Venous and arterial thromboembolic events (TEEs) represent a substantial threat for melanoma patients treated with immune checkpoint inhibition (ICI) and have a significant impact on quality of life, therapy outcome, and survival. Existing risk assessment models for predicting TEE risk have been developed for other patient collectives and show poor performance in melanoma patients treated with ICI. In this cohort analysis, 358 AJCC stage III/IV melanoma patients treated with ICI between April 2013 and July 2024 at the University Skin Cancer Center Hamburg and the University Medical Center Mannheim were included. TEEs were recorded and classified as thrombosis including vein thrombosis, pulmonary embolism, stroke, or transient ischemic attack. Clinical and laboratory data were determined before the start and prospectively during the treatment. We identified elevated serum baseline D-Dimer (p = 0.0098) and elevated C-reactive protein (p = 0.0042) concentrations and measurable tumor burden (p = 0.0039) as main risk factors for the occurrence of TEE. For the final model, points were assigned for the Cancer Immunotherapy Thromboembolism Assessment (CITA) according to the impact of those variables using multiple logistic regression. The score was calculated for each patient. For the high-risk group, the negative predictive value (NPV) was 97.2%; sensitivity and specificity were 83.3% and 62%, respectively. The CITA risk score provides a simple and easily calculated risk assessment tool for stratifying melanoma patients based on their risk for TEE after ICI initiation, but prospective validation is needed before clinical use can be recommended.

Despite therapeutic advancements, approximately 50% of advanced melanoma patients succumb to metastatic disease. Molecular tumor boards (MTB) aim to identify targetable molecular alterations to guide individualized treatment strategies. Yet, real-world data on patient selection, referral timing, recommendation rates, implementation, and clinical impact remain limited. In this exploratory retrospective bicenter analysis, we evaluated 80 patients with advanced melanoma who presented at institutional MTBs of two comprehensive cancer centers. Clinical and molecular tumor data were analyzed using bioinformatic tools to characterize mutation profiles, treatment recommendations, and their real-world implementation. Most patients (88.3%) had stage IV melanoma at the time of presentation and had received a median of three prior systemic treatment lines. Actionable treatment recommendations were formulated in 77.9% of eligible cases, yet only 33.7% of recommendations were implemented. Non-implementation was most commonly attributable to early patient death or regulatory barriers. Importantly, when recommended therapies were applied, patients experienced significantly improved progression-free survival (7.85 vs. 4.34 months; PFS ratio 1.8) and overall survival (10.64 vs. 5.06 months) compared with patients in whom recommended treatments were not implemented. Among patients with implemented MTB recommendations (n = 26), the median intra-patient PFS ratio was 1.68, and 14 of 26 patients (53.8%) achieved a PFS ratio ≥ 1.3. These findings indicate that MTBs frequently generate clinically actionable recommendations for metastatic melanoma, but late-stage referral substantially limits their real-world implementation. When applied, molecularly guided treatment strategies may confer meaningful clinical benefit, underscoring the importance of earlier integration of MTBs into melanoma care pathways.

BACKGROUND:Adjuvant therapy with anti-PD-1 monotherapy in melanoma is well established. However, a perioperative approach starting immunotherapy before surgery appears mechanistically more reasonable and emerging research results suggest a clinical benefit. This study aims to provide a comprehensive overview of the current use of perioperative anti-PD-1 monotherapy in Germany. PATIENTS AND METHODS:Patients with stage III melanoma who received perioperative anti-PD-1 monotherapy from April 2019 to March 2025 were included. Data from eight German skin cancer centers were retrospective collected including histological and radiological assessments. RESULTS:We identified 75 melanoma patients with perioperative anti-PD-1 monotherapy. Surgery was conducted in 75% of patients after a median of 11 weeks after therapy initiation. Pathological assessment revealed a major pathological response (MPR) in 46.5% of cases, a partial pathological response in 23.2%, and no pathological response in 30.4%. A moderate to strong correlation between radiological and pathological responses was identified. During a median follow up period of 11.6 months, melanoma recurrence was observed in 16 patients (21%). The longest recurrence-free survival was seen in the MPR group. CONCLUSIONS:Perioperative anti-PD-1 monotherapy has been implemented in routine clinical practice in German skin cancer centers. The observed outcomes are comparable to data reported from prospective studies.

