Cutaneous Melanoma, Fifth Edition

Charles Balch, Alan Houghton, Arthur Sober, Seng-jaw Soong, Michael Atkins, John Thompsn

Introduction
A History of Melanoma: From Hunter to Milton; Arthur J. Sober, Helen M. Shaw, John F. Thompson
John Hunter (1728-1793)
René Laennec (1781-1826)
William Norris (1792-1877)
Oliver Pemberton (1825-1897)
James Paget (1814-1899)
Sir Jonathan Hutchinson (1828-1913)
William Sampson Handley (1872-1962)
Alexander Breslow (1928-1980)
Vincent J. McGovern (1915-1983)
Sophie Spitz (1910-1956)
Arthur Allen (1910-1994)
Wallace H. Clark, Jr. (1924-1997)
Thomas B. Fitzpatrick, Jr. (1919-2003)
Gerald W. Milton (1924-2007)
Epidemiology, Prognosis, and Staging
Epidemiology of Melanoma; Bruce K. Armstrong, Alisa M. Goldstein

Worldwide incidence and mortality patterns
Correlates of melanoma risk
Demographic correlates
Constitutional correlates
Environmental and behavioral correlates
Present and future trends in melanoma incidence and mortality


Prognostic Factors and Natural History of Melanoma; Jeffrey E. Gershenwald, Charles M. Balch, Seng-jaw Soong, John F. Thompson

AJCC melanoma staging system analyses—overview of the AJCC international melanoma database and 2002 melanoma staging system
Background
Overview of the 2002 (sixth edition) AJCC melanoma database and melanoma staging system
Validation of the AJCC melanoma staging system
Prognostic factors in primary melanoma (stages I and II)
Prognostic factors in regionally metastatic melanoma: lymph node metastases, satellite lesions, and in-transit metastases
AJCC melanoma database: multivariate analysis for stage III patients
Prognostic factor analyses in patients with distant metastatic melanoma (stage IV)
AJCC melanoma database analysis: stage IV

Melanoma Staging and Classification; Charles M. Balch, Jeffrey E. Gershenwald, Seng-jaw Soong, Arthur J. Sober, John M. Kirkwood

Anatomy
Primary sites
Regional lymph nodes
Metastatic sites
Rules for classification
Clinical staging
Pathologic staging
Clinical versus pathologic staging
TNM classification
Primary tumor (T)
Regional lymph nodes (N)
Distant metastatic melanoma (M)
Staging recommendations for metastases from unknown primary site
Stage groupings
Data-recording criteria


Models for Predicting Melanoma Outcome; Seng-jaw Soong, Shouluan Ding, Daniel G. Coit, Charles M. Balch

Description of the statistical model
Hazard function
Survival function
Predicting outcome from initial diagnosis for patients with localized melanoma
Hazard function estimation and parametric modeling for localized melanoma
Predicting outcome from initial diagnosis for patients with regional melanoma
Predicting outcome after a disease-free interval in patients with localized melanoma
Clinical applications
Clinical scoring system
Disease management decisions
Patient risk classification
Planning clinical trials
Analysis of clinical studies
Other applications
Screening: Clinical Assessment and Pathology
Melanoma Prevention and Screening; J. Mark Elwood, Jennifer Kay Makin, Craig A. Sinclair, Robert Burton

Prevention of melanoma
Reducing personal exposure: shade, clothing, and sunscreens
Intervention trials of the prevention of skin cancers and related lesions
Behavioral change programs for reducing personal exposure
Vitamin D
Controlling exposure to sunbeds
Prevention of melanoma: recommendations
Screening for melanoma
Uncertainties and conflicts in melanoma screening
Evidence relating to the effectiveness of screening
Programs of screening
Challenges in the detection of progressive melanoma
Clinical Genetics and Risk Assessment of Melanoma; Graham J. Mann, Hensin Tsao

Clinical risk assessment
Baseline risks attributable to age and sex
Previous melanoma or other skin cancer
Multiple melanocytic nevi
Skin and hair color, skin phototype, and freckling
Sun exposure and its surrogates
Family history of melanoma
Genetic risk of melanoma
Mutations in CDKN2A and CDK4 in familial melanoma
Pancreatic cancer and other phenotypes
CDKN2A mutations in sporadic and multiple primary melanoma
Melanoma risk to CDKN2A mutation carriers
Low-penetrance melanoma susceptibility genes
Genetic testing for melanoma risk?
Management of high-risk individuals
The future

Acquired Precursor Lesions and Phenotypic Markers of Increased Risk for Cutaneous Melanoma; Scott W. Menzies, Hensin Tsao, Arthur J. Sober

Pigment phenotype
Constitutive pigmentation (racial)
Hair and eye color
Oculocutaneous albinism
Ephelis (freckle)
Moles
Benign (common) acquired moles (nevi)
Atypical moles
Lentigo maligna

Clinical Characteristics of Melanoma; Allan C. Halpern, Ashfaq A. Marghoob, Arthur J. Sober

Personal history of skin cancer
Clinical presentation
Signs and symptoms
Clinical features
Growth patterns
Clinical assessment
History
Physical examinations
Diagnostic accuracy and aids to diagnosis
New technologies for diagnosis
Image analysis for diagnosis
Multispectral imaging and automated diagnosis
Confocal scanning laser microscopy
Other techniques: ultrasound imaging, magnetic resonance imaging, and optical coherence tomography
Evolving paradigms in the analysis of dermoscopic images
How we analyze images
Biopsy of Suspected Melanomas; Nanette J. Liégeois,Timothy M. Johnson, Arthur J. Sober

Prebiopsy lesion assessment
Biopsy techniques
Excisional biopsy
Incisional biopsy
Fine-needle aspiration
Frozen sections
Biopsy of the nail unit
Biopsy of the mucosa
Pathology of Melanoma; Richard Anthony Scolyer, Martin C. Mihm, Jr., Alistair J. Cochran, Klaus J. Busam, Stanley William McCarthy

Pathologic assessment of melanocytic tumors: goals and expectations
Biopsy techniques for clinically suspicious melanocytic tumors: the hazards of incomplete biopsies
Pathologic examination of the primary melanoma site
Clinical correlation for enhancement of pathologic accuracy
Specimen orientation
Melanoma tumor progression: the concept of radial and vertical growth phases
Clinicopathologic classification of melanoma
Superficial spreading melanoma
Lentigo maligna melanoma
Acrolentiginous melanoma
Nodular melanoma
Histologic features of vertical growth phase melanoma
Predominantly epithelioid cell vertical growth phase
Predominantly spindle cell vertical growth phase
Pitfalls
Mixed spindle cell and epithelioid cell vertical growth phase
Nevoid vertical growth phase (nevoid melanoma)
Prognostication
The melanoma pathology report including a synoptic format
Uncommon melanoma variants
Metastatic melanoma
Fine-needle biopsy in melanoma patients
Clear cell sarcoma (melanoma of soft parts)
Molecular pathology of melanoma
The concept of the cancer stem cell
The metastatic niche concept
Management of Localized Melanoma
Excision of Primary Melanoma; Merrick I. Ross

Excision of primary melanoma: fundamental concepts
Historical perspective and the emergence of a contemporary paradigm
Thin melanoma (T1 and T2; less than 2 mm) excision trials
The Intergroup Melanoma Surgical Trial (T2 and T3 melanomas; 1 to 4 mm)
Thicker melanoma (T3 and T4; greater than 2 mm) excision trials
Current recommendations
Excisions for histologic variants
Techniques for routine wound closure
Excisions for melanomas in unusual or restrictive locations

Complex Closures of Melanoma Excisions; Maurice Y. Nahabedian, Jonathan R. Stretch, Anthony P.Tufaro

Principles of reconstructive surgery
Assessment of the acquired defect
Reconstructive options for complex wounds
Definitions
Undermining with primary closure
Skin grafts
Composite grafts
Local flaps
Regional flaps
Free tissue transfer
Tissue expansion
Complex closures: regional considerations and clinical application
Head and neck
Trunk
Extremities
Surgical salvage for extensive and recurrent melanoma
Local Recurrences of Melanoma and Their Management; Kenneth K.Tanabe, Douglas S. Reintgen, Charles M. Balch

Definition
Mechanisms
Risk factors for local recurrence
Surgical margins and local recurrence
Sentinel node biopsy and local recurrence
Timing of local recurrences
Local recurrence and survival
Management
Mucosal Melanoma; Merrick I. Ross, Michael A. Henderson

