18 F-FDG positron emission tomography-computed tomography has a low positive predictive value for detecting occult recurrence in asymptomatic patients with high-risk Stages IIB, IIC, and IIIA melanoma.

BACKGROUND AND OBJECTIVES: High recurrence rates of Stages II and IIIA melanoma make close follow-up essential, especially with new adjuvant therapies for metastatic disease. However, there are currently no consensus guidelines for routine imaging for Stages IIB, IIC, and IIIA melanoma. The study's aim is to determine the utility of 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting asymptomatic recurrence of melanoma after primary surgical resection. METHODS: This retrospective cohort study included 158 patients with the American Joint Committee on Cancer 8th edition Stages IIB, IIC, or IIIA cutaneous melanoma who underwent an 18 F-FDG PET/CT from 2010 to 2020. We retrospectively analyzed clinical data after a median follow-up time of 39 months. RESULTS: We calculated a positive predictive value (PPV) of 32% (95% confidence interval: 11%-53%) for 154 routine PET/CTs, including six true positives and 13 false positives (FPs). PPV was 33% for Stage IIB, 50% for Stage IIC, and 14% for Stage IIIA. FPs were mostly benign or inflammatory foci (75%), and some other malignancies were found (21%). CONCLUSIONS: This cohort of patients imaged for high-risk melanoma demonstrated a high FP rate and low PPV. These findings suggest that routine surveillance with 18 F-FDG PET/CT may not be indicated for monitoring recurrence in this population.

Multidisciplinary Care of BRAF-Mutant Stage III Melanoma: A Physicians Perspective Review.

Prognosis among patients with stage III melanoma can vary widely depending on the risk of disease relapse. Therefore, it is vital to optimize patient care through accurate diagnosis and staging as well as thoughtful treatment planning. A multidisciplinary team (MDT) approach, which involves active collaboration among physician specialists across a patient's disease journey, has been increasingly adopted as the standard of care for treatment of a variety of cancers, including melanoma. This review provides an overview of MDT care principles for patients with BRAF-mutant-positive, stage III cutaneous melanoma and summarizes current literature, clinical experiences, and institutional best practices. Therapeutic goals from dermatologic, surgical, and medical oncologist perspectives regarding MDT care throughout a patient's disease course are discussed. Additionally, the role of each specialty's involvement in testing for predictive biomarkers at relevant time points to facilitate informed treatment decisions is discussed. Last, instances of successful MDT treatment of other cancers and key lessons to optimize MDT patient care in cutaneous melanoma are provided. Several aspects of MDT patient care are considered vital, such as the importance of staging via pathological examination and imaging, biomarker testing, and interdisciplinary physician and patient engagement throughout the course of treatment. Use of MDTs has the potential to improve patient care in cutaneous melanoma by improving the speed and accuracy of diagnosis, implementing a personalized treatment plan early on, and being proactive in adverse event management. Physician perspectives described in this review may lead to better outcomes, quality of life, and overall patient satisfaction. IMPLICATIONS FOR PRACTICE: As more cancer therapies emerge, it is critical to optimize patient care and treatment planning. The multidisciplinary team (MDT) approach, which involves active collaboration among specialists, has led to encouraging survival results in multiple cancer types. As MDT care becomes more widely adopted in the treatment of melanoma, accurate diagnosis and staging are important, as clinical outcomes for stage III disease vary widely by substage. Because ~50% of melanomas harbor BRAF mutations, testing is important for an informed treatment decision. Interdisciplinary physician-patient engagement throughout the course of treatment can improve comorbidity and adverse event management to optimize patients' treatment journeys.

Modernizing clinical practice guidelines for the American Academy of Dermatology.

The American Academy of Dermatology is modernizing its clinical practice guidelines to be more timely and easily interpretable, while decreasing the influence of conflicts of interest in guideline generation. The main changes include the transition from SORT to GRADE methodology and the requirement that nonconflicted members of the guideline work groups remain nonconflicted throughout the entire guidelines process.

Neutrophil-predominant bullous pemphigoid induced by checkpoint inhibitors: A case series.

Checkpoint inhibitors have been revolutionary in the treatment of metastatic melanoma, non-small-cell lung cancer, and renal cell carcinoma. By restricting negative feedback of T-cells, checkpoint inhibitors allow the immune system to identify and destroy malignant cells. This enhanced immune response is efficacious in the treatment of the aforementioned malignancies; however, it may lead to immune-related adverse events. Bullous pemphigoid (BP) is a well-documented cutaneous adverse reaction of checkpoint inhibitors, with a majority of cases reporting an eosinophil-predominant or mixed inflammatory infiltrate. We report two cases of neutrophil-predominant BP presenting in patients on checkpoint inhibitors.

Second primary melanomas: Increased risk and decreased time to presentation in patients exposed to tanning beds.

