Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

Bridging the gaps: management of lichen planus subtypes in a joint dermatology-oral surgery clinic.

Lichen planus (LP) presents with a range of clinical subtypes. It can affect the outer skin, involve the nails and present with alopecia and mucosal symptoms to varying degrees. LP of the outer skin mostly shows a self-limiting course; however, this is not the case for lichen planopilaris and the mucosa-affecting subtypes. The pathogenesis of LP is still incompletely understood. As a result, an effective, targeted therapy is currently lacking and different immunomodulatory approaches are being used in clinical practice. The management of patients with severe oral LP mucosae can be particularly challenging. Although the true risk remains controversial, oral LP is considered a risk factor for the development of squamous cell carcinoma and there is a need for regular screening. The quality of life in patients with LP is significantly impaired because of frequent clinical visits, pain, soreness, inability to eat certain foods, side effects to medication, frustrating therapy attempts and worry regarding cancer risk. We highlight here the advantages of an interdisciplinary dermatology and oral surgery clinic, which can address the domains of tooth status, nutrition, pain and malignant transformation and optimized patient management.

Seborrheic keratosis.

Seborrheic keratosis (SK) is the most common benign epidermal tumor in clinical dermatological practice. This review summarizes current knowledge about the clinical and histological appearance, epidemiology, pathogenesis, and treatment of SK. There are different subtypes of SK based on clinical presentation and histologic findings. Several factors, including age, genetic predisposition, and possibly also exposure to ultraviolet radiation, are thought to contribute to the development of SK. The lesions can occur on all areas of the body except for the palms and soles, but the most common sites are the face and upper trunk. The diagnosis is usually made clinically, and in some cases by dermatoscopy or histology. Many patients prefer to have the lesions removed for cosmetic reasons although there is no medical indication. Treatment options include surgical therapy, laser therapy, electrocautery, cryotherapy, and topical drug therapy, which is currently in development. Treatment should be individualized depending on the clinical picture and patient preference.

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells.

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We have previously shown that NC coated with carbohydrates to enable biocompatibility triggered the lectin-dependent complement pathway, resulting in enhanced binding to B cells via complement receptor (CR)1/2. Here we show that such NC also engaged all types of splenic leukocytes known to express CR3 at a high rate when NC were pre-incubated with native mouse serum resulting in complement opsonization. By focusing on dendritic cells (DC) as an important antigen-presenting cell type, we show that CR3 was essential for binding/uptake of complement-opsonized NC, whereas CR4, which in mouse is specifically expressed by DC, played no role. Further, a minor B cell subpopulation (B-1), which is important for first-line pathogen responses, and co-expressed CR1/2 and CR3, in general, engaged NC to a much higher extent than normal B cells. Here, we identified CR-1/2 as necessary for binding of complement-opsonized NC, whereas CR3 was dispensable. Interestingly, the binding of complement-opsonized NC to both DC and B-1 cells affected the expression of activation markers. Our findings may have important implications for the design of nano-vaccines against infectious diseases, which codeliver pathogen-specific protein antigen and adjuvant, aimed to induce a broad adaptive cellular and humoral immune response by inducing cytotoxic T lymphocytes that kill infected cells and pathogen-neutralizing antibodies, respectively. Decoration of nano-vaccines either with carbohydrates to trigger complement activation in vivo or with active complement may result in concomitant targeting of DC and B cells and thereby may strongly enhance the extent of dual cellular/humoral immune responses.

ß2 Integrins-Multi-Functional Leukocyte Receptors in Health and Disease.

ß2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant ß (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding ß2 integrin, but all ß2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of ß2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of ß2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, ß2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, ß2 integrin activity on leukocytes has been implicated in tumor development.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Tolerability of BRAF and MEK Inhibitors for Metastasized Melanoma after Intra-Class Switch: A Multicenter, Retrospective Study.

Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma.

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.

BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy. METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments. RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004). CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma-A Retrospective, Real-World Cohort Study.

The advent of immune-checkpoint inhibitors (CPI) and BRAF/MEK-directed targeted therapy (TT) has improved the treatment landscape of patients with BRAFV600-mutant metastatic melanoma. While TT allows for rapid disease control, the development of secondary TT resistance limits the duration of responses. Responses to CPI have a slower onset but can be durable in a subset of patients. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, single-center, real-world analysis, we identified 135 patients with BRAF-mutated, metastatic melanoma who received consecutive treatment with TT followed by CPI, or vice versa, as first and second-line therapy, respectively. We collected data on clinical-pathological factors, treatment duration, best overall response, progression-free survival and overall survival (OS). Our data revealed that front-line treatment with CPI, followed by TT, showed a non-significant trend towards better OS compared to front-line TT (median OS: 35.0 vs. 18.0 months, p = 0.070). This association was confirmed in a subgroup of patients without systemic pre-treatments (median OS: 41.0 vs. 14.0 months, p = 0.02). Further, we observed significantly better objective response rates to second-line treatments for patients receiving front-line CPI (18.4 vs. 37.8%, p = 0.024). Last, our results indicated that rapid disease progression was less common in patients treated with front-line CPI (27.6% vs. 16.2%) and that subsequent treatment with TT resulted in favorable survival outcomes. Our real-world data indicate that sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in a subgroup of previously untreated BRAF-mutant metastatic melanoma patients.

eHealth Literacy in German Skin Cancer Patients.

The global incidence of skin cancer has steadily increased in recent years, and malignant melanoma still has one of the fastest-growing incidence rates among all malignant tumors in the western world. Thus, newly diagnosed patients have an increased need for health information concerning their disease. Using a standardized questionnaire, our study aims to investigate our patients' primary sources of health-related information as well as their self-proclaimed eHealth literacy. We received 714 questionnaires. Regardless of age, the primary source of information was the treating dermato-oncologist, followed by the treating general practitioner and the Internet. However, with increasing age, the usage of the Internet decreased. Hence, younger participants were better equipped to find health-related information while using the Internet. Additionally, comprehending health-related information and gaining medical knowledge was significantly increased in better-educated participants. Overall, our study shows that with increased use of eHealth services, accessing web-based information increased, correlating with a better eHealth literacy of our patients. eHealth technologies are increasingly becoming more prevalent as a primary source of information in our modern health care system. Thus, it is crucial to educate cancer patients in eHealth literacy to make autonomous, informed decisions and gain more confidence in dealing with their disease.

Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation.

BACKGROUND: Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating proteases in cutaneous diseases are poorly understood. OBJECTIVE: To dissect PAR2 signaling contributions to skin inflammation with new genetic and pharmacological tools. METHODS/RESULTS: We found markedly increased numbers of PAR2+ infiltrating myeloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell-mediated allergic skin inflammation. Cell type-specific deletion of PAR2 in myeloid immune cells as well as mutation-induced complete PAR2 cleavage insensitivity significantly reduced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demonstrated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell-expressed proteases furthermore uncovered a time-dependent regulation of CHS development with an important function of FXa-induced PAR2 activation during the late phase of skin inflammation. CONCLUSIONS: Myeloid cells and the TF-FXa-PAR2 axis are key mediators and potential therapeutic targets in inflammatory skin diseases.

ß2 Integrins on Dendritic Cells Modulate Cytokine Signaling and Inflammation-Associated Gene Expression, and Are Required for Induction of Autoimmune Encephalomyelitis.

Heterodimeric ß2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common ß2 (CD18) subunit, which hampers the analysis of the cell type-specific role of ß2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of ß2 integrins, specifically in dendritic cells (DCs). Stimulated ß2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2-6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific ß2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of ß2 integrins in vivo.

Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment.

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell-cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of ß2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC-Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy.

New diagnostic and imaging technologies in dermatology.

INTRODUCTION: Diagnosis of dermatological disorders is primarily based on clinical examination in combination with histopathology. However, clinical findings alone may not be sufficient for accurate diagnosis and cutaneous biopsies are being associated with morbidity. OBJECTIVE: The objective of this article is to review the newer technologies along with their applications, limitation and future prospectus. METHODOLOGY: Comprehensive literature search was performed using electronic online databases "PubMed" and "Google Scholar". Articles published in English language were considered for the review. RESULTS: In order to improve and/or widen the armamentarium in dermatologic disease diagnosis and therapy, newer emerging technologies are being made available which aid in diagnosis and management. New emerging technologies include confocal microscopy, digital photographic imaging, optical coherence tomography, high frequency ultrasonography, and artificial intelligence. There have been advancements in the dermoscopes. CONCLUSION: Significant progress is seen in the diagnostic methods and imaging technologies in dermatology, each having its advantages and limitations. Artificial intelligence/machine-based learning software may have a great scope to influence the dermatological practice.

Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors-A Retrospective, Real-World Cohort Study.

Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune evasion and might therefore promote resistance to ICI. In particular, recent observations in murine systems demonstrated that myeloid-derived factor Xa (FXa) impedes anti-tumor immunity in the tumor microenvironment and that the oral FXa inhibitor (FXa-i) rivaroxaban synergizes with ICI. The synergistic effect of FXa inhibitors with clinical ICI therapy is unknown. We performed a retrospective study of 280 metastatic melanoma patients who were treated with ICI and stratified them for concomitant anticoagulation (AC) by medical chart review. Data on baseline patient characteristics, specific AC treatment, ICI therapy, other tumor-targeting therapies, and clinical outcomes were analyzed. Of 280 patients who received ICI, 76 received concomitant AC during initial ICI therapy. Patients on AC were treated either with heparins (n = 29), vitamin K antagonists (VKA) (n = 20), or FXa-i (n = 27). Patients requiring AC during ICI therapy showed no significantly reduced objective response rate (ORR) (p = 0.27), or progression-free (PFS; median PFS 4 vs. 4 months; p = 0.71) or overall survival (OS; median OS: 39 vs. 51 months; p = 0.31). Furthermore, patients who underwent AC did not show significantly more bleeding complications (p = 0.605) than those who were not anticoagulated. Remarkably, stratification of patients by the class of AC revealed that patients receiving FXa-i were more likely to obtain CR (26.9 vs. 12.6%, p = 0.037), and showed better ORR (69.2 vs. 36.4%, p = 0.005), PFS (median PFS: 12 months vs. 3 months; p = 0.006), and OS (median OS not reached vs. 42 months; p = 0.09) compared to patients not receiving FXa-i. Patient demographics and tumor characteristics in this patient subcohort did not significantly differ from patients not on FXa-i. In summary, our study provides first clinical evidence that the clinical application of FXa-i may enhance the efficacy of ICI therapy via the restoration of anti-tumor immunity, while patients who received FXa-i were not more likely to encounter bleeding complications.

Merkel Cell Carcinoma: From Pathobiology to Clinical Management.

Merkel cell carcinoma (MCC) is an infrequent, rapidly growing skin neoplasm that carries a greater probability of regional lymph node involvement, and a grim prognosis in advanced cases. While it is seen predominantly in old age in sun-exposed body parts, the prevalence varies among different races and geographical regions. Merkel cell polyomavirus and UV radiation-induced mutations contribute to its etiopathogenesis. The clinical presentation of MCC lacks pathognomonic features and is rarely considered highly at the time of presentation. Histopathological examination frequently reveals hyperchromatic nuclei with high mitotic activity, but immunohistochemistry is required to confirm the diagnosis. Sentinel lymph node biopsy (SLNB) and imaging are advised for effective staging of the disease. Multimodal management including surgery, radiation therapy, and/or immunotherapy are deployed. Traditional cytotoxic chemotherapies may result in an initial response, but do not result in a significant survival benefit. Checkpoint inhibitors have dramatically improved the prognosis of patients with metastatic MCC, and are recommended first-line in advanced cases. There is a need for well-tolerated agents with good safety profiles in patients who have failed immunotherapies.

The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges.

The global incidence of malignant melanoma, the leading cause of skin cancer death, has steadily increased in recent years. Surgical excision is the treatment of choice for early-stage melanoma. However, 40-60% of patients with high-risk melanoma or with nodal involvement eventually experience loco-regional relapse or tumor progression. Adjuvant therapy aims to reduce the rate of recurrence in radically operated high-risk patients with melanoma and thus improves survival. Interferon-α has long been the only approved drug for adjuvant melanoma therapy, despite an unclear survival benefit. The landmark success of immune-checkpoint inhibitors and BRAF/MEK-directed targeted therapies in the treatment of patients with stage IV melanoma led to the initiation of clinical trials in the adjuvant setting. These trials demonstrated the efficacy of immune-checkpoint inhibitors and targeted therapies for the adjuvant treatment of high-risk patients with melanoma, as shown both by an increase in recurrence-free survival and the emergence of long-term survivors, finally resulting in the approval of the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab, PD1 inhibitors (nivolumab, pembrolizumab), and BRAF/MEK inhibitors for adjuvant melanoma therapy. This review aims to delineate the advances in adjuvant melanoma therapy, issuing particularly recent results from clinical trials. Moreover, we also discuss pending issues and future challenges, which comprise the adequate selection of adjuvant regimens for patient subgroups and the identification of markers likely to predict the individual response to adjuvant treatments. Last, we outline the role of emerging neoadjuvant approaches, which may complement adjuvant strategies and are currently investigated in clinical trials.

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma-A Retrospective Multicenter ADOReg Study.

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.