DNA microdensitometry, karyometry and maturation parameters have independent abilities in identifying individual malignant melanomas. Coevaluation of various cytometric features and maturation profiles offers better diagnostic ability in separating benign nevi from MM.

Therefore, while assessment of tumour IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by intertumoral heterogeneity.

We thank Perier-Muzet et al 1 for their comments regarding the importance of adequate dermatologic surveillance in patients with melanoma treated with a BRAF inhibitor in the adjuvant setting.We agree that the use of conventional dermoscopy (not digital dermoscopy) should be the standard of dermatologic assessment for examining pigmented skin lesions.Recently, Perier-Muzet et al 2 reported a high rate of dermoscopic changes occurring on melanocytic lesions of patients receiving the BRAF inhibitor vemurafenib.They pointed out that almost all of the changes were observed by digital dermoscopy and were not visible by naked-eye examination.However, conventional, analog dermoscopy, which is used more commonly than digital dermoscopy in daily routine practice, was not used as a control.It remains unclear whether digital dermoscopy is superior to analog dermoscopy in identifying new primary melanomas (NPMs) in patients treated with vemurafenib.Perier-Muzet et al 1 argued that the true effect of BRAF inhibitors on the incidence of NPMs will not be assessed in the randomized placebo-controlled adjuvant clinical trial of vemurafenib (A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib [RO5185426] Adjuvant Therapy in Patients With Surgically Resected, Cutaneous BRAF Mutant Melanoma at High Risk for Recurrence [BRIM8]; NCT01667419) because of the lack of protocol-driven dermoscopic surveillance.The BRIM8 protocol requires dermatologic assessment by a designateddermatologistwhoisexperiencedinthediagnosisandmanagement ofcutaneousneoplasms.Severalsurveysevaluatedtheuseofconventional dermoscopy by dermatologists in the United States, 3,4 Australia, 5,6 and Europe. 7Surveys published in 2007 5 and 2011 6 of Australian dermatologists found a high prevalence of dermoscopy use, 95% and 98%, respectively.In a US survey, 94% of dermatology chief residents used dermoscopy. 4In a nationwide survey conducted in academic and nonacademic hospital centers in France, 98% reported using dermoscopy. 7aken together, these data suggest that most dermatologists use conventional dermoscopy for examining pigmented lesions.Given that protocol-driven dermatologic surveillance by a dermatologist is required and conventional, and analog dermoscopy is widely used by dermatologists, we adhere to our conclusion that the true effect of BRAF inhibitors on the incidence of NPMs will be assessed in the BRIM8 study.Moreover, regardless of the use of dermoscopy, because the BRIM8 study is a randomized, double-blind, placebo-controlled trial, any important difference in NPM risk should be revealed via any method of dermatologic assessment, as long as the method is consistent between both arms and for a given patient.Furthermore, use of single-agent BRAF inhibition in melanoma may decrease moving forward.The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is currently approved for use in V600 BRAF mutant metastatic melanoma in the United States and Australia because of its superior efficacy and fewer onco-genic toxicities compared with dabrafenib, 8 and is under investigation in the adjuvant setting (NCT01682083).

Hepatic resection for metastatic melanoma is associated with improved survival in selected patients with both primary ocular and cutaneous melanoma. Surgical treatment of hepatic melanoma metastases should be considered when complete resection is feasible.

In melanoma, therapies with inhibitors to oncogenic BRAF^V600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients.

Primary upper gastrointestinal tract melanoma is a rare but well recognised entity, with a poor prognosis because of delay in diagnosis. Furthermore, it may be difficult to determine whether a gastrointestinal melanoma represents a metastasis or a primary tumour. We report a 67-year-old man with a primary oesophageal melanoma, treated with surgical resection, who remains disease-free two years post resection.

Atypical cutaneous melanocytic lesions, including those with Spitzoid features, can be difficult to categorize as benign or malignant. This can lead to suboptimal management, with potential adverse patient outcomes. Recent studies have enhanced knowledge of the molecular and genetic biology of these lesions and, combined with clinicopathological findings, is further defining their biological spectrum, classification, and behavior. Sentinel node biopsy provides important prognostic information in patients with cutaneous melanoma, but its role in the management of melanocytic lesions of uncertain malignant potential (MELTUMP) is controversial. This paper examines the role of molecular testing and sentinel node biopsy in MELTUMPs, particularly atypical Spitzoid tumors.

<b>Purpose:</b> Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response.<b>Experimental Design:</b> Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, <i>n</i> = 21), within 2 months of commencing treatment (EDT, <i>n</i> = 20) and on disease progression after previous response (PROG, <i>n</i> = 5). Thirteen patients responded (defined as CR, PR, or durable SD by RECIST/irRC criteria), and 10 did not respond.<b>Results:</b> PRE intratumoral and peritumoral PD-1⁺ T-cell densities were sevenfold (<i>P</i> = 0.006) and fivefold higher (<i>P</i> = 0.011), respectively, in responders compared with nonresponders and correlated with degree of radiologic tumor response (<i>r</i> = -0.729, <i>P</i> = 0.001 and <i>r</i> = -0.725, <i>P</i> = 0.001, respectively). PRE PD-L1 expression on tumor and macrophages was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders (<i>P</i> = 0.025 and <i>P</i> = 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8⁺ lymphocytes (<i>P</i> = 0.046) and intratumoral CD68⁺ macrophages (<i>P</i> = 0.046).<b>Conclusions:</b> Higher PRE PD-1⁺ T cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies and may allow better selection of patients most likely to benefit from anti-PD-1 therapies and warrants further evaluation. <i>Clin Cancer Res; 23(17); 5024-33. ©2017 AACR</i>.