BACKGROUND: Melanoma incidence has increased; the primary modifiable risk factor is ultraviolet radiation (UVR) from the sun or artificial UVR (arUVR) from tanning beds. OBJECTIVE: To determine whether patients who developed melanoma after arUVR exposure from tanning beds have unique characteristics. METHODS: A retrospective study of 434 melanoma patients was performed. Patients who consented at the initial appointment completed a questionnaire regarding phenotypic traits, medical history, and UVR exposure. RESULTS: Compared with patients aged ≥40 years, younger patients, especially women, had greater lifetime exposure to arUVR. At any age, patients with multiple primary melanomas had a higher probability of exposure to arUVR. For all patients with additional primary melanomas, those exposed to arUVR acquired their second primary melanoma significantly earlier; 67% of patients exposed to arUVR through tanning beds had their second primary diagnosed at the time of or within 1 year of their original diagnosis compared with 28% of nontanners (P = .011). Median time to diagnosis of second primary melanoma in patients exposed to arUVR versus those not exposed was 225 days versus 3.5 years, respectively (P = .027). LIMITATIONS: The study was conducted in 1 geographic area with a relatively small sample size. CONCLUSION: Our findings provide evidence for heightened surveillance in melanoma patients exposed to arUVR.

TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients.

BACKGROUND: The expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease-free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH. METHODS: The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145) and metastatic melanomas (MMs, n = 15). RESULTS: A progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease-free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA. CONCLUSION: Loss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype.

Metastatic melanoma - a review of current and future treatment options.

Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guérin, isolated limb perfusion/infusion, interferon-α, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti-programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti-programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment.

Handheld photoacoustic microscopy to detect melanoma depth in vivo.

We developed handheld photoacoustic microscopy (PAM) to detect melanoma and determine tumor depth in nude mice in vivo. Compared to our previous PAM system for melanoma imaging, a new light delivery mechanism is introduced to improve light penetration. We show that melanomas with 4.1 and 3.7 mm thicknesses can be successfully detected in phantom and in in vivo experiments, respectively. With its deep melanoma imaging ability and handheld design, this system can be tested for clinical melanoma diagnosis, prognosis, and surgical planning for patients at the bedside.

Histopathologic characteristics of therapy-associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma.

BACKGROUND: Activating mutations in BRAF have been observed in up to 60% of melanomas, indicating a pivotal role for kinase deregulation in tumor progression. Vemurafenib is a specific inhibitor of BRAF for treatment of melanomas with activating BRAF V600E mutations and has been a major advancement in melanoma treatment. Treatment with vemurafenib, and to a lesser extent, sorafenib, a relatively non-specific inhibitor of BRAF, has been associated with cutaneous squamous cell carcinoma (SCC). METHODS: Clinical and microscopic characteristics of cutaneous neoplasms were evaluated following vemurafenib administration. RESULTS: Twenty-four of 47 (51%) patients receiving vemurafenib at our institution developed 146 total cutaneous neoplasms, with 75% developing multiple lesions. The median number of lesions in affected patients was three. Body distribution included head/neck (29%), chest/back (21%), upper (23%) and lower extremities (27%). Lesions were biopsied and pathologically showed multiple types of epidermal tumors including, but not limited to, verrucous keratoses with/without partial thickness dysplasia, actinic keratoses and well-differentiated and invasive SCCs with/without keratoacanthomatous features. CONCLUSIONS: We describe the histopathologic findings of skin lesions potentially associated with vemurafenib. Additional investigation is necessary to further elucidate cutaneous neoplasms associated with vemurafenib; however, frequent dermatologic evaluation is warranted in all patients receiving BRAF inhibitors.

Treatment of pagetoid reticulosis with intensity modulated radiation therapy.

Pagetoid reticulosis, also known as Woringer-Kolopp disease, is a rare variant of cutaneous T-cell lymphoma usually presenting as an isolated patch or plaque on the extremities. Immunohistochemical staining of T-cell markers can be variable, but as the name implies the epidermotropic lymphocytes consistently display a "pagetoid" appearance. The following case demonstrates clearance of this condition with intensity modulated radiation therapy, whereas most cases are managed with electron beam therapy if radiation therapy is implemented.

Objective response to immune checkpoint inhibitor therapy in NRAS-mutant melanoma: A systematic review and meta-analysis.

Introduction: NRAS mutations are common in melanoma and confer a worse prognosis. Although most patients with metastatic melanoma receive immune checkpoint inhibitors (ICIs), the impact of NRAS mutational status on their efficacy remains under debate. Methods: We performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by NRAS mutational status in patients with melanoma treated with any line of ICI. At least two reviewers independently screened studies using Covidence software, extracted data, and assessed risk of bias. Standard meta-analysis was performed in R with sensitivity analysis and tests for bias. Results: Data on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare NRAS-mutant and NRAS-wildtype melanoma. The objective response rate was 1.28 (95% confidence interval: 1.01-1.64). Sensitivity analysis identified the study by Dupuis et al. with influential impact on the pooled effect size and heterogeneity, favoring NRAS-mutant melanoma. Discussion: In this meta-analysis evaluating the impact of NRAS mutational status on objective response to ICIs in metastatic melanoma, NRAS-mutant cutaneous melanoma demonstrated an increased likelihood of partial or complete tumor response, relative to NRAS-wildtype cutaneous melanoma. Genomic screening for NRAS mutations in patients with metastatic melanoma may improve predictive ability when initiating ICIs.

Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.

BACKGROUND: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. DESIGN AND METHODS: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. DISCUSSION: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.

Inhibitory effects of Rap1GAP overexpression on proliferation and migration of endothelial cells via ERK and Akt pathways.

Rap1 is expressed in human umbilical vein endothelial cells (HUVECs). Rap1-GTPase activating protein (Rap1GAP), with its specific target, Rap1, has been shown to be important in the regulation of many physiological and certain pathological processes. In this study, we investigated the effect of Rap1GAP expression on endothelial cell function, or, more specifically, proliferation and migration of endothelial cells. HUVECs were transfected with pcDNA3.1 (empty vector), pcDNA3.1 containing Flag-tagged-Rap1GAP or Myc-tagged-Rap1N17. The proliferation, migration and tube formation were examined and compared among the 3 groups. Expression of Rap1, Rap1GAP, extracellular signal-regulated kinase (ERK), phospho-ERK, Akt, phosphor-Akt was detected by Western blotting. The results showed that the proliferation, migration and tube formation were significantly reduced in Rap1GAP- and Rap1N17-transfected HUVECs as compared with empty vector-transfected control. These changes were coincident with increased expression of Rap1GAP and decreased expression of activated Rap1, phospho-ERK and -Akt. After treatment of Rap1GAP-transfected HUVECs with a stimulator of Rap1 guanine-nucleotide-exchange factor (Rap1GEF) 8CPT-2'OMe-cAMP, it was found that Rap1 activity was decreased as compared with empty vector-transfected control. Pretreatment of HUVECs with an ERK inhibitor PD98059 or a PI3K inhibitor LY294002 prior to stimulation not only blocked 8CPT-2'OMe-cAMP-induced phosphorylation of ERK and Akt, but also significantly reduced cell proliferation and migration. Finally, we examined the effect of vascular endothelial growth factor (VEGF) on HUVECs overexpressing Rap1GAP. VEGF-stimulated Rap1 activity, phosphorylation of ERK and Akt, cyclin D1 expression and cell proliferation were repressed in HUVECs overexpressing Rap1GAP as compared to empty vector-transfected control. Taken together, our findings demonstrate that Rap1GAP/Rap1 and their downstream effectors regulate proliferation and migration of HUVECs via ERK and Akt pathways.

Successful administration of sequential TVEC and pembrolizumab followed by Temozolomide in immunotherapy refractory intracranial metastatic melanoma with acquired B2M mutation.

Despite the substantial advances in the management of metastatic melanoma with the introduction of immune checkpoint inhibitors (ICI), many patients develop disease progression during treatment with immunotherapy. This has been suggested to be mediated by several mechanisms that contribute to acquired resistance to ICI, one of which is acquired beta-2 microgloubulin (B2M) mutation. Talimogene laherparepvec (TVEC) is a genetically modified oncolytic virus that can enhance antitumor immunity. Temozolomide (TMZ) is an oral alkylating agent that has been suggested to augment anti-tumor immune response. The clinical significance of TVEC and TMZ in metastatic melanoma patients who are refractory to immunotherapy is unknown. We report a case of a patient with immunotherapy refractory intracranial metastatic melanoma after initial response to ICI who had acquired B2M mutation. The patient received TVEC and pembrolizumab followed by TMZ. The patient maintained durable response of her visceral and intracranial disease for 19 months and ongoing. More research is essential to delineate whether TVEC or TMZ has efficacy in immunotherapy refractory metastatic melanoma with acquired B2M mutation.

Label-free high-throughput photoacoustic tomography of suspected circulating melanoma tumor cells in patients in vivo.

SIGNIFICANCE: Detection and characterization of circulating tumor cells (CTCs), a key determinant of metastasis, are critical for determining risk of disease progression, understanding metastatic pathways, and facilitating early clinical intervention. AIM: We aim to demonstrate label-free imaging of suspected melanoma CTCs. APPROACH: We use a linear-array-based photoacoustic tomography system (LA-PAT) to detect melanoma CTCs, quantify their contrast-to-noise ratios (CNRs), and measure their flow velocities in most of the superficial veins in humans. RESULTS: With LA-PAT, we successfully imaged suspected melanoma CTCs in patients in vivo, with a CNR >9. CTCs were detected in 3 of 16 patients with stage III or IV melanoma. Among the three CTC-positive patients, two had disease progression; among the 13 CTC-negative patients, 4 showed disease progression. CONCLUSIONS: We suggest that LA-PAT can detect suspected melanoma CTCs in patients in vivo and has potential clinical applications for disease monitoring in melanoma.

Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients.

The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4, melanocortin 1 receptor (MC1R) and tyrosinase (TYR)] were resequenced in 109-135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R'R' variants known or predicted to alter its function (P = 0.002), particularly the R160W variant (P = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer.