BRAFV600E-Mutant Melanoma Presenting With Cardiac Involvement

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  • 1 From the Department of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.

Melanoma is an aggressive skin cancer with historically limited treatment options. Approximately 50% of melanomas harbor BRAF V600 mutations. This report describes a 32-year-old man with metastatic BRAF V600-mutant melanoma who presented with cardiac involvement. Recently developed treatment options for patients with BRAF-mutant melanoma include BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib), and immune-based therapeutics (interleukin-2 or ipilimumab), but the most effective strategy for first-line therapy is heavily debated. Opinions vary for treatment selection, but the general consensus recommends immune-based therapies initially for asymptomatic patients with low-volume disease, and BRAF inhibitors for those with highly symptomatic or rapidly progressing disease. In this case, melanoma with cardiac involvement, although clinically uncommon, presents challenging management decisions.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/45599; and 4) view/print certificate.

Release date: May 9, 2014; Expiration date: May 9, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Evaluate immune-based therapies and BRAF inhibitors for patients with melanoma

  • Outline the challenges of cardiac involvement for patients with metastatic melanoma

Case Report

A 32-year-old man presented with axillary swelling in early 2011. A 6.0 x 5.0-cm mass was excised and determined to be consistent with melanoma. The patient underwent a completion axillary lymph node dissection with 2 additional lymph nodes with melanoma involvement; extracapsular extension was not identified (TxN2b; AJCC stage IIIB). Detailed physical examination did not reveal a primary site of melanoma; staging PET/CT scan and brain MRI showed no disseminated metastases. He was treated with high-dose interferon alpha for 1 year, through mid-2012. One month later, he noted supraclavicular fullness and monocular blurred vision. CT scans showed a cardiac mass, enlarged supraclavicular and axillary lymph nodes, and a mass in the chest wall. Brain MRI revealed a 3.0 x 1.5-cm retroorbital mass, and molecular testing revealed a BRAFV600E mutation. Echocardiogram showed a 3.5-cm mass adherent to the right atrial free wall without valvular regurgitation or impaired flow (Figure 1); cardiac MRI showed a 4.7 x 3.8-cm mass filling almost the entire right atrium with tricuspid valve involvement. The patient underwent radiation therapy, with 3250 cGy administered in 5 fractions to his atrial mass and 3500 cGy to the retroorbital mass. He subsequently initiated vemurafenib at 960 mg twice daily.

Two months after starting vemurafenib, restaging scans showed a slight decrease in his lymphadenopathy but unchanged orbital, cardiac, and chest wall masses. One month later, he developed worsening blurred vision, proptosis, and chest wall pain. Scans showed widespread progression of metastatic disease, although his atrial mass was unchanged in size on echocardiogram. He was then enrolled on a clinical trial evaluating combination therapy with experimental MEK and Akt inhibitors. Two months later he developed progressive eye and chest wall pain, fatigue, and hypoxia with exertion. Imaging showed further disease progression, including 2 new brain metastases, for which he underwent stereotactic radiosurgery. Cardiac MRI showed slight enlargement of his atrial metastasis; CT angiogram did not reveal pulmonary embolism or parenchymal abnormalities. He underwent resection of the orbital mass for palliation of refractory pain and proptosis, and ipilimumab was initiated. After receiving 2 doses, he developed anorexia, nausea, intermittent confusion, and progressive functional decline. He was referred to hospice care and subsequently died in May 2013.

Figure 1
Figure 1

Right atrial mass (arrow) shown on transthoracic echocardiogram (apical view).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0065

Discussion

Malignant melanoma is an aggressive cutaneous malignancy that caused more than 9000 deaths in 2012.1 A wide variety of clinical presentations may occur when patients develop metastatic or recurrent disease, ranging from local or in-transit skin involvement to isolated single-organ metastases to widely disseminated metastatic disease. Melanoma may involve every organ, including the heart. The presence of visceral metastases portends a poor prognosis, although recently approved therapeutic options may induce disease regression and extend survival for a prolonged duration in a minority of patients. Two important management issues for clinicians treating metastatic melanoma are illustrated in this case: selection of first-line therapy for BRAFV600E-mutant melanoma and management of cardiac metastases.

