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Melanoma: HELP
Articles by Timothy M. Johnson
Based on 50 articles published since 2008
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Between 2008 and 2019, T. M. Johnson wrote the following 50 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Guidelines of care for the management of primary cutaneous melanoma. 2019

Swetter, Susan M / Tsao, Hensin / Bichakjian, Christopher K / Curiel-Lewandrowski, Clara / Elder, David E / Gershenwald, Jeffrey E / Guild, Valerie / Grant-Kels, Jane M / Halpern, Allan C / Johnson, Timothy M / Sober, Arthur J / Thompson, John A / Wisco, Oliver J / Wyatt, Samantha / Hu, Shasa / Lamina, Toyin. ·Department of Dermatology, Stanford University Medical Center and Cancer Institute, Stanford, California; Veterans Affairs Palo Alto Health Care System, Palo Alto, California. Electronic address: sswetter@stanford.edu. · Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Wellman Center for Photomedicine, Boston, Massachusetts. · Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan; Comprehensive Cancer Center, Ann Arbor, Michigan. · Division of Dermatology, University of Arizona, Tucson, Arizona; University of Arizona Cancer Center, Tucson, Arizona. · Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. · AIM at Melanoma Foundation, Plano, Texas. · Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut; Department of Pathology, University of Connecticut Health Center, Farmington, Connecticut; Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut. · Department of Dermatology, Memorial Sloan-Kettering Cancer Center, New York, New York. · Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Oncology, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington. · Department of Dermatology, Oregon Health and Science University, Portland, Oregon. · Decatur Dermatology, Decatur, Alabama. · Department of Dermatology, University of Miami Health System, Miami, Florida. · American Academy of Dermatology, Rosemont, Illinois. ·J Am Acad Dermatol · Pubmed #30392755.

ABSTRACT: The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.

2 Guideline Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. 2011

Bichakjian, Christopher K / Halpern, Allan C / Johnson, Timothy M / Foote Hood, Antoinette / Grichnik, James M / Swetter, Susan M / Tsao, Hensin / Barbosa, Victoria Holloway / Chuang, Tsu-Yi / Duvic, Madeleine / Ho, Vincent C / Sober, Arthur J / Beutner, Karl R / Bhushan, Reva / Smith Begolka, Wendy / Anonymous6410703. ·Department of Dermatology, University of Michigan Health System and Comprehensive Cancer Center, Ann Arbor, Michigan, USA. ·J Am Acad Dermatol · Pubmed #21868127.

ABSTRACT: The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

3 Editorial Guidelines of care for the management of primary cutaneous melanoma. 2013

Johnson, Timothy M. ·Departments of Dermatology, Otolaryngology, and Surgery (Division of Plastic Surgery), University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, Michigan. Electronic address: timjohn@med.umich.edu. ·J Am Acad Dermatol · Pubmed #24238159.

ABSTRACT: -- No abstract --

4 Review Contemporary Management of Early-Stage Melanoma: A Systematic Review. 2017

Rosko, Andrew J / Vankoevering, Kyle K / McLean, Scott A / Johnson, Timothy M / Moyer, Jeffrey S. ·Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor. · Department of Dermatology, University of Michigan, Ann Arbor. ·JAMA Facial Plast Surg · Pubmed #28114438.

ABSTRACT: Importance: The incidence of melanoma is increasing, with 76 380 new cases of invasive melanoma and 68 480 new cases of melanoma in situ expected in 2016. Objective: To review the contemporary management of early-stage melanoma. Evidence Review: We searched PubMed, MEDLINE, and the Cochrane Database of Systematic Reviews databases from January 1, 2011, to May 1, 2016, yielding 966 articles. We focused our search on early-stage (melanoma in situ, stage I, and stage II) cutaneous melanoma. After excluding articles, 41 articles were manually reviewed. A review of the bibliographies of selected articles generated additional references. Findings: While the majority of recent advances have been in the treatment of advanced melanoma, surgical excision with margins based on the presence and depth of invasion continues to be the cornerstone of management. Sentinel lymph node biopsy plays a central role in the staging and treatment of melanoma. Conclusions and Relevance: Accurate diagnosis and adequate surgical excision are critical in reducing local recurrences and improving outcomes. Sentinel lymph node biopsy is useful in staging the regional nodal basin and guiding treatment in appropriately selected patients.

5 Article Subungual atypical lentiginous melanocytic proliferations in children and adolescents: A clinicopathologic study. 2018

Khatri, Sameer S / Wang, Min / Harms, Kelly L / Durham, Alison B / Johnson, Timothy M / Nazarian, Rosalynn M / Harms, Paul W / Fullen, Douglas R / Andea, Aleodor A / Chan, May P. ·Department of Pathology, University of Michigan, Ann Arbor, Michigan. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan; Department of Otolaryngology, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan. · Pathology Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, University of Michigan, Ann Arbor, Michigan; Department of Dermatology, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, University of Michigan, Ann Arbor, Michigan; Department of Dermatology, University of Michigan, Ann Arbor, Michigan. Electronic address: mpchan@med.umich.edu. ·J Am Acad Dermatol · Pubmed #29601937.

ABSTRACT: BACKGROUND: Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia. OBJECTIVE: To characterize the clinicopathologic features of these rare lesions. METHODS: Subungual atypical lentiginous melanocytic proliferations from patients <20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible. RESULTS: Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome. LIMITATIONS: Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only. CONCLUSION: Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.

6 Article Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA. 2017

Hosono, Yasuyuki / Niknafs, Yashar S / Prensner, John R / Iyer, Matthew K / Dhanasekaran, Saravana M / Mehra, Rohit / Pitchiaya, Sethuramasundaram / Tien, Jean / Escara-Wilke, June / Poliakov, Anton / Chu, Shih-Chun / Saleh, Sahal / Sankar, Keerthana / Su, Fengyun / Guo, Shuling / Qiao, Yuanyuan / Freier, Susan M / Bui, Huynh-Hoa / Cao, Xuhong / Malik, Rohit / Johnson, Timothy M / Beer, David G / Feng, Felix Y / Zhou, Weibin / Chinnaiyan, Arul M. ·Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA. · Department of Urology, University of Michigan, Ann Arbor, MI, USA. · Ionis Pharmaceuticals, Carlsbad, CA, USA. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. · Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. · Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA. · Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu. ·Cell · Pubmed #29245011.

ABSTRACT: Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.

7 Article The natural history of thin melanoma and the utility of sentinel lymph node biopsy. 2017

Durham, Alison B / Schwartz, Jennifer L / Lowe, Lori / Zhao, Lili / Johnson, Andrew G / Harms, Kelly L / Bichakjian, Christopher K / Orsini, Amy P / McLean, Scott A / Bradford, Carol R / Cohen, Mark S / Johnson, Timothy M / Sabel, Michael S / Wong, Sandra L. ·Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan. · Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan. · Department of Biostatistics, University of Michigan Health System, Ann Arbor, Michigan. · University of Michigan Medical School, Ann Arbor, Michigan. · Department of Otolaryngology - Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan. · Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan. · Department of Surgery, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. ·J Surg Oncol · Pubmed #28715140.

ABSTRACT: BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm

8 Article Total versus superficial parotidectomy for stage III melanoma. 2017

Wertz, Aileen P / Durham, Alison B / Malloy, Kelly M / Johnson, Timothy M / Bradford, Carol R / McLean, Scott A. ·Department of Otolaryngology - Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan. · Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan. ·Head Neck · Pubmed #28481438.

ABSTRACT: BACKGROUND: The primary purpose of this study was to describe the parotid recurrence rates after superficial and total parotidectomy. METHODS: A retrospective cohort study was performed on patients with cutaneous melanoma metastatic to the parotid gland who underwent parotidectomy from 1998 through 2014. Primary outcome was parotid bed recurrence. Secondary outcomes were facial nerve function postoperatively and at last follow-up. RESULTS: One hundred twenty-nine patients were included in the study. Thirty-four patients (26%) underwent a total parotidectomy and 95 patients underwent superficial parotidectomy. Twelve patients (13%) developed parotid bed recurrence after superficial parotidectomy alone versus zero after total parotidectomy (P = .035). Facial nerve function, clinically detected disease, stage, and adjuvant treatment were not statistically different between the groups (P = .32, .32, .13, and 0.99, respectively). CONCLUSION: Parotid bed melanoma recurrence was more common after superficial parotidectomy compared to total parotidectomy, and recurrence resulted in significant facial nerve functional deficit. Our results support total parotidectomy when metastatic melanoma involves the parotid nodal basin.