Epidemiology
Pathologic features and diagnosis
Staging and prognosis
Mucosal melanomas in the head and neck
Epidemiology
Clinical presentation
Differential diagnosis
Prognosis and natural history
Treatment
Mucosal melanomas in the female genital tract
Vulvar melanoma
Vaginal melanoma
Treatment
Anorectal mucosal melanomas
Clinical and pathologic features
Treatment
Mucosal melanomas at other sites
Urinary tract
Esophagus
Role of radiotherapy
Melanoma in Children and Teenagers; Julie R. Lange, Ira J. Dunkel, Helen M. Shaw, Arthur J. Sober

Epidemiology
Congenital melanoma
Precursors and risk factors
Giant congenital nevi
Small and medium congenital nevi
Xeroderma pigmentosum
Constitutional risk factors
Ultraviolet exposure
Clinical presentation
Diagnosis and surgical management
Medical management
Interferon
Vaccine trials
Chemotherapy
Outcomes
Follow-up and surveillance
Pregnancy and the Use of Hormones in Melanoma Patients; Rona M. MacKie

Nevi and pregnancy
Pregnancy before melanoma
Melanoma before pregnancy
Melanoma during pregnancy
Effect of pregnancy on disease outcome
Transplacental metastases
Treatment of melanoma during pregnancy
Surgery
Adjuvant nonsurgical therapy for pregnant women
Chemotherapy
Oral contraception and melanoma
Use of oral contraception and subsequent risk of melanoma
Use of oral contraceptives after treatment for melanoma
Hormone replacement therapy and melanoma
Appropriate advice on planning pregnancy after treatment for melanoma
In vitro fertilization and melanoma
Management of Regional MetastasesThe Sentinel Lymph Node and Regional Melanoma Micrometastases; Donald L. Morton, Alistair J. Cochran, John F. Thompson, Vernon K. Sondak

The history and conceptual basis of sentinel node biopsy
Anatomic versus functional definitions of the sentinel lymph node
Incubator versus marker theory
Immunology of the sentinel node
Pathobiology of tumor-induced immunosuppression of the sentinel node
Sentinel node biopsy for staging clinically localized melanoma
Interim results of the first Multicenter Selective Lymphadenectomy Trial
Survival
Should lymphatic mapping and sentinel node biopsy be the standard of care for cutaneous melanoma?
LM/SNB increases the chance of remaining disease free
LM/SNB is a superior staging technique for identifying appropriate candidates for adjuvant therapy
No noninvasive staging alternative is available
Early treatment of patients with a positive sentinel node may improve survival
"False-positivity" does not apply to the sentinel node
LM/SNB for melanomas that are not intermediate in thickness
Unresolved issues and ongoing research
The second Multicenter Selective Lymphadenectomy Trial
Carbon particle mapping


Lymphoscintigraphy in Patients with Melanoma; Roger F. Uren, John F. Thompson, Brendon J. Coventry, Barry E. Chatterton

Definition of a sentinel node
Lymphatic mapping of the skin: early studies
Lymphoscintigraphy
The first radiocolloid and early experience with lymphoscintigraphy
Radiopharmaceuticals
99mTc-labeled colloids
99mTc–antimony sulfide colloid
99mTc–rhenium sulfide colloid and 99mTc-albumin nanocolloid
99mTc-sulfur colloid
99mTc–human serum albumin
What is the ideal radiocolloid?
Lymphoscintigraphy for sentinel lymph node biopsy procedures
Lymphoscintigraphy technique
Injecting the tracer
Immediate dynamic imaging
Delayed static imaging
Unexpected lymphatic drainage pathways
Marking the surface location of the sentinel node
Radiation dosimetry: risks to the patient
Radiation dosimetry: risks to the pregnant patient
Radiation dosimetry: risks to attending staff
Patterns of lymphatic drainage from the skin
Trunk
Head and neck
The limbs
Interval nodes
Drainage to multiple node fields
Complex lymphatic drainage patterns
Lymphoscintigraphy in clinically involved node fields
The future
New tracers for lymphatic mapping
Gamma probes for intraoperative detection of radioactivity
Gamma cameras for intraoperative imaging
Alternate methods of lymphatic mapping

Intraoperative Mapping and Sentinel Node Technology in Patients with Melanoma; Jeffrey E. Gershenwald, John F. Thompson, Nicola Mozzillo, Charles M. Balch