First-Line Therapy: Immune-Based Versus Targeted

Therapeutic options for advanced melanoma are classified into 2 broad categories. Targeted, small molecule inhibitors are effective in patients with BRAFV600E-mutant melanoma, which constitute approximately 50% of all melanoma cases.2,3 Vemurafenib, a specific BRAF inhibitor, prompts rapid and often dramatic tumor regression in 50% to 60% of patients with objective RECIST responses, and improves overall survival (OS) compared with cytotoxic chemotherapy.4,5 Dabrafenib, another selective BRAF inhibitor, was FDA-approved in May 2013 and seems to have equivalent activity in BRAFV600-mutant melanoma.6 Trametinib, an MEK inhibitor, also demonstrates a survival advantage in BRAF-mutant melanoma, with a response rate of 20% to 30%, and was also FDA-approved in May 2013.7 Combined inhibition of BRAF and MEK with dabrafenib and trametinib produces responses greater than 70% and seems to delay the onset of acquired resistance, with a median progression-free survival of 9.4 months compared with 5.8 months for dabrafenib monotherapy (P<.001).8 Unfortunately, resistance to these agents inevitably develops and almost all patients experience disease progression within 2 years of therapy initiation.

The second major class of therapeutics is immune-based and includes ipilimumab and interleukin-2 (IL-2), which have activity regardless of BRAF mutational status. Ipilimumab is a monoclonal antibody that blocks the immune checkpoint CTLA-4 (cytotoxic T-lymphocyte antigen 4) and has demonstrated a survival advantage in patients with melanoma compared with an experimental peptide vaccine.9 In contrast to small molecule inhibitors, ipilimumab may induce delayed responses that may be preceded by tumor enlargement. Autoimmune toxicities, including colitis, endocrinopathies, hepatitis, and dermatitis, may complicate therapy. High-dose IL-2 has been used for many years and produces prolonged disease-free survival in 6% to 8% of patients.10 Its severe associated toxicities require inpatient administration at an experienced center and may only be used in patients with normal organ function.11 These immune-based therapies induce disease regression in a minority of patients, although these responses are often durable.10,12,13

The most effective first-line treatment strategy for patients with BRAFV600-mutant melanoma has not been clearly defined because the agents have not been directly compared prospectively. Additionally, whether initial therapy influences the antitumor efficacy of subsequent treatments is unclear. Future trials are being planned to determine the best sequence of therapy in a randomized phase III clinical trial for untreated patients with melanoma, and will compare the best combination of targeted agents with the best immunotherapy approach, followed by planned cross-over at disease progression. These trials will provide critical insight into the management of patients with melanoma. In the interim, several retrospective studies provide some guidance for clinicians.14,15

A retrospective analysis evaluated 274 patients treated with BRAF inhibitors, 32 of whom had been treated with immune therapy.14 The group initially treated with immune therapy had favorable OS compared with the entire cohort (19.6 vs 13.4 months). Of the 40 patients who received BRAF inhibitors followed by ipilimumab, only half could finish all 4 doses; median progression-free survival and OS were 2.7 and 5.0 months, respectively. An additional retrospective study evaluated 28 patients treated with vemurafenib followed by ipilimumab; 12 patients experienced rapid disease progression and were unable to receive all 4 doses of ipilimumab because of symptomatic deterioration.15 Brain metastases, elevated lactate dehydrogenase, and an ECOG performance status of 1 predicted a poor response to ipilimumab. These studies suggest that the efficacy of immune-based therapies in the setting of BRAF inhibitor resistance is limited for at least a subset of patients.

Subgroup analyses from multicenter phase III trials of ipilimumab and vemurafenib may also help guide clinical practice. Ipilimumab showed improved survival compared with a peptide vaccine. However, a greater benefit was seen in patients with stage IIIc, IVa, and IVb disease compared with stage IVc (hazard ratio [HR], 0.47; 95% CI, 0.27-0.82 vs HR 0.72; 95% CI, 0.53-0.97, respectively).9 Conversely, vemurafenib was clearly superior to chemotherapy in patients with stage IVc melanoma than in those with stage IIIc, IVa, and IVb disease (HR, 0.32; 95% CI, 0.21-0.50 vs HR 0.64; 95% CI, 0.29-1.38, respectively).4

If immune-based therapy is selected for initial treatment, whether IL-2 or ipilimumab is superior is unclear. Ipilimumab is generally more tolerable and can be administered to an elderly and frail population, although the volume of experience is less and responses are not evaluable until 24 weeks after therapy initiation (unless rapid and obvious disease progression occurs earlier). IL-2 has been used for many years and responses may be evaluable at approximately 8 weeks, although severe acute toxicities limit its use to selected patients at experienced centers. Analysis of the pivotal ipilimumab versus peptide vaccine trial showed similar survival benefit in those with prior IL-2 therapy compared with those without.9 However, theoretical concerns exist about the converse treatment order, such as IL-2 producing delayed immune-related adverse events from ipilimumab, or that subsequent use of IL-2 may be precluded by ongoing ipilimumab toxicity.