9 Article Detection of Occult Invasion in Melanoma in Situ-Reply. 2017

Chan, May P / Fullen, Douglas R / Johnson, Timothy M. ·Department of Dermatology, University of Michigan, Ann Arbor2Department of Pathology, University of Michigan, Ann Arbor. · Department of Dermatology, University of Michigan, Ann Arbor3Division of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor4Department of Otolaryngology, University of Michigan, Ann Arbor. ·JAMA Dermatol · Pubmed #28384696.

ABSTRACT: -- No abstract --

10 Article Efficacy of Staged Excision With Permanent Section Margin Control for Cutaneous Head and Neck Melanoma. 2017

Moyer, Jeffrey S / Rudy, Shannon / Boonstra, Philip S / Kraft, Casey / Chinn, Steven B / Baker, Shan R / Schwartz, Jennifer L / Bichakjian, Christopher K / Fullen, Douglas / Durham, Alison B / Lowe, Lori / Johnson, Timothy M. ·Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor. · Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor. · Department of Dermatology, University of Michigan Medical School, Ann Arbor. · Department of Dermatology, University of Michigan Medical School, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor. · Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor3Department of Dermatology, University of Michigan Medical School, Ann Arbor5Division of Plastic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor. ·JAMA Dermatol · Pubmed #28002553.

ABSTRACT: Importance: Melanoma arising in chronically photodamaged skin, especially on the head and neck, is often characterized by poorly defined clinical margins and unpredictable occult extension. Staged excision techniques have been described to treat these challenging melanomas. Objective: To investigate the local recurrence rates and margin to clearance end points using staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control. Design, Setting, and Participants: In this observational cohort study performed from October 8, 1997, to December 31, 2006, with a median follow-up of 9.3 years, 806 patients with melanoma on the head and neck, where clinical occult extension is common, were studied at an academic medical center. Interventions: Staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control commonly known as the square technique. Main Outcomes and Measures: Local recurrence rates and margin to clearance end points. Results: A total of 806 patients (276 women [34.2%]; 805 white [99.9%]) with a median age at the time of first staged excision procedure of 65 years (range, 20-94 years) participated in the study. The estimated local recurrence rates were 1.4% at 5 years, 1.8% at 7.5 years, and 2.2% at 10 years. For each 50-mm2 increase in the size of the clinical lesion, there was a 9% increase in the rate of local recurrence (hazard ratio, 1.09; 95% CI, 1.02-1.15; P = .02). The mean (SD) margin from lesion to clearance for melanoma in situ was 9.3 (5.1) mm compared with 13.7 (5.9) mm for invasive melanoma. For melanoma in situ, margins were clear after 5 mm or less in 232 excisions (41.1%) and after 10 mm or less in 420 excisions (74.5%). For invasive melanoma, margins were clear after 5 mm or less in 8 excisions (3.0%) and after 10 mm or less in 141 excisions (52.2%). Conclusions and Relevance: Staged excision with comprehensive permanent section margin control of melanomas arising in chronically sun-damaged skin on the head and neck has favorable recurrence rates when melanoma margins are difficult to assess, and recurrence rates are high with traditional techniques.

11 Article Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. 2016

Eskiocak, Ugur / Ramesh, Vijayashree / Gill, Jennifer G / Zhao, Zhiyu / Yuan, Stacy W / Wang, Meng / Vandergriff, Travis / Shackleton, Mark / Quintana, Elsa / Johnson, Timothy M / DeBerardinis, Ralph J / Morrison, Sean J. ·Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA. · Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. · Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia. · Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. · Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas Texas 75390, USA. ·Nat Commun · Pubmed #27545456.

ABSTRACT: New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.

