Recurrent Melanoma Research Articles

Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021

To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed. To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates. Retrospective cohort study of prospectively collected nationwide population-based registry data. Nationwide, population-based cohort study. The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021. First diagnosis of stage IA to IV cutaneous melanoma. Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival. We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models. This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

Factors affecting recurrence and metastasis in conjunctival melanoma.

To evaluate clinical and demographic characteristics and factors affecting recurrence, metastasis, and survival in conjunctival melanoma (CM). The clinical records of 45 patients who were treated for CM between October 1998 and June 2022 were retrospectively evaluated. Age, gender, presence of underlying conjunctival nevus-primary acquired melanosis (PAM), tumor stage according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, tumor basal diameter, tumor thickness, lymph node (LN) involvement, metastasis, presence of tumor at the surgical margin, treatment method, need for adjuvant therapy, local tumor control, recurrence, and survival were recorded. Twenty-one (46.7%) patients were female and 24 (53.3%) patients were male. The mean age at diagnosis was 53.2 ± 16.1years. Median follow up time was 12 (1-300) months. Fifteen (33.3%) patients had conjunctival PAM; 2 (4.4%) patients had conjunctival nevus. The tumor stage was T1 in 24 (55.8%), T2 in 13 (30.2%), and T3 in 6 (14.0%) of the cases. The T stage in 2cases could not be determined.For stage T1 and T2 CM, in addition to excisional biopsy (EB) and cryotherapy, alcohol epitheliectomy (AE) was performed in 17 cases (37.8%), superficial sclerectomy (SS) was performed in 7 (15.6%), and amnion membrane transplantation (AMT) due to a large conjunctival defect in 9 (20.0%). Six (14.0%) T3 cases underwent primary exenteration. Positive surgical margins were observed in 23 (51.1%) of the excised tumors at histopathologic examination. Adjuvant topical mitomycin-C (MMC) was used in 7 (30.4%) and strontium-90 episcleral brachytherapy in 4 (17.4%) of the 23 cases with tumor-positive borders. During the follow-up, recurrence was seen in 14 (31.1%) cases. According to Kaplan Meier analysis, the mean time to recurrence development was 90.5 ± 16.1months and the 5-year recurrence free rate was 52.0%. Fourteen of the recurrent cases underwent EB + cryotherapy, 3 underwent AE + SS, and 3 underwent secondary exenteration. Metastasis and LN involvement occurred in 11 (24.4%) and 8 (17.8%) of the cases, respectively. Four (8.9%) cases expired during follow-up. According to Kaplan-Meier analysis, the mean time to metastasis was 106.2 ± 17.3months and the 5-year metastasis free rate was 52.0%. While recurrence was more frequent in CM developing from PAM/nevus, metastasis was more frequent in men and those with LN involvement. Conjunctival melanoma was a malignant tumor with high recurrence and metastasis rates. Precursor nevus/PAM is a risk factor for recurrence, while male gender and regional LN involvement were risk factors for metastasisin this study.

Activated Akt expression is associated with the recurrence of primary melanomas and further refines the prognostic and predictive values for relapse in acral melanomas.

A PTEN deficiency leads to the activation of phospho-Akt at serine 473 (p-Akt) and promotes the tumorigenesis of melanomas by coupling with NUAK2 amplification. We tested the prognostic impact of p-Akt and/or NUAK2 expression on the relapse-free survival (RFS) and overall survival (OS) of melanoma patients. Primary tumors from patients with acral melanomas (112), Low-cumulative sun damage (CSD) melanomas (38), and High-CSD melanomas (18) were examined using immunohistochemistry and their prognostic significance was analyzed statistically. The expression of p-Akt was found in 32.1%, 68.4%, and 55.6% of acral, Low-CSD, and High-CSD melanomas, while NUAK2 expression was found in 46.4%, 76.3%, and 50.0%, respectively. Either p-Akt or NUAK2 expression was inversely correlated with the RFS of primary melanoma patients and acral melanoma patients (p-Akt: p < .0001, p < .0001; NUAK2; p = .0005, p < .0001, respectively). Strikingly, multivariate analyses revealed that p-Akt had a significant impact on RFS (Hazard ratio = 4.454; p < .0001), while NUAK2 did not. Further subset analyses revealed that p-Akt expression had an inferior RFS of patients with acral melanomas (Hazard ratio = 4.036; p = .0005). We conclude that the expression of p-Akt has a significant impact on RFS of patients with primary melanomas and can predict the relapse of patients with acral melanomas.

Recurrence and survival in early-stage acral lentiginous melanoma: A retrospective analysis

Recurrence and survival in early-stage acral lentiginous melanoma: A retrospective analysis

Immune Inhibitory Molecule PD-1 Homolog (VISTA) Colocalizes with CD11b Myeloid Cells in Melanoma and Is Associated with Poor Outcomes

Tumors evade immunity through the overexpression of immune inhibitory molecules in the tumor microenvironment such as PD-L1/B7-H1. An immune inhibitory molecule named PD-1 homolog (also known as V-domain Ig-containing suppressor of T cell activation [VISTA]) functions to control both T cells and myeloid cells. Current clinical trials using anti-VISTA-blocking agents for treatment of cancer are ongoing. We sought to determine the extent of VISTA expression in primary cutaneous melanomas (n= 190), identify the critical cell types expressing VISTA, and correlate its expression with PD-L1 expression using multiplexed quantitative immunofluorescence. Within the tumor subcompartments, VISTA is most highly expressed on CD11b myeloid cells, and PD-L1 is most highly expressed on CD68 myeloid cells in our melanoma cohort. There is little correlation between VISTA and PD-L1 expression intensity, suggesting that individual tumors have distinct immunosuppressive tumor microenvironments. High levels of VISTA expression on CD11b myeloid cells but not PD-L1 expression were associated with greater melanoma recurrence and greater all-cause mortality. Our findings suggest that cell-specific VISTA expression may be a negative prognostic biomarker for melanoma and a future potential therapeutic target.

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis

BackgroundThe tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate...

CLINICAL CASE OF RECURRENT NEVUS

Abstract. Introduction. Recurrent nevus is a benign proliferation of melanocytes that occurs at the site of non-radical removal of a previously existing nevus. Recurrence rates range from 0.3% to 28% and most often occur within 6 weeks to 6 months after removal. Clinically recurrent nevus is characterized by uneven pigmentation with uneven edges in the area of the scar.&#x0D; Walton et al. began researching the phenomenon of recurrent nevus in 1957. In 1975, Kornberg and Ackerman reported that a pigmented recurrent nevus can resemble superficially spreading melanoma both clinically and histologically, and proposed the term pseudomelanoma to describe this benign phenomenon. Currently, the term is rarely used, but it motivates a thorough examination of patients with such a problem.&#x0D; Case presentation. Patient A. complained about the presence of a formation in the area of the outer surface of the right forearm, which has existed for many years, it was injured several times, but has recently changed the colour. On examination, a nodule up to 0.5 cm in size, heterogeneously pigmented, with peripheral erythema was found in the indicated place. During dermoscopy, chaotic unevenly distributed pigmentation, consisting of dots, globules, forming a cellular structure in a scattered manner is determined, zones of segmental radial lines are present as well. The vascular pattern in the central part of the formation is not defined, on the periphery it is represented by slightly noticeable point vessels. Digital post-processing using machine learning technology was carried out to improve visualization of blood supply. Multiple point, curved, and convoluted vessels with few branches around the formation, and several central vessels in the pigment cells are determined. Surgical removal of the tumor was performed with involvement of the erythema zone, taking into account the peculiarities of pigmentation and vascular pattern. The pathogistological structure is presented in the photomicrograph. The epidermis has a typical structure, with areas of slight acanthosis; hyperpigmentation of the basal layer is also observed. In the dermis, foci of brown pigment deposition, single lymphocytes, there are areas of intradermal lobular-horizontal fibrosis with angiomatosis and scattered lymphocytic infiltration. Taking into account the clinical data, there is a recurrence of a melanocytic nevus on the background of a skin scar (Recurrent neavus).&#x0D; Teaching point. Dermoscopy allows obtaining additional data for the differential diagnosis of recurrent nevus and recurrent melanoma. A recurrent nevus is characterized by relative symmetry of formation and a pattern of segmental radial lines. The formation is limited to the area of the scar and does not go beyond it. Also, in the case of recurrent melanoma, a continuous growth in dynamics and a later appearance of recurrence from the moment of intervention will be obvious.&#x0D; Conclusions. As clinical practice demonstrates, under certain circumstances, recurrent pigmentation can be observed in cases of nevi that have been traumatized. It will be visible both dermoscopically and pathohistologically. Sometimes it is difficult even for experts to distinguish between a highly irritated nevus and a melanoma.

IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory

Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7Rhi tumor-specific CD8+ population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8+ population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7Rhi and antigen-specific T cells allows for enrichment of a potent functional CD8+ population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Brachytherapy With 15- Versus 20-mm Ruthenium 106 Plaques Without Verification of Plaque Position Is Associated With Local Tumor Recurrence and Death in Posterior Uveal Melanoma

Brachytherapy with episcleral plaques is the most common primary tumor treatment for uveal melanoma. This study aims to compare the risk of tumor recurrence and metastatic death between two frequently used ruthenium-106 plaque designs: CCB (20.2 mm) and CCA (15.3 mm). Data were obtained from 1387 consecutive patients treated at XXX between 1981 and 2022 (439 with CCA and 948 with CCB plaques). During the period, scleral transillumination was performed to delineate tumor margins before plaque insertion, but no minimum scleral dose was used, and accurate plaque positioning was not verified after scleral attachment. Patients treated with CCA plaques had smaller tumors than those treated with CCB plaques (mean diameter 8.6 vs. 10.5 mm, P<0.001). There were no differences in patient sex, age, tumor distance to the optic disc, tumor apex dose, dose rate, or in rates of ciliary body involvement, eccentric plaque placement, or adjunct transpupillary thermotherapy. The average difference between plaque and tumor diameter was greater with the CCB plaque, and a smaller difference was an independent predictor of tumor recurrence. The 15-year incidence of tumor recurrence was 28% and 15% after treatment with CCA and CCB plaques, respectively (competing risk analysis, P<0.001). Multivariate Cox regression analysis revealed a lower risk for tumor recurrence with CCB plaques (HR 0.50). Similarly, patients treated with CCB plaques had a lower risk for uveal melanoma-related mortality (HR 0.77). Adjunct transpupillary thermotherapy did not reduce these risks. Uni- and multivariate time-dependent Cox regressions demonstrated that tumor recurrence was associated with uveal melanoma-related and all-cause mortality. Compared to 20 mm plaques, brachytherapy with 15 mm ruthenium plaques is associated with a higher risk for tumor recurrence and death. These adverse outcomes may be avoided by increasing safety margins and implementing effective methods to verify accurate plaque positioning.

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5years they would require to tolerate defined side-effects. By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Acceptability of a Hypothetical Reduction in Routinely Scheduled Clinic Visits Among Patients With History of a Localized Melanoma (MEL-SELF): Pilot Randomized Clinical Trial.

After treatment for a localized melanoma, patients attend routinely scheduled clinics to monitor for new primary or recurrent melanoma. Patient-led surveillance (skin self-examination with patient-performed teledermoscopy) is an alternative model of follow-up that could replace some routinely scheduled visits. This study aims to assess the acceptability of a hypothetical reduction in routinely scheduled visits among participants of the Melanoma Self Surveillance (MEL-SELF) pilot randomized clinical trial of patient-led surveillance (intervention) versus usual care (control). Patients previously treated for localized melanoma in New South Wales who were participating in the MEL-SELF pilot randomized clinical trial were asked to respond to a web-based questionnaire at baseline and after 6 months on trial. We used mixed methods to analyze the data. The main outcome of interest was the acceptability of a hypothetical reduction in routinely scheduled visits for melanoma surveillance. Of 100 randomized participants, 87 answered the questionnaire at baseline, 66 answered the questionnaire at 6 months, and 79 provided a free-text explanation at either time point. At 6 months, 33% (17/51) of the control group and 35% (17/49) of the intervention group indicated that a hypothetical reduction in routinely scheduled visits with all melanoma doctors was at least slightly acceptable (difference in proportions -1%, 95% CI -20% to 17%; P=.89). Participants suggested that prerequisites for a reduction in routinely scheduled visits would include that sufficient time had elapsed since the previous diagnosis without a new primary melanoma or recurrence, an unscheduled appointment could be made at short notice if the patient noticed something concerning, their melanoma doctor had suggested reducing their clinic visit frequency, and patients had confidence that patient-led surveillance was a safe and effective alternative. Participants suggested that a reduction in routinely scheduled visits would not be acceptable where they perceived a very high risk of new or recurrent melanoma, low self-efficacy in skin self-examination and in the use of technologies for the patient-led surveillance intervention, and where they had a preference for clinician-led surveillance. Some patients said that a partial reduction to once a year may be acceptable. Some patients may be receptive to a reduction in routinely scheduled visits if they are assured that patient-led surveillance is safe and effective. Australian New Zealand Clinical Trials Registry ACTRN12616001716459; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865&isReview=true; ClinicalTrials.gov NCT03581188; https://clinicaltrials.gov/ct2/show/NCT03581188. RR2-10.1001/jamadermatol.2021.4704.