Taken together, the general consensus by experts is that patients who are relatively asymptomatic with low-volume BRAFV600-mutant melanoma should receive immune-based therapies, either with ipilimumab or IL-2, as first-line treatment to experience long-term benefit.16 Patients who are highly symptomatic with either large-volume or rapidly progressing disease should be treated initially with vemurafenib or dabrafenib. Patients whose disease presentation falls in the middle of this spectrum may be treated with immune-based therapies or BRAF inhibitors. The advent of newer immune checkpoint inhibitors targeting programmed cell death-1 receptor or its ligand (PD-1/PD-L1; including nivolumab, pembrolizumab, or MPDL3280A) as monotherapy or in combination with ipilimumab may change this paradigm in the near future, because both rapid and durable responses have been observed in early trials.17-19

Cardiac Metastases in Melanoma

Melanoma has a propensity for cardiac involvement, generally through hematogenous spread. Lung and breast carcinomas also commonly involve the heart, usually through direct extension of the tumor. Autopsy series show an incidence of cardiac metastases in up to 64% of patients who die with metastatic melanoma.20-22 Involvement is often multifocal and may involve the pericardium, epicardium, or myocardium, usually on the right side.23 Most cases are clinically silent and commonly undetectable on imaging. Even massive involvement (“charcoal heart”) may confer few symptoms.24,25 Occasionally, asymptomatic metastases may be detected with staging CT or PET scans. In symptomatic patients, more definitive imaging with echocardiogram or cardiac MRI may be performed for surgical planning or to evaluate for outflow obstruction.23 When clinically apparent, these cardiac metastases commonly cause dyspnea and peripheral edema from obstruction of forward flow or pericardial effusion. Chest discomfort and tachycardia may also be presenting symptoms; cases of acute aortic occlusion from melanoma embolism, heart block, and acute coronary syndrome have also been reported.26-28

Therapeutic options for cardiac metastases include systemic therapies or local measures. Systemic therapies are generally preferred for asymptomatic lesions. BRAF inhibitors often cause rapid disease regression in patients with BRAFV600E-mutant melanoma and may be an effective treatment in patients with symptomatic cardiac involvement. Ipilimumab is another therapeutic option, although symptomatic lesions have an extremely high risk of progression before a benefit is seen, even in patients who experience a response. IL-2 causes significant cardiac stress and is generally not administered in the setting of symptomatic cardiac metastases.

Surgical resection of cardiac metastases may be an effective palliative option, and even curative in some cases. Resection is not commonly performed because of the invasive nature of the surgery and usual presence of concurrent widespread metastatic disease. However, appropriately selected patients may derive prolonged benefits from resection, which may allow for administration of systemic therapy.29 Additionally, referral to a cardiothoracic surgeon is strongly encouraged for the rare cases of isolated cardiac involvement, because resection may be curative.30 Surgical techniques are evolving and include aggressive strategies, such as cardiac autotransplantation.31 Radiation therapy is an additional therapeutic option that may cause tumor shrinkage or prolonged stabilization, and has been used successfully.32 The present patient seemed to derive palliative benefit from radiation, with minimal growth of his atrial mass over several months despite widespread systemic worsening. Clinicians should consider referring patients with symptomatic cardiac metastases to a cardiothoracic surgeon or radiation oncologist for local treatment. Additionally, cardiac involvement should be part of the differential diagnosis when patients with melanoma present with cardiopulmonary complaints. Nevertheless, until systemic therapy is greatly improved, the control of cardiac metastases will remain difficult and will confer a poor prognosis in most cases.

Dr. Johnson has disclosed that he received research support from grant K12 CA 0906525. He has disclosed no other financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Sosman has disclosed that he is on the advisory board for Bristol-Myers Squibb Company and Genentech, Inc.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants Ms. Moonan has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education & Grants

Ms. Gianola has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations

Ms. Gregory has disclosed that she has no relevant financial relationships.

References

  • 1.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:1130.

  • 2.

    Curtin JA, Fridlyand J, Kageshita T et al.. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:21352147.

  • 3.

    Lovly CM, Dahlman KB, Fohn LE et al.. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One 2012;7:e35309.