12 Article Detection of Occult Invasion in Melanoma In Situ. 2016

Bax, Michael J / Johnson, Timothy M / Harms, Paul W / Schwartz, Jennifer L / Zhao, Lili / Fullen, Douglas R / Chan, May P. ·Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor. · Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor2Department of Otolaryngology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor3Division of Plastic Surgery, Department of Surgery, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor. · Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor4Department of Pathology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor. · Department of Biostatistics, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor. ·JAMA Dermatol · Pubmed #27533878.

ABSTRACT: Importance: It is unclear why some patients with in situ melanoma develop metastases. Few reports demonstrate occult invasion with immunohistochemistry staining, which were discordant with reports interpreting such staining as false-positive. Objective: To investigate the occurrence of occult invasive disease within in situ melanoma by using methods to circumvent potential limitations in prior study designs. Design, Setting, and Participants: Unequivocal in situ melanoma without associated nevi or regression was identified using a consecutive sample of 33 cases plus 1 index case in an academic medical center. After cutting deeper into the most representative tissue block, 3 sequential slides were stained with hematoxylin-eosin (H-E), melanoma antigen (melan-A), and again with H-E. Melan-A-stained slides showing definitive invasion were double-stained with Sry-related HMg-Box gene 10 (SOX10) to confirm the melanocytic nature of the cells of interest. The study evaluated the possibilities of occult invasion detected by immunohistochemistry, sectioning deeper into the tissue block, or both. Slides were independently scored by 3 dermatopathologists with interrater reliability assessed. The study was conducted from January 1, 2012, to July 31, 2014. Main Outcomes and Measures: Assessment of the occurrence of occult invasion, diagnosis of invasion by immunohistochemistry alone vs cutting deeper into the tissue block, and occurrence of false-positive results using immunohistochemistry alone. Results: Occult invasive melanoma was detected in 11 of 33 consecutive cases (33%) of previously diagnosed unequivocal in situ melanoma. Six of 11 melanomas (55%) were diagnosable only by immunohistochemistry. The remaining 5 tumors (45%) were diagnosable by both melan-A and H-E staining, likely as a result of simply cutting deeper into the tissue block. Four cases (12%) showed a few melan-A-positive cells in the dermis, which was insufficient for a diagnosis of invasive melanoma and most consistent on a cytomorphologic basis with occult nevi. Conclusions and Relevance: Although rare, in situ melanoma may metastasize. Occult microinvasion was demonstrated in up to one-third of the specimens in the present study, which provides a plausible explanation for this adverse event. Thus, history and physical examination including regional lymph nodes, education, and surveillance recommendations should be based on a very low, but not zero, risk of metastasis.

13 Article Association of nevus count with prevention attitudes and behaviors before melanoma diagnosis. 2016

Mayer, Jonathan E / Swetter, Susan M / Miller, Donald R / Sober, Arthur J / Johnson, Timothy M / Geller, Alan C. ·aDepartment of Medicine, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland bDepartment of Dermatology, Stanford University Medical Center and Cancer Institute, Stanford cVeterans Affairs Palo Alto Health Care System, Palo Alto, California dDepartment of Health Policy and Management, Boston University School of Public Health eDepartment of Dermatology, Massachusetts General Hospital fDepartment of Dermatology, Harvard Medical School gDepartment of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts hDepartment of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. ·Melanoma Res · Pubmed #27387129.

ABSTRACT: Although melanoma risk factors are commonly known to healthcare professionals, the extent to which the at-risk public is either aware of these factors or perceives their risk accordingly has rarely been studied. We sought to investigate whether the presence of known melanoma risk factors, such as high total nevus and atypical nevus counts, was associated with increased prevention attitudes and behaviors, such as skin self-examinations and physician skin examinations. This was a retrospective study of 566 individuals recently diagnosed with melanoma in two large academic centers. Most prevention attitudes and behaviors did not vary on the basis of total nevi or atypical nevi counts. However, younger patients (<60 years) with many total nevi (>50) were more likely than those with fewer nevi (<20) to believe that they were at-risk for melanoma (42 vs. 23%; P<0.05), and more likely to state that they had been instructed on the signs of melanoma (36 vs. 21%; P<0.05). Patient and health provider recognition of the impact of nevus count on melanoma risk presents a unique and mostly untapped opportunity for earlier detection.

