Merrick I. Ross

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6–12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic capture of CD146-positive cells and anti-MEL-PE. The presence of one or more CTCs was considered positive. We analyzed the cohort of patients with relapse confirmed by radiologic imaging. CTC collection dates were assessed to determine the lead time for CTC detection. CTC-negative patients were significantly less likely to relapse compared to patients positive for CTCs (p-value < 0.001). Within the 325-patient cohort, 143 patients (44%) had recurrence, with a median follow-up of 52 months from diagnosis. The cohort (n = 143) with positive imaging and CTC results revealed 76% of patients (108/143) had CTC+ results before the radiological identification of relapse. The median time between positive CTC and positive imaging was 9 months. CTCs were positive in >75% of patients prior to relapse at a median of 9 months before radiologic detection.

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA–mRNA networks in melanoma tissues and cell lines corresponding to ‘MITF-low’ and ‘Keratin’ transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA–mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.

As part of the 2017 Melanoma Bridge congress (November 30–December 2, 2017, Napoli, Italy), the great debate session featured counterpoint views from leading experts on three contemporary controversial clinical issues in the care of the melanoma patient. These were: (1) whether complete lymph node dissection should be routinely offered to all melanoma patients with sentinel lymph node-positive disease; (2) whether first-line treatment of BRAF-mutated melanoma should consist of BRAF-targeted therapy or immunotherapy with checkpoint inhibitors; and (3) whether combined or sequential administration of treatments should be the preferred option in the management of patients with advanced melanoma. Discussion of these three important issues and audience responses are reported here.

This case report presents the ultrasound and positron emission tomography-computed tomography (PET-CT)imaging findings related to a patient with metastatic melanoma to the testis. We review this very rare entity and discuss the role of imaging. Differential considerations for a patient presenting with scrotal pain and swelling are quite wide, ranging from benign to malignant processes. The former include such entities as testicular torsion and epididymo-orchitis, and the latter, primary and secondary malignancies. Distinction between these entities is critically important because treatment pathways vary widely according to the precise diagnoses. Metastatic melanoma to the testicle has only been rarely reported and there have been very limited previous descriptions of its imaging findings. To the best of our knowledge, there have been no previous radiological reports describing both the ultrasound and PET-CT imaging findings in the same patient.

Background Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. Methods We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). Results Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025). Conclusions Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. Trial registration ClinicalTrials.gov identifier, NCT00769704 (https://clinicaltrials.gov/ct2/show/NCT00769704) October 7, 2008

Rose Bengal is a novel injectable agent that has been evaluated as a rational treatment strategy for melanoma patients with recurrent unresectable local/regional metastases accessible for intralesional injection. PV‐10 (10% Rose Bengal) has completed phase 1 and phase 2 multi‐center clinical trials demonstrating significant local/regional disease control and also responses in non‐injected regional bystander lesions and distant metastases. The published results of studies that have assessed PV‐10 are presented, and the rationale for combining its use with recently approved immunotherapeutic agents is discussed. J. Surg. Oncol. 2014 109:314–319.

Respondent burden has been defined as the cumulative demand placed on study participants related to the use of questionnaires or measurement instruments. The aim of this study was to reduce respondent burden associated with the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), a melanoma-specific quality-of-life questionnaire, through item reduction using multiple psychometric approaches. Data for this study were pooled from three institutional review board-approved protocols. Poorly performing items were identified through distributional and correlation analyses, confirmatory factor analysis, reliability estimation, and Rasch-based approaches in a developmental dataset, and the reduced scale was assessed in a separate testing cohort. Validity, reliability, goodness of fit, and Rasch-based testing were carried out for both the full and the reduced scales. The clinical characteristics of the development (n=198) and testing (n=204) cohorts were similar. Three items identified through classical psychometric approaches and three items identified by Rasch-based analyses were excluded from the FACT-M subscale. Two additional items were identified for potential reduction but were ultimately maintained due to the adverse consequences to the psychometric integrity of the reduced instrument. The reduced FACT-M module contains 18 items. In addition to psychometric assessment, expert consultation was essential when examining areas of content redundancy and was critical when considering specific items for removal. This methodological approach reduced respondent burden by 25% while maintaining the psychometric integrity of the FACT-M.

The vast majority of patients with newly diagnosed melanoma are “early‐stage” ‐ ie, clinically localized to the primary cutaneous site. For such patients, surgery represents the mainstay of treatment; current standards of surgical management have evolved based on evidence obtained from randomized trials, large multi‐center and single institutional databases, and consensus panels. Treatment strategies include wide excision of the primary site with margins dictated by important biological features such as Breslow tumor thickness, and sentinel node biopsy to surgically evaluate the regional nodal basins at risk. Sentinel node biopsy has become an important component of the initial management of many of these patients for accurate staging of regional lymph nodes, as well as enhanced regional disease control and improved survival in the patients with microscopically involved nodes. Evidence is presented that supports the rational use of these surgical strategies and reconciles some of the controversies that have emerged. The degree to which established national treatment guidelines are followed and the consequences of non‐compliance with these guidelines have become the focus of recent clinical investigations; results of these efforts are also discussed. J. Surg. Oncol. 2011; 104:341–353.

When detected and treated early, melanoma has an excellent prognosis. Unfortunately, as the tumor invades deeper into tissue the risk of metastatic spread to regional lymph nodes and beyond increases and the prognosis worsens significantly. Therefore, accurately detecting any regional lymphatic metastasis would significantly aid in determining a patient's prognosis and help guide his or her treatment plan. In 1991, Don Morton and colleagues presented new paradigm in diagnosing regional lymphatic involvement of tumors termed sentinel lymph node biopsy (SLNB). By mapping the regional lymph system around a tumor and tracing the lymphatic flow, a determination of the most likely lymph node or nodes the cancer will spread to first is made. Then, a limited biopsy of the most likely nodes is performed rather than a more-invasive removal of the entire local lymphatic chain. In 20 years that have followed, a great deal of information has been gained as to its accuracy, prognostic value, appropriate candidates, and its impact on regional disease control and survival. The SLNB has been shown to accurately stage regional lymph node basins in stage I and II melanoma patients with minimal morbidity. More sensitive histologic techniques are now being applied that may allow even greater accuracy in the staging of melanoma patients. Although specific percent risk thresholds are still in question, recommendation for SLNB when melanomas are 1 mm or thicker has gained wide acceptance. SLNB may also be appropriate for patients with melanomas that are between 0.76 and 1 mm thick and have ulceration, high mitotic rates, or reach a Clark level IV. Therefore, melanomas with IB or greater staging should be considered for SLNB.