    • Search Google Scholar
    • Export Citation
  • 4.

    Chapman PB, Hauschild A, Robert C et al.. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:25072516.

  • 5.

    Sosman JA, Kim KB, Schuchter L et al.. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707714.

  • 6.

    Hauschild A, Grob JJ, Demidov LV et al.. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358365.

    • Search Google Scholar
    • Export Citation
  • 7.

    Flaherty KT, Robert C, Hersey P et al.. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107114.

  • 8.

    Flaherty KT, Infante JR, Daud A et al.. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:16941703.

  • 9.

    Hodi FS, O’Day SJ, McDermott DF et al.. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711723.

  • 10.

    Rosenberg SA, Yang JC, Topalian SL et al.. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994;271:907913.

    • Search Google Scholar
    • Export Citation
  • 11.

    Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother 2001;24:287293.

  • 12.

    Atkins MB, Lotze MT, Dutcher JP et al.. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:21052116.

    • Search Google Scholar
    • Export Citation
  • 13.

    Prieto PA, Yang JC, Sherry RM et al.. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012;18:20392047.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ackerman A, Klein O, McDermott DF et al.. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer, in press.

    • Search Google Scholar
    • Export Citation
  • 15.

    Ascierto PA, Simeone E, Giannarelli D et al.. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med 2012;10:107.

    • Search Google Scholar
    • Export Citation
  • 16.

    Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol 2013;14:e609.

  • 17.

    Topalian SL, Hodi FS, Brahmer JR et al.. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:24432454.

  • 18.

    Hamid O, Robert C, Daud A et al.. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134144.

  • 19.

    Wolchok JD, Kluger H, Callahan MK et al.. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122133.

  • 20.

    Glancy DL, Roberts WC. The heart in malignant melanoma. A study of 70 autopsy cases. Am J Cardiol 1968;21:555571.

  • 21.

    Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990;65:14561459.

  • 22.

    MacGee W. Metastatic and invasive tumours involving the heart in a geriatric population: a necropsy study. Virchows Arch A Pathol Anat Histopathol 1991;419:183189.

    • Search Google Scholar
    • Export Citation
  • 23.

    Allen BC, Mohammed TL, Tan CD et al.. Metastatic melanoma to the heart. Curr Probl Diagn Radiol 2012;41:159164.

  • 24.

    Waller BF, Gottdiener JS, Virmani R et al.. The “charcoal heart;” melanoma to the cor. Chest 1980;77:671676.

  • 25.

    Savoia P, Fierro MT, Zaccagna A et al.. Metastatic melanoma of the heart. J Surg Oncol 2000;75:203207.

  • 26.

    de Vasconcelos VT, Arias VE, Ikeda S. Cardiac metastasis of melanoma presenting as acute aortic occlusion. J Thromb Thrombolysis 2013;36:536538..

    • Search Google Scholar
    • Export Citation
  • 27.

    Auer J, Schmid J, Berent R et al.. Cardiac metastasis of malignant melanoma mimicking acute coronary syndrome. Eur Heart J 2012;33:676.

  • 28.

    Cheng G, Newberg AB, Alavi A. Metastatic melanoma causing complete atrioventricular block--the role of FDG PET/CT in diagnosis. Clin Imaging 2011;35:312314.

    • Search Google Scholar
    • Export Citation
  • 29.

    Gibbs P, Cebon JS, Calafiore P et al.. Cardiac metastases from malignant melanoma. Cancer 1999;85:7884.

  • 30.

    Kontozis L, Soteriou M, Papamichael D et al.. Isolated right atrial metastasis of malignant melanoma mimicking a myxoma. Hellenic J Cardiol 2011;52:281284.

    • Search Google Scholar
    • Export Citation
  • 31.

    Leja MJ, Kim M, Perryman L et al.. Metastatic melanoma to the intracavitary left ventricle treated using cardiac autotransplantation technique for resection. Methodist Debakey Cardiovasc J 2011;7:4446.

    • Search Google Scholar
    • Export Citation
  • 32.

    Magnuson WJ, Halligan JB. Successful treatment of melanoma metastatic to the left atrium using external beam radiation therapy. Oncology (Williston Park) 2010;24:650653.

    • Search Google Scholar
    • Export Citation

Correspondence: Douglas B. Johnson, MD, Vanderbilt University Medical Center, 777 Preston Research Building, Nashville, TN 37232. E-mail: douglas.b.johnson@vanderbilt.edu
  • View in gallery

    Right atrial mass (arrow) shown on transthoracic echocardiogram (apical view).

  • 1.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:1130.

  • 2.

    Curtin JA, Fridlyand J, Kageshita T et al.. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:21352147.

  • 3.

    Lovly CM, Dahlman KB, Fohn LE et al.. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One 2012;7:e35309.

    • Search Google Scholar
    • Export Citation
  • 4.

    Chapman PB, Hauschild A, Robert C et al.. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:25072516.

  • 5.

    Sosman JA, Kim KB, Schuchter L et al.. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707714.

  • 6.

    Hauschild A, Grob JJ, Demidov LV et al.. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358365.

    • Search Google Scholar
    • Export Citation
  • 7.

    Flaherty KT, Robert C, Hersey P et al.. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107114.

  • 8.

    Flaherty KT, Infante JR, Daud A et al.. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:16941703.

  • 9.

    Hodi FS, O’Day SJ, McDermott DF et al.. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711723.

  • 10.

    Rosenberg SA, Yang JC, Topalian SL et al.. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994;271:907913.

    • Search Google Scholar
    • Export Citation
  • 11.

    Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother 2001;24:287293.

  • 12.

    Atkins MB, Lotze MT, Dutcher JP et al.. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:21052116.

    • Search Google Scholar
    • Export Citation
  • 13.

    Prieto PA, Yang JC, Sherry RM et al.. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012;18:20392047.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ackerman A, Klein O, McDermott DF et al.. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer, in press.

    • Search Google Scholar
    • Export Citation
  • 15.

    Ascierto PA, Simeone E, Giannarelli D et al.. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med 2012;10:107.

    • Search Google Scholar
    • Export Citation
  • 16.

    Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol 2013;14:e609.

  • 17.

    Topalian SL, Hodi FS, Brahmer JR et al.. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:24432454.

  • 18.

    Hamid O, Robert C, Daud A et al.. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134144.

  • 19.

    Wolchok JD, Kluger H, Callahan MK et al.. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122133.

  • 20.

    Glancy DL, Roberts WC. The heart in malignant melanoma. A study of 70 autopsy cases. Am J Cardiol 1968;21:555571.

  • 21.

    Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990;65:14561459.

  • 22.

    MacGee W. Metastatic and invasive tumours involving the heart in a geriatric population: a necropsy study. Virchows Arch A Pathol Anat Histopathol 1991;419:183189.

    • Search Google Scholar
    • Export Citation
  • 23.

    Allen BC, Mohammed TL, Tan CD et al.. Metastatic melanoma to the heart. Curr Probl Diagn Radiol 2012;41:159164.

  • 24.

    Waller BF, Gottdiener JS, Virmani R et al.. The “charcoal heart;” melanoma to the cor. Chest 1980;77:671676.

  • 25.

    Savoia P, Fierro MT, Zaccagna A et al.. Metastatic melanoma of the heart. J Surg Oncol 2000;75:203207.

  • 26.

    de Vasconcelos VT, Arias VE, Ikeda S. Cardiac metastasis of melanoma presenting as acute aortic occlusion. J Thromb Thrombolysis 2013;36:536538..

    • Search Google Scholar
    • Export Citation
  • 27.

    Auer J, Schmid J, Berent R et al.. Cardiac metastasis of malignant melanoma mimicking acute coronary syndrome. Eur Heart J 2012;33:676.

  • 28.

    Cheng G, Newberg AB, Alavi A. Metastatic melanoma causing complete atrioventricular block--the role of FDG PET/CT in diagnosis. Clin Imaging 2011;35:312314.

    • Search Google Scholar
    • Export Citation
  • 29.

    Gibbs P, Cebon JS, Calafiore P et al.. Cardiac metastases from malignant melanoma. Cancer 1999;85:7884.

  • 30.

    Kontozis L, Soteriou M, Papamichael D et al.. Isolated right atrial metastasis of malignant melanoma mimicking a myxoma. Hellenic J Cardiol 2011;52:281284.

    • Search Google Scholar
    • Export Citation
  • 31.

    Leja MJ, Kim M, Perryman L et al.. Metastatic melanoma to the intracavitary left ventricle treated using cardiac autotransplantation technique for resection. Methodist Debakey Cardiovasc J 2011;7:4446.

    • Search Google Scholar
    • Export Citation
  • 32.

    Magnuson WJ, Halligan JB. Successful treatment of melanoma metastatic to the left atrium using external beam radiation therapy. Oncology (Williston Park) 2010;24:650653.

    • Search Google Scholar
    • Export Citation
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