Despite substantial clinical benefit from immune checkpoint inhibitors (ICI), advanced melanoma remains challenging due to frequent treatment resistance. Resistance may be intrinsic (primary) or emerge over time (secondary). Biomarkers predicting distinct resistance phenotypes before therapy are lacking. As key mediators of cellular communication, extracellular vesicles (EVs) represent promising biomarkers. This study aimed to identify baseline EV proteome-derived pathways and biomarkers associated with overall, primary, and secondary resistance to ICI in advanced melanoma and to derive biomarker signatures predictive of progression-free survival (PFS). EVs were isolated from pretreatment plasma samples of 46 patients with advanced melanoma using size exclusion chromatography and ultracentrifugation. Proteomic profiling was performed by liquid chromatography-mass spectrometry using DIA-NN. Pathway enrichment and network analyses were conducted using Reactome, Metascape, Cytoscape, and DAVID. Resistance-associated proteins were integrated into composite biomarker signatures and evaluated for association with PFS. Overall resistance was characterized by enrichment of platelet- and complement-associated pathways. Primary resistance was associated with enhanced Fc gamma receptor (FCGR) signaling and downregulation of KSRP-associated post-transcriptional regulatory processes. In contrast, secondary resistance was preceded by distinct baseline EV proteomic patterns involving complement activation and reduced hemostasis- and platelet-related pathways. EV-derived biomarker signatures for overall, primary, and secondary resistance independently discriminated patients according to PFS. Baseline plasma EV proteomics reveals distinct systemic biological programs associated with different resistance phenotypes to ICI in advanced melanoma. EV-derived biomarker signatures enable stratification by PFS and warrant validation in larger, multicentric cohorts.

BACKGROUND:Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced cutaneous squamous cell carcinoma (cSCC). The influence of comorbidities and concomitant medications on treatment efficacy remains incompletely defined. OBJECTIVES:To evaluate the impact of comorbid conditions and commonly prescribed medications on progression-free survival (PFS) and overall survival (OS) in patients with advanced cSCC receiving ICI. METHODS:In this multicentre cohort study, 273 patients with unresectable or metastatic cSCC treated with ICI were identified from the prospective ADOReg skin cancer registry. Data on comorbidities, such as haematologic malignancies, immunosuppressive conditions, cardiovascular disease and concomitant medications, such as immunosuppressive agents and anticoagulants, were analysed. Treatment outcomes were measured as PFS and OS. RESULTS:Among first-line patients (n = 253), immunosuppressive conditions were associated with shorter PFS (5.5 vs. 24.4 months, p = 0.012) and OS (16.6 vs. 34.1 months, p < 0.001). Haematologic malignancies were likewise linked to poorer PFS (18.6 vs. 27.0 months, p = 0.032) and OS (17.0 vs. 33.6 months, p = 0.0067). Concomitant anticoagulant therapy correlated with longer PFS (49.3 vs. 17.4 months, p = 0.032), but not OS (p = 0.22). In multivariate analysis, immunosuppressive disease remained independently associated with shorter OS (HR = 9.88, 95% CI: 1.11-87.5, p = 0.040) and anticoagulant use with longer PFS (HR = 0.34, 95% CI: 0.15-0.80, p = 0.014). These associations were confirmed in Cox models weighted by inverse probability of treatment (IPTW), supporting robustness to confounding. No effect was attributable to any specific anticoagulant subclass. CONCLUSIONS:Our analyses suggest that immunosuppressive disease is an independent predictor of shortened OS, underscoring the critical role of host immune competence. We further report a novel, independently significant association between anticoagulant use and prolonged PFS. Other associations should be regarded as exploratory. These findings highlight host-related factors as potential modulators of ICI efficacy and merit prospective validation.