14 Article Total Nevi, Atypical Nevi, and Melanoma Thickness: An Analysis of 566 Patients at 2 US Centers. 2016

Geller, Alan C / Mayer, Jonathan E / Sober, Arthur J / Miller, Donald R / Argenziano, Giuseppe / Johnson, Timothy M / Swetter, Susan M. ·Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Department of Medicine, Johns Hopkins Bayview Medical Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Dermatology, Massachusetts General Hospital, Boston. · Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts. · Dermatology Unit, Second University of Naples, Naples, Italy. · Department of Dermatology, University of Michigan, Ann Arbor. · Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California8Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center and Cancer Institute, Stanford, California. ·JAMA Dermatol · Pubmed #26934430.

ABSTRACT: IMPORTANCE: Nevi are among the strongest risk factors for melanoma. However, little is known about the association of many total nevi (TN) or atypical nevi (AN) with tumor thickness. OBJECTIVES: To examine the association between age and the number of TN and AN and to explore whether there was a relationship between TN or AN and tumor thickness, controlling for multiple variables. DESIGN, SETTING, AND PARTICIPANTS: Survey of patients with melanoma at 2 academic sites and an affiliated Veteran Affairs medical center. Participants included 566 patients surveyed within 3 months of diagnosis. Patients were surveyed in the melanoma clinics from May 17, 2006, through March 31, 2009, within 3 months of diagnostic biopsy. The dates of the analysis were April 1, 2015, to August 1, 2015. MAIN OUTCOMES AND MEASURES: Counts of TN and AN were performed at the first visit after diagnosis and were categorized as 0 to 20, 20 to 50, or more than 50 for TN and as 0, 1 to 5, or more than 5 for AN. Tumor thickness was categorized as 2.00 mm or less or as 2.01 mm or greater. All analyses were stratified by patient age (<60 or ≥60 years). Logistic regression was used to test associations, controlling for age, sex, anatomic location of melanoma, institution, histologic subtype, marital status, performance of skin self-examination, number of health care visits in the past year, mode of melanoma discovery, and receipt of skin examination by a physician. RESULTS: The study population included 566 patients. Their mean (SD) age was 56.7 (15.9) years, and 39.0% (n = 221) were female. Of 566 patients, the number of TN was classified as 0 to 20 (66.4% [n = 376]), 20 to 50 (20.5% [n = 116]), or more than 50 (13.1% [n = 74]). Atypical nevus counts were 0 (73.3% [n = 415]), 1 to 5 (14.5% [n = 82]), or more than 5 (12.2% [n = 69]). For those younger than 60 years, the presence of more than 50 TN was associated with a sharply reduced risk of thick melanoma (odds ratio, 0.32; 95% CI, 0.12-0.81), and the presence of more than 5 AN compared with no AN was associated with thicker melanoma (odds ratio, 2.43; 95% CI, 1.02-5.75). CONCLUSIONS AND RELEVANCE: Most patients with melanoma had few nevi and no AN. In younger patients (<60 years), thick melanomas were commonly found in those with fewer TN but more AN, suggesting that physicians and patients should not rely on the total nevus count as a sole reason to perform skin examinations or to determine a patient's at-risk status. Younger patients should be educated on the increased risk of thicker melanomas that is associated with having more AN.

15 Article Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. 2016

Chan, May P / Andea, Aleodor A / Harms, Paul W / Durham, Alison B / Patel, Rajiv M / Wang, Min / Robichaud, Patrick / Fisher, Gary J / Johnson, Timothy M / Fullen, Douglas R. ·Department of Pathology, University of Michigan, Ann Arbor, MI, USA. · Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. ·Mod Pathol · Pubmed #26743478.

ABSTRACT: Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.

16 Article Oxidative stress inhibits distant metastasis by human melanoma cells. 2015

Piskounova, Elena / Agathocleous, Michalis / Murphy, Malea M / Hu, Zeping / Huddlestun, Sara E / Zhao, Zhiyu / Leitch, A Marilyn / Johnson, Timothy M / DeBerardinis, Ralph J / Morrison, Sean J. ·Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. · Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ·Nature · Pubmed #26466563.

