoner  M, Nordlund  JJ, Lerner  AB.  Vitiligo or halo nevi occurring in two patients with choroidal melanoma. Arch Dermatol. 1982;118(1):34-36.
PubMed   |  Link to Article
Duh  EJ, Schachat  AP, Albert  DM, Patel  SM.  Long-term survival in a patient with uveal melanoma and liver metastasis. Arch Ophthalmol. 2004;122(2):285-287.
PubMed   |  Link to Article
Nirankari  MS, Khanna  KK, Mathur  RP.  Uveal malignant melanoma with leucoderma. J All India Ophthalmol Soc. 1968;16(2):63-66.
PubMed
Sarici  AM, Shah  SU, Shields  CL, Birdsong  RH, Shields  JA.  Cutaneous halo nevi following plaque radiotherapy for uveal melanoma. Arch Ophthalmol. 2011;129(11):1499-1501.
PubMed   |  Link to Article
Houghton  AN, Eisinger  M, Albino  AP, Cairncross  JG, Old  LJ.  Surface antigens of melanocytes and melanomas: markers of melanocyte differentiation and melanoma subsets. J Exp Med. 1982;156(6):1755-1766.
PubMed   |  Link to Article
Cui  Z, Willingham  MC.  Halo naevus: a visible case of immunosurveillance in humans? Lancet Oncol. 2004;5(7):397-398.
PubMed   |  Link to Article
Baron  J, Krol  A.  Management of nevi in transplant patients. Dermatol Ther. 2005;18(1):34-43.
PubMed   |  Link to Article
Piaserico  S, Alaibac  M, Fortina  AB, Peserico  A.  Clinical and dermatoscopic fading of post-transplant eruptive melanocytic nevi after suspension of immunosuppressive therapy. J Am Acad Dermatol. 2006;54(2):338-340.
PubMed   |  Link to Article
Zattra  E, Fortina  AB, Bordignon  M, Piaserico  S, Alaibac  M.  Immunosuppression and melanocyte proliferation. Melanoma Res. 2009;19(2):63-68.
PubMed   |  Link to Article
Jensen  P, Hansen  S, Møller  B,  et al.  Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2, pt 1):177-186.
PubMed   |  Link to Article
Ram  M, Shoenfeld  Y.  Harnessing autoimmunity (vitiligo) to treat melanoma: a myth or reality? Ann N Y Acad Sci. 2007;1110:410-425.
PubMed   |  Link to Article
Becker  JC, Guldberg  P, Zeuthen  J, Bröcker  EB, Straten  PT.  Accumulation of identical T cells in melanoma and vitiligo-like leukoderma. J Invest Dermatol. 1999;113(6):1033-1038.
PubMed   |  Link to Article
Le Gal  FA, Avril  MF, Bosq  J,  et al.  Direct evidence to support the role of antigen-specific CD8+ T cells in melanoma-associated vitiligo. J Invest Dermatol. 2001;117(6):1464-1470.
PubMed   |  Link to Article
Schallreuter  KU, Levenig  C, Berger  J.  Vitiligo and cutaneous melanoma: a case study. Dermatologica. 1991;183(4):239-245.
PubMed   |  Link to Article
Koh  HK, Sober  AJ, Nakagawa  H, Albert  DM, Mihm  MC, Fitzpatrick  TB.  Malignant melanoma and vitiligo-like leukoderma: an electron microscopic study. J Am Acad Dermatol. 1983;9(5):696-708.
PubMed   |  Link to Article
Nordlund  JJ, Lerner  AB.  Vitiligo and melanoma. Arch Dermatol. 1979;115(5):636. doi:10.1001/archderm.1979.04010050060026.
PubMed   |  Link to Article
Phan  GQ, Attia  P, Steinberg  SM, White  DE, Rosenberg  SA.  Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 2001;19(15):3477-3482.
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.
Vitiligo in a Patient Treated With Plaque Radiotherapy

A 39-year-old man (patient 5) with an amelanotic melanoma (A) 9.9 mm in thickness on ultrasonography (B) was treated with plaque radiotherapy. Seventeen years later, the right eye displayed cataract (C) and regressed melanoma (D). Cutaneous vitiligo was found on both arms (E and F), and there was no evidence of metastatic disease.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Vitiligo in a Patient Treated With Enucleation and Immunotherapy

A 65-year-old woman (patient 2) with eyelid edema, chemosis, and total hyphema (A) of the left eye had an ill-defined large intraocular mass filling the globe on ultrasonography (B), necessitating enucleation. At the 28-month follow-up, with a prosthesis in place (C), systemic metastases were detected and immunotherapy with vaccination was provided (D). Fifty-nine months later, cutaneous vitiligo of the periocular region (E) and arms (F) was detected.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 3.  Details of Cutaneous Vitiligo Following Uveal Melanoma in 6 Patients

References

Taïeb  A, Picardo  M; VETF Members.  The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 2007;20(1):27-35.
Link to Article
Taïeb  A, Picardo  M.  Clinical practice: vitiligo. N Engl J Med. 2009;360(2):160-169.
PubMed   |  Link to Article
Bystryn  JC, Rigel  D, Friedman  RJ, Kopf  A.  Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol. 1987;123(8):1053-1055.
PubMed   |  Link to Article
Quaglino  P, Marenco  F, Osella-Abate  S,  et al.  Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol. 2010;21(2):409-414.
PubMed   |  Link to Article
Nordlund  JJ, Kirkwood  JM, Forget  BM, Milton  G, Albert  DM, Lerner  AB.  Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9(5):689-696.
PubMed   |  Link to Article
Shields  CL, Maktabi  AM, Jahnle  E, Mashayekhi  A, Lally  SE, Shields  JA.  Halo nevus of the choroid in 150 patients: the 2010 Henry van Dyke Lecture. Arch Ophthalmol. 2010;128(7):859-864.
PubMed   |  Link to Article
Albert  DM, Todes-Taylor  N, Wagoner  M, Nordlund  JJ, Lerner  AB.  Vitiligo or halo nevi occurring in two patients with choroidal melanoma. Arch Dermatol. 1982;118(1):34-36.
PubMed   |  Link to Article
Duh  EJ, Schachat  AP, Albert  DM, Patel  SM.  Long-term survival in a patient with uveal melanoma and liver metastasis. Arch Ophthalmol. 2004;122(2):285-287.
PubMed   |  Link to Article
Nirankari  MS, Khanna  KK, Mathur  RP.  Uveal malignant melanoma with leucoderma. J All India Ophthalmol Soc. 1968;16(2):63-66.
PubMed
Sarici  AM, Shah  SU, Shields  CL, Birdsong  RH, Shields  JA.  Cutaneous halo nevi following plaque radiotherapy for uveal melanoma. Arch Ophthalmol. 2011;129(11):1499-1501.
PubMed   |  Link to Article
Houghton  AN, Eisinger  M, Albino  AP, Cairncross  JG, Old  LJ.  Surface antigens of melanocytes and melanomas: markers of melanocyte differentiation and melanoma subsets. J Exp Med. 1982;156(6):1755-1766.
PubMed   |  Link to Article
Cui  Z, Willingham  MC.  Halo naevus: a visible case of immunosurveillance in humans? Lancet Oncol. 2004;5(7):397-398.
PubMed   |  Link to Article
Baron  J, Krol  A.  Management of nevi in transplant patients. Dermatol Ther. 2005;18(1):34-43.
PubMed   |  Link to Article
Piaserico  S, Alaibac  M, Fortina  AB, Peserico  A.  Clinical and dermatoscopic fading of post-transplant eruptive melanocytic nevi after suspension of immunosuppressive therapy. J Am Acad Dermatol. 2006;54(2):338-340.
PubMed   |  Link to Article
Zattra  E, Fortina  AB, Bordignon  M, Piaserico  S, Alaibac  M.  Immunosuppression and melanocyte proliferation. Melanoma Res. 2009;19(2):63-68.
PubMed   |  Link to Article
Jensen  P, Hansen  S, Møller  B,  et al.  Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2, pt 1):177-186.
PubMed   |  Link to Article
Ram  M, Shoenfeld  Y.  Harnessing autoimmunity (vitiligo) to treat melanoma: a myth or reality? Ann N Y Acad Sci. 2007;1110:410-425.
PubMed   |  Link to Article
Becker  JC, Guldberg  P, Zeuthen  J, Bröcker  EB, Straten  PT.  Accumulation of identical T cells in melanoma and vitiligo-like leukoderma. J Invest Dermatol. 1999;113(6):1033-1038.
PubMed   |  Link to Article
Le Gal  FA, Avril  MF, Bosq  J,  et al.  Direct evidence to support the role of antigen-specific CD8+ T cells in melanoma-associated vitiligo. J Invest Dermatol. 2001;117(6):1464-1470.
PubMed   |  Link to Article
Schallreuter  KU, Levenig  C, Berger  J.  Vitiligo and cutaneous melanoma: a case study. Dermatologica. 1991;183(4):239-245.
PubMed   |  Link to Article
Koh  HK, Sober  AJ, Nakagawa  H, Albert  DM, Mihm  MC, Fitzpatrick  TB.  Malignant melanoma and vitiligo-like leukoderma: an electron microscopic study. J Am Acad Dermatol. 1983;9(5):696-708.
PubMed   |  Link to Article
Nordlund  JJ, Lerner  AB.  Vitiligo and melanoma. Arch Dermatol. 1979;115(5):636. doi:10.1001/archderm.1979.04010050060026.
PubMed   |  Link to Article
Phan  GQ, Attia  P, Steinberg  SM, White  DE, Rosenberg  SA.  Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 2001;19(15):3477-3482.
PubMed

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