Approach to clinically negative regional lymph node basins in patients with early-stage primary cutaneous melanoma
Rationale for lymphatic mapping and sentinel lymph node biopsy
Technique for lymphatic mapping and sentinel lymph node biopsy
Role of sentinel lymph node biopsy in pathologic regional lymph node staging: prognostic value of sentinel lymph node pathologic status
Early results
Prognostic significance
Patterns of failure after negative sentinel lymph node biopsy
Clinical relevance of submicroscopic disease
Ongoing clinical trials of lymphatic mapping and sentinel lymph node biopsy
Technical planning: overall approach
Patient selection
Special situations
Approach to patients after previous wide local excision
Approach to patients with irregular lymphatic drainage patterns
Desmoplastic histology
Complications and morbidity after lymphatic mapping and sentinel lymph node biopsy
Technical considerations: lymphatic mapping and sentinel lymph node biopsy
General operating room positioning strategies
Axillary and Epitrochlear Lymph Node Dissection for Melanoma; Kelly M. McMasters, Sandra L.Wong, Douglas S.Tyler, Charles M. Balch, John F. Thompson

Axillary dissection
Anatomy
Surgical technique
Operative approaches to the upper axilla for recurrent or bulky axillary metastases
Postoperative management
Complications
Epitrochlear dissection
Rationale
Anatomy
Surgical technique

Inguinofemoral, Iliac/Obturator, and Popliteal Lymphadenectomy in Patients with Melanoma; Lisa K. Jacobs, Charles M. Balch, Daniel G. Coit

Inguinofemoral dissection
Indications
Technique
Modifications of the classic technique of inguinofemoral lymphadenectomy
Iliac/obturator (deep pelvic) lymph node dissection
Indications
Benefits
Operative technique
Postoperative complications: incidence and risk factors
Complications of lymph node dissection
Management of postoperative complications
Popliteal dissection
Indications
Operative technique
Neck Dissection and Parotidectomy for Melanoma; Anthony P. Tufaro, Suhail K. Mithani, Joseph A. Califano III, Ashok Shaha

Anatomy
Sublevels
Patterns of metastatic spread and extent of dissection
Neck dissection
Comprehensive neck dissection
Selective neck dissection
Complications
Parotidectomy
Preoperative evaluation
Anesthesia and positioning
Technique
Complications
Clinical outcome
Adjuvant radiotherapy
Recurrent Regional Metastases of Melanoma; Daniel G. Coit, Cristina R. Ferrone

In-transit metastases
Incidence
Treatment
Adjuvant therapy
Prognosis
Recurrent nodal metastases after lymph node dissection
Incidence
Treatment
Prognosis
Adjuvant therapy
Radiotherapy for Primary and Regional Melanoma; Graham Stevens, Bryan Burmeister

Role of radiotherapy in the management of primary melanoma
Adjuvant radiotherapy after surgical excision
Results of curative radiotherapy alone
Radiotherapy for lentigo maligna and lentigo maligna melanoma
Treatment recommendations for the use of radiotherapy in primary melanoma and lentigo maligna
Illustrative cases
Role of radiotherapy in the management of in-transit metastasis
Treatment recommendations for the use of radiotherapy for in-transit melanoma
Illustrative cases
Role of radiotherapy in the management of regional lymph node metastasis
Adjuvant postoperative radiotherapy after regional lymph node dissection
Results of adjuvant radiotherapy after complete lymph node dissection
Adjuvant radiotherapy after limited lymph node dissection
Preoperative radiotherapy for bulky nodal disease
Palliative radiotherapy for unresectable regional nodal disease
Treatment recommendations for the use of radiotherapy in regional nodal metastasis
Adjuvant radiotherapy after complete lymph node dissection
Adjuvant radiotherapy after limited lymph node dissection or no dissection
Therapeutic (palliative) radiotherapy
Illustrative cases
Hyperthermic Regional Perfusion for Melanoma of the Limbs; H. Richard Alexander, Jr., Douglas L. Fraker, Alexander M.M. Eggermont

Epidemiology and natural history
Historical perspective and early clinical series
Technical aspects of isolated limb perfusion
Melphalan
Pharmacokinetics of melphalan in isolated limb perfusion
Other chemotherapeutic agents
Hyperthermia
Tumor necrosis factor
Toxicity of isolated limb perfusion
Adjuvant isolated limb perfusion
Therapeutic limb perfusion
Melphalan alone
Melphalan and tumor necrosis factor
Isolated Limb Infusion for Melanoma; Georgia M. Beasley, Hidde M. Kroon, Merrick I. Ross, Peter C. A. Kam, John F. Thompson, Douglas S. Tyler