Background Circulating tumor DNA (ctDNA) is a promising biomarker in melanoma, with higher sensitivity for tumor burden detection than conventional diagnostics. While well established in research, clinical routine implementation remains pending. Key global questions concern optimal clinical applications and barriers to adoption. Methods A web-based survey of 116 members of the Melanoma World Society Study Group assessed international expert opinions on ctDNA utility across predefined clinical scenarios. The questionnaire included 18 general questions on ctDNA use and 5 clinical vignettes with de-identified patient data and retrospectively obtained ctDNA results. Results ctDNA was rated most valuable for detecting minimal residual disease (mean score 3.63), surveillance of recurrent disease (3.85), and stage IV melanoma (3.82), with limited utility in early stages. Experts considered ctDNA superior to S100 and LDH for early relapse detection and identifying progressive disease. Most participants (80%) agreed that ctDNA correlates with radiographic response, and 82% favored its integration into routine follow-ups. In urgent high-tumor-burden settings, 82.8% would initiate BRAFi/MEKi therapy based on ctDNA if tissue analysis was pending, and 93.9% if unavailable. For central nervous system lesions, 62% did not support blood ctDNA, while 66% considered cerebrospinal fluid valuable. Pragmatic approaches with small to mid-size targeted panels and short turnaround times were preferred. Major barriers included the need for prospective trials (85%), standardized guidelines (83%), and reimbursement policies (82%). Conclusion Key opinion leaders regarded ctDNA as a valuable adjunct selected melanoma scenarios. Validation through prospective studies, guideline development, and reimbursement frameworks are essential for broader clinical implementation.

BackgroundCancer-associated fibroblasts (CAFs), frequently present in many tumor tissues, have received increasing attention over the past decade, while research on CAFs circulating in the blood of cancer patients is still in its infancy. This is the first study to assess the incidence, concentration, and potential prognostic value of cCAFs alone or in combination with other biomarkers such as circulating tumor cells (CTCs) or cancer-associated proteins, in melanoma patients.MethodsCTCs and cCAFs were enriched from whole blood samples of 31 melanoma patients (stage IIB–IV) using the CTCeptor system, which makes use of automated density-based enrichment and CD45-based negative depletion. The isolated cells were stained with DAPI, and antibodies against MART-1, MCAM, α-SMA, and CD45. CTCs were defined as DAPI+, MART-1/MCAM+, CD45−cells, while cCAFs were defined as DAPI+, α-SMA+, CD45−cells.ResultsCTCs and cCAFs were detected in approximately half of the melanoma patients, respectively. On average, more cCAFs (mean: 11 cells, range: 1–60) than CTCs (mean: 4.5 cells, range: 1–20) were found in the patients’ blood samples. The median progression-free survival (PFS) for patients with an increased cCAF count (≥5) was 2.07 months, while for those with a lower cCAF count (<5), it was 10.35 months (p = 0.51). When combined with elevated lactate dehydrogenase (LDH) (≥245 U/L) or S100B (≥0.152 μg/L) levels, high cCAF counts tend to a reduced PFS (high LDH/high cCAF: 1.92 months, high S100B/high cCAF: 1.77 months), compared to patients with low LDH/S100B, indicating improved risk stratification when cCAFs are used alongside established biomarkers.ConclusionThis study demonstrates the possibility of co-detecting CTCs and cCAFs in the blood of melanoma patients for the first time. A higher mean number of cCAFs was detected and showed a trend toward shorter progression-free survival. The encouraging results of this pilot study need to be validated on a larger cohort of melanoma patients.

