Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. METHODS: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). RESULTS: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. CONCLUSION: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Patterns of radiological response to tebentafusp in patients with metastatic uveal melanoma.

Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P  = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab.

BACKGROUND: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. METHOD: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. RESULTS: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. CONCLUSIONS: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.

The genetic evolution of acral melanoma.

Acral melanoma is an aggressive type of melanoma with unknown origins, arising on the sole, palm, or nail apparatus. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. Our study examined exome sequencing data from 139 tissue samples, spanning different progression stages, collected from 37 patients. We found that 78.4% of the melanomas displayed one or more clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These genomic "hailstorms" were typically shared across all progression stages within individual patients. Genetic alterations known to activate TERT also arose early. By contrast, mutations in the MAP-kinase pathway appeared later during progression, often leading to different tumor areas harboring non-overlapping driver mutations. We conclude that the evolutionary trajectories of acral melanomas substantially diverge from those of melanomas on sun-exposed skin, where MAP-kinase pathway activation initiates the neoplastic cascade followed by immortalization later. The punctuated formation of hailstorms, paired with early TERT activation, suggests a unique mutational mechanism underlying the origins of acral melanoma. Our findings highlight an essential role for telomerase, likely in re-stabilizing tumor genomes after hailstorms have initiated the tumors. The marked genetic heterogeneity, in particular of MAP-kinase pathway drivers, may partly explain the limited success of targeted and other therapies in treating this melanoma subtype.

What Is New in Cutaneous T Cell Lymphoma?

PURPOSE OF REVIEW: This review focuses on updates in prognosis, pathogenesis, and treatment of cutaneous T cell lymphoma (CTCL). RECENT FINDINGS: Cohort studies indicate imaging may be necessary in early-stage CTCL. Risk factors for progression of CTCL have been identified. Interactions between malignant cells and the tumor microenvironment (TME) and the skin microbiome advance the understanding of pathogenesis and tumor cell dissemination. Studies support a hypothesis of circulating malignant tumor cells. MicroRNA (miR) influence tumor progression and prognosis; the IL22-STAT3-CCL20 cascade may be a novel target. IL-4, IL-5, and IL-31 cytokines are relevant for pruritus and could be targets for therapeutic interventions. Systemic therapies, such as JAK inhibitors, targeted antibodies, and checkpoint inhibitors, show promise in advanced stages. Allogenic hematopoietic stem cell transplantation provides a potential curative option for patients. Further investigations of prognosis and translational research are necessary to improve stratification of patients for treatment.

Immune-Related Sclerosing Cholangitis and Subsequent Pyogenic Liver Abscesses in Two Patients With Melanoma Treated by Triplet Therapy: A Case Report.

Immune checkpoint inhibitors have improved the treatment of many cancers. However, immune-related (IR) adverse events can limit their use. A rare but potentially severe IR adverse event is IR-cholangitis, which is mostly induced by anti-programmed cell death 1 (PD1) antibodies and is often corticosteroid-resistant. Consequently, immunosuppressive therapy is increased, which interferes with the antitumor response and bears the risk of infection. We report on 2 patients with BRAF V600E mutant melanoma, who presented with IR-sclerosing cholangitis under triplet therapy with atezolizumab [anti-programmed cell death ligand 1 (PD-L1) antibody], vemurafenib (BRAF inhibitor), and cobimetinib (MEK inhibitor). In both cases, the administration of corticosteroids initially resulted in a marginal improvement but was followed by a rebound of biliary enzymes and the subsequent emergence of pyogenic liver abscesses with bacteremia. Liver abscesses developed without preceding invasive procedures, which implies that a more restrictive approach to immunosuppressive therapy for IR-cholangitis should be considered. To our knowledge, we report the first 2 cases of IR-cholangitis and subsequent liver abscesses without prior invasive intervention, the first cases of IR-cholangitis induced by triplet therapy, and 2 of the few anti-PD-L1 induced cases contributing to the evidence that both anti-PD1 and anti-PD-L1 antibodies induce IR-cholangitis. Treatment strategies for IR-cholangitis need to be improved to prevent life-threatening infectious complications.