Similarities and differences between isolated limb infusion and conventional hyperthermic isolated limb perfusion
Patient selection for isolated limb infusion
Technical details of the isolated limb infusion procedure
Preoperative assessment and management
Insertion and positioning of arterial and venous catheters
Procedure in the operating room
Postoperative care
Pharmacokinetics of melphalan
Use of microdialysis to monitor drug concentrations in limb tissues and tumor deposits during isolated limb infusion
Limb and systemic toxicity after isolated limb infusion
Factors predicting toxicity after isolated limb infusion
Clinical results of isolated limb infusion
Factors predicting outcome after isolated limb infusion
Limb temperatures during isolated limb infusion
Tourniquet times
Interpretation of prognostic factors data
Repeat isolated limb infusion for disease progression after initial isolated limb infusion
Comparison with hyperthermic isolated limb perfusion
Laboratory studies of isolated limb infusion
Potential use of the isolated limb infusion technique to evaluate other drugs and biologic agents

Diagnosis and Local Treatment of Distant MetastasesMetastatic Surveillance and Follow-up of Melanoma Patients; Julie R. Lange, Axel Hauschild, Anne Brecht Francken

Goals of surveillance
Patterns of melanoma recurrence
Risk of local and regional recurrence
Time to recurrence
Strategies for active follow-up of melanoma patients
Detection of recurrences
Role of physical examination
Patient education
Patient well-being and follow-up
Follow-up schedules
Radiologic studies and laboratory tests
Screening for risk of new primary melanomas
Screening for other primary cancers
Current recommendations for surveillance
Diagnosis of Stage IV Melanoma; Michael B. Atkins, Axel Hauschild, Richard L.Wahl, Charles M. Balch

Timing of distant metastasis
Pattern of metastasis
Prognosis and prognostic factors
Sites of distant metastases
Number of metastatic sites
Elevated serum lactate dehydrogenase
Duration of remission
Performance status
Other prognostic factors
Clinical evaluation of metastasis
History and physical examination
Laboratory tests/biomarkers
Radiologic tests
Pathologic tests
Sites of distant metastases
Skin, subcutaneous tissues, and distant lymph nodes
Lung, pleura, and mediastinum
Brain and spinal cord
Gastrointestinal tract
Liver, biliary tract, and spleen
Bone
Kidneys and urinary tract
Heart and pericardium
Pancreas
Peritoneum and mesentery
Endocrine organs
Breast
Ovaries, uterus, and placenta
Testes and penis
Oral cavity, pharynx, and larynx
Eye and orbit
Cutaneous melanosis
Metastatic melanoma from an unknown primary site
Surveillance in patients who have localized melanoma
Surgical Excision of Distant Melanoma Metastases; John F. Thompson, Donald L. Morton, Charles M. Balch, Merrick I. Ross

Current status of surgery for stage IV melanoma
Relationships between tumor burden, immune function, and surgical treatment
Selection of patients and prognostic factors
Outcomes after surgical resection of melanoma metastases at specific sites
Skin, subcutaneous tissue, and lymph nodes
Lung, trachea, and bronchi
Brain and spinal cord
Gastrointestinal tract
Liver, biliary tract, and spleen
Bone
Kidney and urinary tract
Heart and pericardium
Endocrine organs
Breast
Ovaries, uterus, and vagina
Testes and penis
Oral cavity and pharynx
Eye and orbit
Radiotherapy for Distant Metastases and Clinical Radiobiology of Melanoma; Graham Stevens, Angela Hong, Michael J. McKay

Radiotherapy for distant metastases
Skin and subcutaneous metastases
Lymph node metastases
Brain metastases
Malignant spinal cord compression
Bone metastases
Sites irradiated less commonly
Developing sites for focused radiation treatment
Illustrative cases
Clinical radiobiology of melanoma
Biologic factors affecting the ionizing radiation response of melanoma
Intrinsic cellular radiosensitivity
Tumor oxygenation and microenvironmental
Factors
Tumor cell proliferation kinetics
Number of clonogenic tumor cells
Influence of melanization on radiosensitivity
Host factors in melanoma response and outcome
Future possibilities
Methods to improve the response of melanoma cells
Methods to improve the delivery of radiation to melanoma metastases
Multidisciplinary Management of CNS Melanoma Metastases; Kim A. Margolin, George M. Cannon, Minesh P. Mehta, Michael Y. Chen