PURPOSE:Circulating tumor DNA (ctDNA) refers to small DNA fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a noninvasive tool for real-time disease monitoring. Although ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. In this study, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities. EXPERIMENTAL DESIGN:To assess ctDNA monitoring as a tool in evaluating therapy response and clinical outcomes in patients with mUM, using an IVDR-certified digital PCR assay targeting GNAQQ209 and GNA11Q209 mutations. RESULTS:We analyzed 655 samples from 75 patients with mUM. Absence of detectable ctDNA in baseline samples prior to first-line therapy was associated with improved OS (HR = 0.13; P = 0.02) and progression-free survival (PFS; HR = 0.31; P = 0.008). Similar associations were observed in patients treated with any line of therapy (OS: HR = 0.19, P = 0.002; PFS: HR = 0.27, P = 0.02). Detection of ctDNA within 3 months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF > 5% any time point had a significantly poorer prognosis compared with patients with MAF < 5% (median OS 4 months vs. 21 months, P < 0.001; median PFS 2.5 months vs. 3.6 months, P = 0.004), emphasizing the added value of quantitative assessment. CONCLUSIONS:Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3 months of starting of treatment, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a noninvasive tool for disease monitoring.

INTRODUCTION:Cutaneous T-cell lymphomas (CTCL) comprise a clinically, histologically, and molecularly heterogeneous group of subtypes. They fulfil aspects of both chronic and malignant skin conditions and may thus affect health-related quality of life (HRQL) in various ways. To date, there is little information known about the topology of CTCL patients in routine care. OBJECTIVES:This study aims to characterize the frequency and distribution of body sites affected by CTCL in routine care and to analyze the impact on HRQL. METHODS:Cross-sectional survey study as part of the routine care at a University Medical Center. Topical distribution was identified with a detailed grid scheme filled by the patient and the affected body surface area (BSA) was recorded by the physician. Skindex-29 measured HRQL. RESULTS:153 patients with CTCL were included, with a mean age of 59.5 ± 16.5 years and a majority of male patients (61.4%). The mean number of grids marked was 129.2, corresponding to 12.7% of the BSA, and the most frequently affected body areas were thighs, back, and lower legs. Skindex-29 revealed that HRQL in CTCL patients is impaired on a mild level, with a mean of 27.5 ± 21.3. Patients with involvement of the visible or genital area showed a significantly poorer HRQL. Overall, 70% of patients reported relevant pruritus (NRS ≥3), which was strongly associated with worse HRQL, independent of localization. Linear regression analysis revealed a significant correlation between an increased impairment of HRQL and a higher BSA, a manifestation in visible areas, and a higher itching intensity. CONCLUSION:This analysis provides data on the distribution of CTCL in routine care. Our study highlights the importance of specific areas, such as visible body areas or the genital area, as determinants for the reduction of HRQL. This knowledge can help to improve patient-centered healthcare in CTCL.

Cellular communication network factor 1 (CCN1, also referred to as CYR61), a secreted matricellular protein, has been implicated in tumor progression and stromal remodeling within the metastatic tumor microenvironment of melanoma. Here, we investigated, for the first time, whether CCN1 circulating in the blood can serve as a biomarker in melanoma patients. In this retrospective study, serum CCN1 levels before treatment initiation were measured by enzyme-linked immunosorbent assay (ELISA) in 95 patients with advanced melanoma (unresectable AJCC stage III and AJCC IV) treated with immune checkpoint inhibitors. The association between CCN1 serum levels and clinico-pathological parameters, as well as clinical outcomes, was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Moreover, CCN1 levels were also evaluated in relation to established biomarkers, including S100B. An optimal cutoff of 221.76 pg/mL was calculated for serum CCN1 to stratify patients into high and low CCN1 groups. No significant associations, despite T status, with demographic, clinico-pathological, or laboratory parameters of the CCN1 groups were detected. High serum CCN1 levels were significantly associated with reduced OS (median OS: 15 months vs. median OS not reached, p = 0.011), but only a trend was toward impaired PFS was detected. Combination of CCN1 with established prognosticators in melanoma, such as S100B serum levels, enhances risk stratification. Patients with high serum levels of both CCN1 and S100B exhibited the poorest prognosis (median OS: 5 months), while those with low levels of CCN1 and S100B had the most favorable outcomes (median OS not reached; overall log-rank p < 0.0001, adjusted p = 0.00032), indicating the complementary value of CCN1. In the multivariate Cox-regression analysis, CCN1 sustained as an independent prognostic factor of impaired OS (HR = 3.50, 95