The role of triple therapy and therapy sequence in treatment of BRAF-mutant metastatic melanoma. Response to overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

Novel therapies have achieved unprecedented benefit in survival of advanced melanoma patients. While immunotherapy (ICI) can be administered independent of mutational status, BRAF and MEK kinase inhibitors represent another effective treatment option for patients with BRAF mutant melanoma. Given the benefits these therapies demonstrate, the natural instinct was to combine. Three studies have investigated the benefit of combination of ICI using anti-PD-1 or anti-PD-L1 antibody and targeted therapy (TT) with BRAF and MEK inhibitors over TT and placebo. Among these studies, statistically significantly superior duration of response was observed, however overall and progression-free survival were only numerically superior, if at all. One triple combination was approved for BRAF mutant metastatic melanoma; however, the expected synergistic effect of triple therapy could not be universally confirmed and the observed benefits with triple seem to depend on statistical considerations rather than a biological reason. As patients with BRAF mutant melanoma have both ICI and TT as their first-line treatment options, the question whether the sequence matters was addressed. Two prospective trials compared first-line ICI, followed by TT at progression, or vice-versa, with additional "sandwich" approach (8 weeks of TT followed by ICI until progression, then TT again) in the Secombit study. The benefit of first-line ICI was demonstrated in both studies with Secombit study showing the "sandwich" approach to have similar effect. Current data advices for immunotherapy based regiments in patients with BRAF mutant melanoma or, possibly, sandwich approach. Whether triple therapy is superior to ICI monotherapy still needs to be addressed considering not only efficacy, but also safety.

Clock-like Mutation Signature May Be Prognostic for Worse Survival Than Signatures of UV Damage in Cutaneous Melanoma.

Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort's mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma.

Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB-IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient's treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker.

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma.

BACKGROUND: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. METHODS: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. CONCLUSION: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Effects of COVID-19 Lockdown on Melanoma Diagnosis in Switzerland: Increased Tumor Thickness in Elderly Females and Shift towards Stage IV Melanoma during Lockdown.

At the early stages of the COVID-19 outbreak in 2020, Switzerland was among the countries with the highest number of SARS-CoV2-infections per capita in the world. Lockdowns had a remarkable impact on primary care access and resulted in postponed cancer screenings. The aim of this study was to investigate the effects of the COVID-19 lockdown on the diagnosis of melanomas and stage of melanomas at diagnosis. In this retrospective, exploratory cohort study, 1240 patients with a new diagnosis of melanoma were analyzed at five tertiary care hospitals in German-speaking Switzerland over a period of two years and three months. We compared the pre-lockdown (01/FEB/19-15/MAR/20, n = 655) with the lockdown (16/MAR/20-22/JUN/20, n = 148) and post-lockdown period (23/JUN/20-30/APR/21, n = 437) by evaluating patients' demographics and prognostic features using Breslow thickness, ulceration, subtype, and stages. We observed a short-term, two-week rise in melanoma diagnoses after the major lift of social lockdown restrictions. The difference of mean Breslow thicknesses was significantly greater in older females during the lockdown compared to the pre-lockdown (1.9 ± 1.3 mm, p = 0.03) and post-lockdown period (1.9 ± 1.3 mm, p = 0.048). Thickness increase was driven by nodular melanomas (2.9 ± 1.3 mm, p = 0.0021; resp. 2.6 ± 1.3 mm, p = 0.008). A proportional rise of advanced melanomas was observed during lockdown (p = 0.047). The findings provide clinically relevant insights into lockdown-related gender- and age-dependent effects on melanoma diagnosis. Our data highlight a stable course in new melanomas with a lower-than-expected increase in the post-lockdown period. The lockdown period led to a greater thickness in elderly women driven by nodular melanomas and a proportional shift towards stage IV melanoma. We intend to raise awareness for individual cancer care in future pandemic management strategies.

Eight Years of Real-Life Experience with Smoothened Inhibitors in a Swiss Tertiary Skin Referral Center.

BACKGROUND: The hedgehog inhibitors vismodegib and sonidegib are approved for the treatment of advanced basal cell carcinoma. This study reports the experiences with these therapies in a tertiary skin referral center in daily practice. METHODS: A retrospective, observational, single-center study analyzing medical records of patients with aBCC treated with a smoothened (SMO) inhibitor outside a clinical trial for at least one month between 2013 and 2021. RESULTS: In total, 33 patients were included: 21 (64%) patients were treated with vismodegib, 3 (9%) patients with sonidegib and 9 (27%) patients with both treatments subsequently. With vismodegib, the best overall response was complete response (CR) in 33% cases, and partial response (PR) in 33% cases. Under sonidegib, 42% patients achieved CR and 17% PR. Mean duration to next treatment was 33 and 14 months for vismodegib and sonidegib, respectively. Adverse events varied in frequency between continuous and intermittent dosing and they were the most common reason for therapy discontinuation. CONCLUSIONS: Our real-world data illustrate the pitfalls and benefits of HhIs as well as the impact of different dosing regimens on adverse events, patient adherence and response. Treatment duration remains limited by adverse events and resistance. Additional treatment options, including immunotherapy and drug combinations, are needed.

Advances in the drug management of basal cell carcinoma.

INTRODUCTION: Basal cell carcinoma (BCC) is the most common skin cancer in humans. Recently, BCCs were suggested to be classified into 'easy to treat' and 'difficult to treat,' and different therapeutic options are suggested for their management. AREAS COVERED: In this review, the authors discuss treatment options that are approved, recommended for, or are still in development for treatment of BCC. The review covers approved local therapies, such as imiquimod and 5-fluorouracil, and systemic therapies, such as hedgehog inhibitors. New medical agents, investigated in clinical trials, are reviewed. These include: targeted therapies, such as GLI antagonists or anti-VEGFR agents, immunotherapies, such as checkpoint inhibitors, recombinant cytokines or silencing RNA, as well as intralesional virotherapies with modified adeno- or herpes viruses. EXPERT OPINION: The progress made in recent years has improved the management of patients with advanced BCC; however, neither tumor targeting nor immune system engaging agents provide a cure. New treatment approaches directed not only to known targets but also the tumor microenvironment are in development and are anticipated to improve the management of difficult to treat BCC.

Cutaneous T cell lymphoma.

Primary cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. CTCL subtypes demonstrate a variety of clinical, histological, and molecular features, and can follow an indolent or a very aggressive course. The underlying pathogenetic mechanisms are not yet entirely understood. The pathophysiology of CTCL is complex and a single initiating factor has not yet been identified. Diagnosis is based on clinicopathological correlation and requires an interdisciplinary team. Treatment decision is made based on short-term and long-term goals. Therapy options comprise skin-directed therapies, such as topical steroids or phototherapy, and systemic therapies, such as monoclonal antibodies or chemotherapy. So far, the only curative treatment approach is allogeneic haematopoietic stem cell transplantation. Novel therapies, such as chimeric antigen receptor T cells, monoclonal antibodies or small molecules, are being investigated in clinical trials. Patients with CTCL have reduced quality of life and a lack of effective treatment options. Further research is needed to better identify the underlying mechanisms of CTCL development and course as well as to better tailor treatment strategies to individual patients.

Clinicopathological and Genomic Profiles of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma Identify Overlapping Signatures with a High Mutational Burden.

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare tumors developing in chronically sun-exposed skin. Clinicopathological features are similar, but they differ in prognosis, while PDS has a more aggressive course with a higher risk for local recurrence and metastases. In current clinical practice, they are diagnosed by exclusion using immunohistochemistry. Thus, stringent diagnostic criteria and correct differentiation are critical in management and treatment for optimal outcomes. This retrospective single-center study collected clinicopathological data and tumor samples of 10 AFX and 18 PDS. Extracted genomic DNA from tumor specimens was analyzed by a next-generation sequencing (NGS) platform (FoundationOne-CDx™). Among 65 identified mutations, TP53 inactivating mutations were observed in all tumor specimens. In both AFX and PDS, the known pathogenic gene alterations in CDKN2A, TERT promoter, and NOTCH1 were frequently present, along with high mutational burden and stable Micro-Satellite Instability status. The mutational profiles differed only in ASXL1, which was only present in AFX. Further differences were identified in likely pathogenic and unknown gene alterations. Similarities in their genomic signatures could help to distinguish them from other malignancies, but they are not distinguishable between each other using the FoundationOne-CDx™ NGS panel. Therefore, histological criteria to determine diagnosis remain valid. For further insight, performing deep tumor profiling may be necessary.

Collection and preprocessing of fine needle aspirate patient samples for single cell profiling and data analysis.

High cell viability and recovered cell concentration are typical quality control requirements for single-cell processing and quality data. This protocol describes procedures for sampling, live-cell biobanking, preprocessing for single-cell RNA sequencing, and analysis of fine-needle aspiration (FNA) samples of the skin. The minimally invasive nature of FNA collection is more accepted by patients and allows for frequent longitudinal sampling, resulting in high-quality single-cell sequencing data that capture cellular heterogeneity in clinical samples.