Risk factors and prognosis
Clinical features
Neurosurgical management of brain metastasis
Radiotherapeutic and radiosurgical management of melanoma metastatic to the brain or spine
Whole-brain radiotherapy
Whole-brain radiotherapy alone
Surgery followed by whole-brain radiotherapy
Stereotactic radiosurgery
Systemic therapy for melanoma metastatic to the central nervous system
Systemic therapy considerations after adequate control of the central nervous system
Palliative approach
Aggressive approach
Investigational approach
Systemic Treatment of Metastatic DiseaseAdjuvant Systemic Therapy for High-Risk Melanoma Patients; John M. Kirkwood, Vernon K. Sondak, Peter Hersey, Helen Gogas

Who should be considered for adjuvant therapy?
Chemotherapy alone or in multiagent combinations as adjuvant therapy for melanoma
Microbial immunostimulants
Bacillus Calmette-Guérin
Corynebacterium parvumLevamisole
Hormonal therapy
Melanoma vaccines tested in phase III adjuvant trials
Adjuvant interferons as postoperative adjuvant therapy for melanoma
Adjuvant applications of interferon-alpha-2
Adjuvant applications of interferon-gamma
Emerging new modalities of adjuvant therapy
Biomarkers of prognosis and response
Chemotherapy-Based Treatment of Metastatic Melanoma; Michael B. Atkins, Mark R. Middleton, Paul B. Chapman

Single-agent chemotherapy
Dacarbazine and temozolomide
Nitrosoureas
Platinums
Microtubule toxins
Combination cytotoxic chemotherapy
Nitrosourea combinations
Taxane-based combination therapy
Cisplatin-based combination therapy
Chemohormonal therapy
Biochemotherapy
Interferon alpha–based biochemotherapy regimens
Interleukin-2–based regimens
Interleukin-2 and DTIC/temozolomide combinations
Cisplatin and interleukin-2–based biochemotherapy regimens
Inpatient concurrent biochemotherapy regimens
Phase III biochemotherapy trials
Other biochemotherapy investigations
Non–interleukin-2 or interferon-based biochemotherapy combinations
Chemotherapy and antiangiogenic or targeted therapy
Antiangiogenic agents
Antiapoptosis-inducing agents
Selection of future phase III trials
Interferon Therapy for Melanoma; Ernest C. Borden, Stergios J. Moschos, John M. Kirkwood

Endogenous interferons as part of the host response to cancer
The family of interferon proteins and signaling activation
Mechanisms of antitumor action in melanoma
Signaling by interferons
Cellular mechanisms of action of interferons
Interferon-alpha-2 in the treatment of melanoma
The future of interferons in melanoma biology and therapy

Interleukins and Cellular Therapies for Melanoma; Douglas J. Schwartzentruber

Pharmacology of interleukin-2
Immunologic activity of interleukin-2
Systemic effects of interleukin-2
Clinical efficacy of high-dose interleukin-2 alone
Clinical efficacy of alternate doses, routes, and schedules of interleukin-2 alone
Clinical efficacy of interleukin-2 combined with interferon-alpha
Clinical efficacy of interleukin-2 combined with other cytokines, immune modulators, antibodies, or vaccines
Agents to reduce the toxicity of interleukin-2
Predictors of clinical response
Other cytokines for treatment of metastatic melanoma
Clinical efficacy of interleukin-2 combined with cellular therapy
Melanoma Vaccines; Jedd D.Wolchok, Jeffrey S.Weber

Tumor immunology
Antigen discovery
Adjuvants
Vaccine approaches
Cell vaccines
Transduced cell vaccines
HLA-restricted melanoma-associated antigenic peptides
Ganglioside vaccines
Antiidiotypic monoclonal antibodies mimicking ganglioside antigens
Protein antigens
Heat-shock protein–based vaccines
DNA vaccination
Dendritic cell vaccines
Recombinant viral vaccines
Combination strategies and the future of melanoma vaccines
Immune Modulators in the Treatment of Patients with Melanoma; James P. Allison, F. Stephen Hodi, Yvonne M. Saenger, Jedd D. Wolchok

Biology of CTLA-4–mediated immune inhibition
Preclinical development of anti-CTLA-4 as an anticancer agent
Anti-CTLA-4: clinical experience in melanoma
Efficacy of CTLA-4 blockade: summary of clinical trials to date
CTLA-4 blockade and immune-related adverse events
Kinetics of response
Patient selection and predictors of toxicity and antitumor response
Dose and schedule of anti-CTLA-4 administration
Correlative immunologic studies
Vaccination strategies in combination with CTLA-4 blockade
Combination of CTLA-4 blockade and GM-CSF vaccination in murine models
Clinical investigation of combination CTLA-4 blockade and autologous GM-CSF–secreting tumor vaccination
CTLA-4 blockade with peptide vaccines
Other CTLA-4 antibody and immunotherapy combinations
Melanoma-Specific Targeted Therapies; Paul B. Chapman, David B. Solit, Keith T. Flaherty

Targeting cell surface molecules
Targeting receptor tyrosine kinases expressed in melanoma
Monoclonal antibodies
Targeting intracellular molecules
The mitogen-activated protein kinase pathway in melanoma
Drugs that inhibit BRAF
Hsp90 inhibitors
Drugs that inhibit MEK
Targeting PI3/AKT pathway
Angiogenesis inhibition in melanoma
Biology of MelanomaGenetics and Molecular Pathology of Melanoma; Boris C. Bastian, Daniel Pinkel, Amaya Viros

Distinct patterns of epidemiologic, clinical, and histopathologic features in melanoma
Emerging melanoma subtypes based on genotypephenotype correlations
Melanomas on sun-exposed sites
Melanomas on relatively or absolutely UV-protected sites
Melanocytic tumors arising without associations to epithelial structures

Biology of Melanocytes and Primary Melanoma; Glenn Merlino, Vincent J. Hearing

Development of melanoblasts
Regulation of specification
Regulation of migration
Regulation of survival and proliferation
Differentiation of melanocytes
Regulation of differentiation
Regulation of survival
Melanomagenesis
From melanocyte to melanoma: a multistep process
Molecular genetics: early lessons from familial and sporadic melanoma
Melanoma: a consequence of homeostatic disruption
Melanoma: cell of origin
Melanoma and the environment
Sun exposure and epidemiology
Photobiology and melanoma
Biology of Melanoma Metastasis; Menashe Bar-Eli, Isaiah J. Fidler

The pathogenesis of melanoma metastasis
Transcriptional regulation of melanoma progression
Role of AP-2-α in melanoma progression
Role of CREB/ATF-1 in melanoma progression
Involvement of ATF-2 in melanoma progression
SNAIL: its regulatory pathway in melanoma
MITF: its role in melanoma progression
Regulation of melanoma metastasis by the tumor microenvironment
Role of platelet-activating factor receptor
Potential therapeutic approaches to inhibiting melanoma metastasis
Using fully humanized antibodies to MCAM/MUC18 to inhibit tumor growth and metastasis of human melanoma
Using fully humanized neutralizing antibodies to interleukin-8 (ABX-IL-8) to inhibit angiogenesis, tumor growth, and metastasis of human melanoma

Immunology of Melanoma; Suzanne L.Topalian, Lieping Chen, Janis M.Taube, Paul F. Robbins, Jedd D.Wolchok, Alan N. Houghton

Innate immunity
Adaptive immunity
Melanoma antigens
General principles for identification of tumor antigens recognized by T cells and antibodies
Nonmutated self-antigens
Mutant melanoma antigens
Altered peptide ligands: enhancing the immunogenicity of low-affinity melanoma epitopes
Experimental models
Immune regulation and tolerance
Costimulatory/coinhibitory receptors
Regulatory T cells
Cytokines
Implications for immunotherapy
Biomarkers for Melanoma; Elizabeth A. Grimm, Dave S.B. Hoon, Lyn McDivitt Duncan

Potential clinical impact of melanoma biomarkers
Melanoma heterogeneity
Melanoma biomarker discovery and validation process
Biomarkers in early-stage melanoma
Molecular markers in primary cutaneous melanoma
Biomarkers for later-stage melanoma
Molecular markers in sentinel lymph nodes
Molecular markers in blood
Molecular markers in metastatic tumors

Additional Credits
Index