Background The rapidly advancing field of cancer therapy has sparked growing interest in the potential synergy between anticoagulation and immune checkpoint inhibitor (ICI) therapy. Recent research highlights that anticoagulants, traditionally used for thromboprophylaxis and managing thromboembolic events, may also exhibit immunomodulatory properties. These properties can influence the tumor microenvironment by promoting immune cell infiltration, enhancing antitumor immune responses, and potentially reducing metastasis. This emerging evidence underscores the complex interplay between coagulation pathways and immune regulation, paving the way for further exploration of the clinical benefits of combining anticoagulation with ICI therapy.Methods A systematic review was conducted to synthesize the current evidence on the interplay between anticoagulation and ICI. Relevant studies examining their mechanisms of action, clinical outcomes, and potential interactions were identified and analyzed. Comprehensive database searches were performed to ensure a thorough and inclusive review of the literature.Results Preclinical studies consistently show that combining ICIs with anticoagulants can enhance cancer treatment by inhibiting tumor growth and metastasis. In particular, low molecular weight heparin, oral factor Xa (FXa) inhibitors, and platelet inhibitors have demonstrated synergistic effects with ICI. However, these findings have not been consistently replicated in clinical settings. While two retrospective studies reported no significant impact of anticoagulants on ICI efficacy, one retrospective study found improved outcomes in advanced melanoma patients treated with ICI and FXa inhibitors. Additionally, another retrospective study revealed a significant association between platelet aggregation inhibition and extended progression-free survival.Conclusions Our literature review underscores the intricate relationship between anticoagulation and ICIs in cancer therapy. Future studies should prioritize exploring the interactions between ICI, FXa inhibitors, and antiplatelet agents.

Background and objectivesLimited representation of diverse skin types in dermatology training hinders physicians' ability to diagnose and treat patients with skin of color (SoC), thus contributing to health disparities. This study evaluated the effectiveness of a mandatory seminar in improving medical students' ability to correctly identify skin conditions in SoC, as measured by objective tests.MethodsThe pre-post design study was conducted among fourth year medical students at the University of Hamburg (Germany) between October 2024 and February 2025. A multiple-choice test using clinical images of eight SoC skin conditions assessed visual diagnostic skills at the beginning and end of a seminar.ResultsThe analysis included surveys from a total of 142 students (57.7% female, mean age: 25.2 years). The lowest pre-seminar identification rates were observed for melasma (26.8%) and keloids (40.1%). The overall identification rate improved significantly from 54.8% at the beginning of the seminar to 92.5% at the end of the seminar. The greatest increases in the proportion of correct diagnoses were found for melasma (+ 65.5%), keloids (+ 51.4%), and tinea (+ 47.9%). Furthermore, self-assessed knowledge on skin type classification scales and anatomical and physiological differences between light skin and SoC increased at the end of the seminar.ConclusionThe seminar effectively improved students' ability to correctly identify skin conditions in SoC. Integrating SoC-focused training into medical curricula can bridge knowledge lacunae and thus help reduce health disparities by equipping future physicians in providing equitable care.

Hauterkrankungen bei Menschen mit Skin of Color (SoC, Hauttyp IV bis VI nach Fitzpatrick) finden in der dermatologischen Ausbildung in Deutschland bisher keine ausreichende Berücksichtigung. Die vorliegende Arbeit zielt darauf ab, den aktuellen Stand zu bisher entwickelten Lehrformaten für Medizinstudierende zur Steigerung der Kompetenz beim Umgang mit Hauterkrankungen bei SoC aufzuzeigen. In einer Literaturrecherche mit vordefinierten Kriterien in PubMed MEDLINE wurden 7 Studien eingeschlossen. Der Großteil der Lehrformate wurde auf freiwilliger Basis angeboten. Die Anzahl der Teilnehmenden reichte von 20–172. Unser Review verdeutlicht, dass Interventionen zu SoC in der dermatologischen Lehre sowohl die diagnostische Kompetenz als auch das subjektive Vertrauen in die eigenen Fertigkeiten von Medizinstudierenden verbessern können. Diese Übersichtsarbeit kann als Ausgangspunkt für die stärkere Integration einer diversitätssensiblen Lehre im Rahmen der medizinischen Ausbildung genutzt werden.