ABSTRACT: Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

17 Article Sentinel Lymph Node Biopsy Use Among Melanoma Patients 75 Years of Age and Older. 2015

Sabel, Michael S / Kozminski, David / Griffith, Kent / Chang, Alfred E / Johnson, Timothy M / Wong, Sandra. ·Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA, msabel@med.umich.edu. ·Ann Surg Oncol · Pubmed #25834993.

ABSTRACT: INTRODUCTION: While SLN biopsy is recommended for melanoma ≥1 mm in depth, its use among the elderly population is more controversial. We reviewed our experience at the University of Michigan with melanoma patients ≥75 years of age. METHODS: A total of 952 melanoma patients ≥75 years of age from 1996 to 2011 were identified from our institutional review board-approved database. In addition to clinicopathologic features and outcome data, comorbidity data were collected to calculate the Charlson comorbidity index (CCI). Univariate and multivariate Cox regression analysis was performed to characterize predictors of outcome. Kaplan-Meier analysis was used to generate survival curves. RESULTS: Among 553 clinically node-negative patients with melanoma ≥1 mm in Breslow thickness, 213 had wide excision alone, whereas 340 had excision and SLN biopsy, with 83 (24 %) having a positive SLN. SLN biopsy was less likely with older age (p < 0.0001) and H&N location (p = 0.007), but not CCI. SLN involvement was associated with female gender [odds ratio (OR) 2.15, p = 0.009], Breslow thickness [OR 1.23/mm increase, p = 0.004], and satellitosis (OR 4.43, p = 0.004). Distant disease-specific survival was negatively associated with male gender (OR 1.5, p = 0.007), increasing age (OR 1.05/year, p < 0.001), increasing Breslow thickness (OR 1.07/year, p = 0.013), ulceration (OR 1.51, p = 0.004), a positive SLN (OR 2.61, p < 0.001), and not having a SLN biopsy (OR 1.72, p < 0.001). CCI did not predict worse disease-free or melanoma-specific survival. CONCLUSIONS: WLE and SLN biopsy was not only strongly prognostic, but compared with WLE alone was associated with improved outcome, even after factoring for age and comorbidities. If otherwise healthy, SLN biopsy should be strongly considered for this population.

18 Article Discordance in histopathologic evaluation of melanoma sentinel lymph node biopsy with clinical follow-up: results from a prospectively collected database. 2014

Dandekar, Monisha / Lowe, Lori / Fullen, Douglas R / Johnson, Timothy M / Sabel, Michael S / Wong, Sandra L / Patel, Rajiv M. ·Department of Pathology, Tufts University School of Medicine, Boston, MA, USA. ·Ann Surg Oncol · Pubmed #24845727.

ABSTRACT: BACKGROUND: Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. METHODS: A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. RESULTS: After internal review of the SLN material, 13 (8 %) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. CONCLUSIONS: There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.

19 Article Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. 2014

Balch, Charles M / Thompson, John F / Gershenwald, Jeffrey E / Soong, Seng-Jaw / Ding, Shouluan / McMasters, Kelly M / Coit, Daniel G / Eggermont, Alexander M M / Gimotty, Phyllis A / Johnson, Timothy M / Kirkwood, John M / Leong, Stanley P / Ross, Merrick I / Byrd, David R / Cochran, Alistair J / Mihm, Martin C / Morton, Donald L / Atkins, Michael B / Flaherty, Keith T / Sondak, Vernon K. ·Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA, balch@asoeditorial.org. ·Ann Surg Oncol · Pubmed #24531700.

ABSTRACT: PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

20 Article Age as a prognostic factor in patients with localized melanoma and regional metastases. 2013

Balch, Charles M / Soong, Seng-jaw / Gershenwald, Jeffrey E / Thompson, John F / Coit, Daniel G / Atkins, Michael B / Ding, Shouluan / Cochran, Alistair J / Eggermont, Alexander M M / Flaherty, Keith T / Gimotty, Phyllis A / Johnson, Timothy M / Kirkwood, John M / Leong, Stanley P / McMasters, Kelly M / Mihm, Martin C / Morton, Donald L / Ross, Merrick I / Sondak, Vernon K. ·Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA, charles.balch@utsouthwestern.edu. ·Ann Surg Oncol · Pubmed #23838920.

