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.

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.

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.

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.

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.

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.

Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin's lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors. CASE PRESENTATION: We describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD). CONCLUSION: This is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD.

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention.

BACKGROUND: Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown. METHODS: We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T cell immunity in the skin. RESULTS: Calcipotriol plus 5-FU-induced tissue-resident memory T (Trm) cell formation in face and scalp skin associated with significantly higher erythema scores compared with control (P < 0.01). Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = 0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], P = 0.032). Accordingly, significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU-treated face and scalp skin compared with control (P = 0.0028). There was no significant difference in BCC incidence between the treatment groups. CONCLUSION: A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within 3 years of treatment. FUNDING: This research was supported by internal academic funds and by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute, and NIH.

Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

IMPORTANCE: Extramammary Paget disease (EMPD), a rare intraepithelial adenocarcinoma, poses a therapeutic challenge with high postoperative recurrence rates and a limited number of effective local treatment options. OBJECTIVE: To describe the use and efficacy of a topical combination of fluorouracil and calcipotriene as a palliative therapy for refractory EMPD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series of 3 women with recurrent, refractory EMPD was conducted at Beth Israel Deaconess Medical Center, Boston, Massachusetts and Washington University School of Medicine, St Louis, Missouri. All patients were treated with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream or ointment. MAIN OUTCOMES AND MEASURES: Clinical and histopathological findings. RESULTS: All 3 women (1 in her 50s, 2 in their 70s) presented with recurrent EMPD (vulvar, perianal, and perioral) after surgery and/or irradiation, and their EMPD was refractory to treatment with imiquimod, 5%, cream. Owing to disease progression and/or intolerable adverse effects from imiquimod, the patients began treatment with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream. This treatment, which was well tolerated, was followed by clinical improvement in symptoms and appearance of the lesions in all 3 cases and histopathological signs of decreased tumor burden in 2 cases. Patients applied the combination topical therapy to affected areas with differing frequencies, ranging from 1 to 2 days per month to 4 consecutive days every 2 weeks. CONCLUSIONS AND RELEVANCE: Extramammary Paget disease frequently recurs even after aggressive surgical management and can be refractory to many topical and locoregional therapies. Palliative treatment with a combination of fluorouracil and calcipotriene may be a viable option for patients with recurrent, refractory EMPD.

HMGB1/RAGE Mediates UVB-Induced Secretory Inflammatory Response and Resistance to Apoptosis in Human Melanocytes.

The major modifiable risk factor in melanomagenesis is UV exposure and mutagenesis of melanocytes. Other UV-induced events that contribute to early tumorigenesis are poorly understood. Herein we show that the repeated exposure of human primary melanocytes to UVB results in a sustained senescence response, increases in expression of signal transducer and activator of transcription 1, MX1, OAS2, and IRF7 proteins of up to 75-fold, and resistance to subsequent UVB-induced apoptosis. In the setting of UVB-induced DNA damage, we detected time-dependent increases in the release of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1). After intermittent UVB exposure, melanocytes treated with the JAK inhibitor ruxolitinib reduced expression of HMGB1 and MX1 as well as activation of JAK1 (pJAK1) and signal transducer and activator of transcription 1 (pSTAT1). In addition, melanocytes expressing small hairpin RNA selective for the HMGB1 receptor, receptor for advanced glycosylation end product (RAGE), exhibited decreased expression of both HMGB1 and MX1 after UVB exposure. The response of small hairpin RAGE-infected cells to human recombinant HMGB1 was blunted with decreased MX1 expression and JAK activation. Finally, depletion of receptor for advanced glycosylation end product decreased UVB-induced resistance to apoptosis (P < 0.05). These findings highlight a cell autonomous response to UV damage, contribute to their resistance to apoptosis and cell death, and may have implications for early stages of melanoma development.