P56 Trial redesign for the phase II/III DETECTION trial: circulating tumour DNA-guided therapy for stage IIB/C melanoma after surgical resection

Abstract Despite patients with stage II melanoma being relatively high risk, contributing to 30% of melanoma-associated deaths, there remains a relatively low individual chance of melanoma recurrence. Therefore, strategies are required to better select those patients at highest risk of recurrence. We have developed assays using circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) or molecular recurrence of melanoma. Originally, the DETECTION trial was designed to perform ctDNA sampling in addition to clinical follow-up in patients with stage IIB/C melanoma. Those with ctDNA detected were randomized 1 : 1 in a double-blind fashion to continue routine follow-up with the investigators’ choice of treatment if they developed disease recurrence or were unblinded and treated with nivolumab. Since its opening, adjuvant therapy has been licensed, with trials showing approximately 6% absolute reduction in distant metastasis in stage IIB/C melanoma with 1 year of antiprogrammed cell death protein 1 therapy; however, grade 3 or 4 toxicity was observed in 16% of patients, with 25% experiencing lifelong endocrine disorders. Better enrichment of patients at high risk of recurrence, and avoiding treatment toxicity in those who do not require it, therefore remains highly relevant. As DETECTION had only started recruitment, there was opportunity to redesign it, which we present here. We have designed tumour-informed assays targeting BRAF (V600E/K/R), NRAS (G12D, Q61K/L/R) and the H-TERT promoter region (−124 and −146) mutations for ctDNA detection using droplet digital polymerase chain reaction. DETECTION has been redesigned as a phase III trial with the primary objectives of elucidating (i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse and (ii) whether early treatment of molecular recurrence based on ctDNA detection is noninferior to adjuvant therapy in preventing distant metastasis. Patients (n = 1000) with stage IIB/C/III/IV resected BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1 and adequate organ function, with complete resection performed within 12 weeks and radiological/clinical disease-free status confirmed and no prior immune/targeted therapy will be included. Patients will be randomized 1 : 1 to either 1 year of adjuvant therapy (arm A) or longitudinal ctDNA monitoring (arm B) and treatment only if a local recurrence (surgery followed by 1 year of adjuvant therapy with ongoing ctDNA monitoring) or ctDNA detection (2 years of the investigators’ choice of therapy). The primary endpoint is distant metastasis-free survival. CtDNA is a useful tool to monitor for MRD/molecular relapse. The DETECTION trial will assess whether it can be used to safely monitor patients and systemically treat only those at highest risk of melanoma progression.

P20 A mysterious case of recurrent malignant melanoma

Abstract A 74-year-old White man presented to community dermatology services in 2020 with one lesion on the right temple and one on the left forehead. These were investigated with punch biopsies and reported as benign intradermal melanocytic naevi. One year later, he was referred to our teledermatology clinic with a pink nodule on the right temple, which had never healed following the 2020 biopsy. The teledermatology photos were more in keeping with basal cell carcinoma (BCC) and he was booked in for an excision. Histology reported the lesion as ulcerated invasive malignant melanoma (Breslow thickness 3.1 mm and mitotic figures). At this stage, previous biopsies from 2020 were reviewed and invasive malignant melanoma (MM) was confirmed. He was reviewed in the clinic and, on skin examination, he had a 7-mm BCC on the right upper nasal bridge. We found a small scar, but no lesions, on the left temple. He had areas of psoriasis on his elbows and knees. No organomegaly or lymphadenopathy was identified on systemic examination. He underwent wide local excision (WLE) of the right temple MM scar with sentinel lymph node biopsies from the right neck, which were negative. Initial radiological imaging did not show any metastases. Three-month follow-up computed tomography showed colon thickening, and the patient was diagnosed with hepatic flexure tumour, which was treated with right hemicolectomy. Further imaging showed no evidence of metastases. In September 2022, a new 6-mm, light-brown indentation was identified on the medial edge of the melanoma scar on the right temple. Initially, the biopsy results reported recurrent melanoma. Further histological slide review and immunochemical analysis demonstrated langerin with multinucleated histiocyte-like cell infiltrates and lymphohistiocytic inflammatory cell infiltrates; Langerhans cell histiocytosis (LCH) was diagnosed. He underwent WLE of this lesion and positron emission tomography; we are still awaiting the results. He has been referred to a specialist haematology team and is awaiting further management. LCH is a rare, multisystem haematological disorder of the clonal proliferation of Langerhans cells. Existing case reports document LCH with concomitant presentations of myeloproliferative disorders, particularly myeloid leukaemias, or noncutaneous manifestations, including pulmonary presentations. To the best of our knowledge, there have been no reports of LCH presenting exclusively with cutaneous manifestations clinically mimicking recurrent MM. The rare incidence and misleading presentation of LCH often results in its lack of consideration as a differential diagnosis for recurrent solitary skin lesions in adults. This case also highlights the diagnostic challenges and thorough investigation required for this unique condition.

BI24 Cutaneous pseudolymphoma secondary to pembrolizumab

Abstract A 35-year-old man presented with a 7-week history of itchy, nontender, indurated erythematous plaques and nodules on his forehead and upper back, with no discriminatory clinical features. He was systemically well. Three months previously, he had completed a 12-month course of adjuvant pembrolizumab for stage IIIC melanoma. The primary melanoma had been excised from his left cheek, with involvement of left parotid and supraclavicular lymph nodes, treated with clearance via superficial parotidectomy and left neck dissection. Clinical and imaging surveillance revealed no evidence of melanoma recurrence. Incisional biopsies of the lesions on his back and forehead both demonstrated a superficial and deep dermal perivascular and periadnexal infiltrate of small- and medium-sized lymphoid cells. There was no epidermotropism and B- and T-cell clonality studies were negative. Morphological appearance and immunophenotype favoured a CD4+-reactive lymphoid process in keeping with cutaneous pseudolymphoma (CPL), secondary to pembrolizumab. The conspicuous forehead lesion was unresponsive to clobetasol propionate under occlusion. A single course of intralesional triamcinolone acetonide 10 mg mL–1 resulted in significant improvement within days, with subsequent complete resolution. The lesion on the back resolved spontaneously. Drug-induced CPL describes an adverse cutaneous drug reaction mimicking B- or T-cell lymphomas clinically and/or histologically. It has been described with anticonvulsants, antidepressants and biologic agents, often with resolution on cessation of the responsible drug (Etesami I, Kalantari Y, Tavakolpour S et al. Drug-induced cutaneous pseudolymphoma: a systematic review of the literature. Australas J Dermatol 2023; 64:41–9). It has been proposed that the drugs affect immune surveillance, leading to an abnormal cutaneous lymphocyte response. A case report (Ayoubi N, Haque A, Vera N et al. Ipilimumab/nivolumab-induced pseudolymphoma in a patient with malignant melanoma. J Cutan Pathol 2020; 47:390–3) has described drug-induced CPL secondary to ipilimumab and nivolumab in a 38-year-old man presenting with erythematous plaques on the hands and face, similar to the presentation of our patient, which responded to prednisolone. As with the other adverse effects of immunotherapy, it is likely that CPL in this cohort is due to an iatrogenic immune dysregulation leading to T-cell overactivity. We present the first reported case of CPL secondary to pembrolizumab and highlight the successful use of intralesional steroid as a treatment option. It is important to recognize CPL as an adverse cutaneous effect of immunotherapy and be aware that it can present after completing treatment due to an ongoing immune response.

BI25 Immunotherapy-associated Sweet syndrome in a patient with metastatic melanoma

Abstract Ipilimumab, an anti-CTLA-4 monoclonal antibody, is used in the treatment of metastatic melanoma. As with other immune checkpoint inhibitors, it can cause a spectrum of immune-related adverse events (irAEs), including a cutaneous pathology, in 25% of patients. To date, there have been five case reports of Sweet syndrome solely due to ipilimumab therapy. We present a suspected further case in a patient with metastatic melanoma of unknown primary origin, who concurrently developed vitiligo. A 65-year-old man presented to the dermatology department with a 2-week history of a mildly tender, erythematous papulonodular rash localized to the right forearm. He had also developed extensive vitiligo on all limbs over a similar period of time. Histology from a skin punch biopsy demonstrated a predominantly neutrophilic dermal inflammatory infiltrate without features of vasculitis, confirming Sweet syndrome. There were no recent medication changes or disease recurrence on repeat imaging. Nine months prior, the patient had been diagnosed with cerebral and pulmonary metastatic melanoma of unknown primary origin (BRAF V600 mutation positive). He underwent an evacuation of a left temporal cortical mass and subsequent stereotactic radiosurgery. The oncology team then commenced ipilimumab (3 mg kg–1) and nivolumab (1 mg kg–1) every 21 days. Four cycles were completed until discontinuation after 3 months due to multiple severe irAEs, namely, panhypopituitarism and liver toxicity. He was commenced on 80 mg (1 mg kg–1) oral prednisolone, which was slowly reduced over subsequent months and completed a few weeks prior to the development of Sweet syndrome and vitiligo. We prescribed topical clobetasol propionate 0.05% once daily, with resolution of Sweet syndrome after 2 months. The oncology team elected to withhold further immunotherapy due to the multiple irAEs, instead monitoring for melanoma recurrence by serial radiological imaging. The five previously documented cases of ipilimumab-associated Sweet syndrome report an average time to clinical presentation of 8.9 weeks. Our case differs as the patient developed Sweet syndrome 5 months after the discontinuation of immunotherapy. However, the development of any cutaneous adverse effect may have been masked by high-dose steroids for the other systemic irAEs soon after the fourth cycle of treatment. Despite a lack of temporality between immunotherapy and Sweet syndrome in our case, the addition of vitiligo at the same presentation suggests an irAE. This case highlights the importance of monitoring patients on immunotherapy for dermatological side-effects and working closely with oncology colleagues to manage these complex cases.

Role of Sleep Apnea and Long-Term CPAP Treatment in the Prognosis of Patients With Melanoma: A Prospective Multicenter Study of 443 Patients

OSA has been associated with increased incidence and aggressiveness of melanoma. However, the long-term impact of OSA and CPAP treatment on the prognosis of melanoma remains unexplored. Are OSA and CPAP treatment associated independently with a poor prognosis for cutaneous melanoma? Four hundred forty-three patients with a diagnosis of cutaneous melanoma (2012-2015) underwent a sleep study within 6months of diagnosis. The main 5-year outcome of the study was a composite of melanoma recurrence, metastasis, or mortality. Patients were divided into four groups: baseline apnea-hypopnea index (AHI) of fewer than 10 events/h (no OSA; control group), OSA treated with CPAP and good adherence, untreated or poor CPAP adherence in moderate (AHI, 10-29 events/h), and severe OSA (AHI,≥ 30 events/h). Survival analysis was used to determine the independent role of OSA and CPAP treatment on melanoma composite outcome. Three hundred ninety-one patients (88.2%) were available for analysis at 5-year follow-up (mean age, 65.1 ± 15.2 years; 49%male; Breslow index, 1.7 ± 2.5mm). One hundred thirty-nine patients had AHI of fewer than 10 events/h (control group); 78 patients with OSA were adherent to CPAP; and 124 and 50 patients had moderate and severe OSA, respectively, without CPAP treatment. Median follow-up was 60months (interquartile range, 51-74months). During follow-up, 32 relapses, 53 metastases, and 52 deaths occurred (116 patients showed at least one of the main composite outcomes). After adjusting for age, sex, sentinel lymph nodes affected at diagnosis, BMI, diabetes,nighttime with an oxygen saturation below 90%, Breslow index, Epworth sleepiness scale scores, and melanoma treatment, moderate (hazard ratio [HR], 2.45; 95%CI, 1.09-5.49) and severe OSA (HR, 2.96; 95%CI, 1.36-6.42) were associated with poorer prognosis of melanoma compared with the control group. However, good adherence to CPAP avoided this excess risk (HR, 1.66; 95%CI, 0.71-3.90). Moderate to severe untreated OSA is an independent risk factor for poor prognosis of melanoma. Treatment with CPAP is associated with improved melanoma outcomes compared with untreated moderate to severe OSA.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial.

LBA9503 Background: mRNA-4157 is a novel mRNA-based personalized cancer vaccine which encodes up to 34 patient-specific tumor neoantigens. The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of recurrence free survival (RFS) in patients with resected high-risk stage IIIB/C/D and IV melanoma. The study has shown a statistically significant and clinically meaningful improvement in RFS in the combination therapy compared to pembrolizumab monotherapy, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); 1-sided p-value of 0.0266). This report provides the first analysis of the secondary efficacy endpoint of distant metastasis-free survival (DMFS). Methods: mRNA-4157-p201 is an ongoing multicenter, open-label, randomized Phase II trial in patients with completely resected, high-risk Stage IIIB/C/D and IV cutaneous melanoma. Patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18cycles. The primary endpoint was investigator-assessed RFS, defined as local, locoregional, distant recurrence, or new primary melanoma. The secondary endpoint of DMFS was pre-specified and hierarchically tested following positive RFS. All tests were performed at 1-sided alpha = 0.99. Results: 157 patients were randomized to the combination of mRNA-4157 with pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary analysis for the primary endpoint occurred after all patients completed a minimum of 12 months on study and 44 RFS events were observed. At a median follow-up of 23 (combination) and 24 (pembrolizumab) months in the primary analysis, RFS events were reported in 22.4% (24/107) of patients in the combination arm and in 40% (20/50) of patients in the monotherapy arm. The 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%,74.3%) in the combination and monotherapy arms respectively. There was also a statistically and clinically significant improvement in DMFS for the combination versus pembrolizumab monotherapy (HR = 0.347; 95% CI: (0.145, 0.828); 1-sided p-value 0.0063). Distant recurrence or death was reported in 8.4% (9/107) and 24% (12/50) of patients, with 18-month DMFS rates (95% CI) were 91.8% (84.2%, 95.8%) vs 76.8% (61.0%, 86.8%) in the combination and monotherapy arm, respectively. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged DMFS compared to pembrolizumab. These results provide further evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 randomized study will be initiated in patients with melanoma. Clinical trial information: NCT03897881 .

Brachytherapy in the prevention of recurrence of conjunctival melanoma : Results of a case report in aUniversity Hospital in Valladolid, Spain.

Describe the results of brachytherapy in the prevention of recurrences in conjunctival melanoma (CM) and describe adosimetric protocol. Retrospective and descriptive case report. Eleven consecutive patients with aconfirmed histopathological diagnosis of CM treated with brachytherapy between 1992 and 2023 were reviewed. Demographic, clinical, and dosimetric characteristics as well as recurrences were recorded. Quantitative variables were represented by the mean, median, and standard deviation, and qualitative variables by frequency of distribution. Of atotal of 27patients diagnosed with CM, 11who were treated with brachytherapy were included in the study (7female; mean age at time of treatment: 59.4years). Mean follow-up was 58.82months (range 11-141months). Of atotal of 11patients, 8were treated with ruthenium-106 and 3with iodine-125. Brachytherapy was performed in 6patients as adjuvant therapy after biopsy-proven CM on histopathology and in the other 5patients after recurrence. The mean dose was 85 Gy in all cases. Recurrences outside of the previously irradiated area were observed in 3patients, metastases were diagnosed in 2patients, and one case of an ocular adverse event was reported. Brachytherapy is an adjuvant treatment option in invasive conjunctival melanoma. In our case report, only one patient had an adverse effect. However, this topic requires further research. Furthermore, each case is unique and should be evaluated by experts in amultidisciplinary approach involving ophthalmologists, radiation oncologists, and physicists.