ABSTRACT: BACKGROUND: We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. MATERIALS AND METHODS: The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. RESULTS: With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. CONCLUSIONS: Melanomas in patients at the extremes of age have a distinct natural history.

21 Article Transcriptome profiling identifies HMGA2 as a biomarker of melanoma progression and prognosis. 2013

Raskin, Leon / Fullen, Douglas R / Giordano, Thomas J / Thomas, Dafydd G / Frohm, Marcus L / Cha, Kelly B / Ahn, Jaeil / Mukherjee, Bhramar / Johnson, Timothy M / Gruber, Stephen B. ·Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, USA. Electronic address: leonid.raskin@vanderbilt.edu. · Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA. · Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA. · Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA. · Department of Biostatistics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA. · Department of Internal Medicine, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Epidemiology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Human Genetics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. ·J Invest Dermatol · Pubmed #23633021.

ABSTRACT: The genetic alterations contributing to melanoma pathogenesis are incompletely defined, and few independent prognostic features have been identified beyond the clinicopathological characteristics of the primary tumor. We used transcriptome profiling of 46 primary melanomas, 12 melanoma metastases, and 16 normal skin (N) samples to find genes associated with melanoma development and progression. Results were confirmed using immunohistochemistry and real-time PCR and replicated in an independent set of 330 melanomas using AQUA analysis of tissue microarray (TMA). Transcriptome profiling revealed that transcription factor HMGA2, previously unrecognized in melanoma pathogenesis, is significantly upregulated in primary melanoma and metastases (P-values=1.2 × 10(-7) and 9 × 10(-5)) compared with N. HMGA2 overexpression is associated with BRAF/NRAS mutations (P=0.0002). Cox proportional hazard regression model and log-rank test showed that HMGA2 is independently associated with disease-free survival (hazard ratio (HR)=6.3, 95% confidence interval (CI)=1.8-22.3, P=0.004), overall survival (OS) (stratified log-rank P=0.008), and distant metastases-free survival (HR=6.4, 95% CI=1.4-29.7, P=0.018) after adjusting for American Joint Committee on Cancer (AJCC) stage and age at diagnosis. Survival analysis in an independent replication TMA of 330 melanomas confirmed the association of HMGA2 expression with OS (P=0.0211). Our study implicates HMGA2 in melanoma progression and demonstrates that HMGA2 overexpression can serve as an independent predictor of survival in melanoma.

22 Article Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part II: Management of stage IV disease. 2013

Fox, Matthew C / Lao, Christopher D / Schwartz, Jennifer L / Frohm, Marcus L / Bichakjian, Christopher K / Johnson, Timothy M. ·Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, Michigan, USA. matfox@med.umich.edu ·J Am Acad Dermatol · Pubmed #23244384.

ABSTRACT: Part II of this continuing medical education article will discuss the treatment options for stage IV melanoma, including novel therapies, such as ipilimumab and vemurafenib; established therapies, including high-dose interleukin-2, conventional chemotherapy, and biochemotherapy; and additional therapies currently under investigation in the form of clinical trials. The approach to patients with brain metastases will be discussed, as will recommendations for distress screening and defining aspects of palliative care.

23 Article Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part I: Management of stage III disease. 2013

Fox, Matthew C / Lao, Christopher D / Schwartz, Jennifer L / Frohm, Marcus L / Bichakjian, Christopher K / Johnson, Timothy M. ·Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, Michigan, USA. matfox@med.umich.edu ·J Am Acad Dermatol · Pubmed #23244383.

ABSTRACT: The incidence of melanoma has increased for decades, and while surgical treatment of early stage disease is often curative, metastatic disease continues to carry a significantly less promising outlook with high associated health burden and economic cost. An expanding number of dermatologists are playing a key role in coordinating the care of patients with melanoma, including in an increasingly important role among multidisciplinary melanoma clinics, many of which are anchored in dermatology departments. Advances in the understanding of the genetic and immunoregulatory aspects of melanoma development and progression have yielded a wave of novel therapeutics that has made significant impact on the approach to patients with metastatic disease. Frequently updated management guidelines and unfamiliarity with approved adjuvant treatment options, including interferon, clinical trials, or radiation therapy, can pose a challenge for dermatologists seeking to effectively coordinate the care of and establish proper expectations for patients with stage III disease. Moreover, greater awareness of treatment modalities for in-transit disease may allow dermatologists to play a more active role in the treatment of these patients and to expand their ability to explain and coordinate options, such as limb perfusion or infusion. Part I of this continuing medical education article will use clinical scenarios to outline the current management options for patients with stage III melanoma, including both adjuvant treatment options for resected stage III disease and primary treatment options for in-transit metastases. Part II of this series will address stage IV disease.

24 Article Human melanoma metastasis in NSG mice correlates with clinical outcome in patients. 2012

Quintana, Elsa / Piskounova, Elena / Shackleton, Mark / Weinberg, Daniel / Eskiocak, Ugur / Fullen, Douglas R / Johnson, Timothy M / Morrison, Sean J. ·Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, MI 48109-2216, USA. ·Sci Transl Med · Pubmed #23136044.

ABSTRACT: Studies of human cancer metastasis have been limited by a lack of experimental assays in which cancer cells from patients metastasize in vivo in a way that correlates with clinical outcome. This makes it impossible to study intrinsic differences in the metastatic properties of cancers from different patients. We recently developed an assay in which human melanomas readily engraft in nonobese diabetic/severe combined immunodeficient interleukin-2 receptor-γ chain null (NSG) mice. We show that melanomas from 25 patients exhibited reproducible differences in the rate of spontaneous metastasis after transplantation into NSG mice and that these differences correlated with clinical outcome in the patients. Stage IIIB/C melanomas that formed distant metastases within 22 months in patients also formed tumors that metastasized widely in NSG mice, whereas stage IIIB/C melanomas that did not form distant metastases within 22 to 50 months in patients metastasized more slowly in NSG mice. These differences in the efficiency of metastasis correlated with the presence of circulating melanoma cells in the blood of NSG mice, suggesting that the rate of entry into the blood is one factor that limits the rate of metastasis. The study of NSG mice can therefore yield information about the metastasis of human melanomas in vivo, in this case revealing intrinsic differences among stage III melanomas in their ability to circulate/survive in the blood and to metastasize.

25 Article Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. 2012

Asangani, Irfan A / Harms, Paul W / Dodson, Lois / Pandhi, Mithil / Kunju, Lakshmi P / Maher, Christopher A / Fullen, Douglas R / Johnson, Timothy M / Giordano, Thomas J / Palanisamy, Nallasivam / Chinnaiyan, Arul M. ·Michigan Center for Translational Pathology. ·Oncotarget · Pubmed #22948084.

ABSTRACT: MicroRNAs (miRs) play a key role in cancer etiology by coordinately repressing numerous target genes involved in cell proliferation, migration and invasion. The genomic region in chromosome 9p21 that encompasses miR-31 is frequently deleted in solid cancers including melanoma; however the expression and functional role of miR-31 has not been previously studied in melanoma. Here, we queried the expression status and performed functional characterization of miR-31 in melanoma tissues and cell lines. We found that down-regulation of miR-31 was a common event in melanoma tumors and cell lines and was associated with genomic loss in a subset of samples. Down-regulation of miR-31 gene expression was also a result of epigenetic silencing by DNA methylation, and via EZH2-mediated histone methylation. Ectopic overexpression of miR-31 in various melanoma cell lines inhibited cell migration and invasion. miR-31 targets include oncogenic kinases such as SRC, MET, NIK (MAP3K14) and the melanoma specific oncogene RAB27a. Furthermore, miR-31 overexpression resulted in down-regulation of EZH2 and a de-repression of its target gene rap1GAP; increased expression of EZH2 was associated with melanoma progression and overall patient survival. Taken together, our study supports a tumor suppressor role for miR-31 in melanoma and identifies novel therapeutic targets.

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