Die personalisierte Therapie des Melanoms gewinnt zunehmend an Bedeutung. Biomarker bieten die Möglichkeit, Therapien präziser zu steuern und Nebenwirkungen zu reduzieren. Ziel dieses Beitrags ist es, eine Übersicht über aktuelle gewebebasierte, blutbasierte und radiologische Biomarker und deren klinische Anwendung beim Melanom zu geben. Es erfolgten eine Literaturrecherche und Analyse aktueller Studien zu Biomarkern in der adjuvanten und neoadjuvanten Melanomtherapie; relevante Kongressbeiträge wurden zusätzlich herangezogen. Gewebebasiert zeigen sich PD-L1(„programmed death-ligand 1“)-Expression, IFN(Interferon)-γ-Signatur, Genexpressionsprofile (GEP) und „tumor mutational burden“ (TMB) von prognostischer und prädiktiver Relevanz. Blutbasiert ist die zirkulierende Tumor-Desoxyribonukleinsäure (ctDNA) im Sinne einer „liquid biopsy“ als personalisierter Biomarker zur longitudinalen Nachverfolgung unter Therapie oder Nachsorge hervorzuheben. Positronenemissionstomographie-Computertomographie (PET-CT) und Körperzusammensetzung („body composition“) ermöglichen eine verbesserte Einschätzung der Therapieeffizienz. Aktuell gibt es keine Daten aus prospektiven Validierungsstudien zu diesen Biomarkern; erste Daten der NivoMela-Studie werden erwartet. Die Kombination gewebe-, blutbasierter und radiologischer Biomarker im Sinne multiparametrischer Ansätze ist vielversprechend, jedoch bedarf es weiterer prospektiver Validierungen für eine breite klinische Nutzung. Aktuell sind diese noch nicht in die klinische Routine zentrenübergreifend oder kostenerstattend implementiert.

Background Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT. Methods We analyzed 1,296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016-2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1,125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists). Results Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 percent CI 0.39-0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 percent CI 0.19-0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 percent CI 0.25-0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 percent CI 0.27-0.87, p = 0.015). Conclusion Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.

BACKGROUND:Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT. METHODS:We analyzed 1296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016-2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists). RESULTS:Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 % CI 0.39-0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 % CI 0.19-0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 % CI 0.25-0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 % CI 0.27-0.87, p = 0.015). CONCLUSION:Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.

BACKGROUND:Cutaneous squamous cell carcinoma (cSCC) is the second most frequent skin cancer. In locally advanced and metastatic cases, the PD-1 inhibitor cemiplimab has transformed treatment, with response rates around 50 %. Despite its success, predictive biomarkers remain an unmet clinical need. D-dimer levels have been associated with poor outcomes in various cancers but have not been studied in cSCC. OBJECTIVES:To assess the potential of serum D-dimer levels as predictive and monitoring biomarkers for disease control in advanced cSCC patients receiving cemiplimab. METHODS:In this retrospective monocentric study, 45 advanced cSCC patients treated with cemiplimab were analyzed. D-dimer levels before and during treatment were correlated with clinical disease control data. Clinical characteristics, including cardiovascular disease and anticoagulatory medication, were monitored and mapped among groups. RESULTS:Elevated baseline D-dimer levels were significantly associated with reduced time to progression (TTP; HR 3.46, p = 0.007). Multivariable logistic regression showed that high baseline D-dimers independently predicted lower disease control rate (DCR; OR 0.13, p = 0.011) and overall response rate (ORR; OR 0.06, p = 0.0182). After treatment start, D-dimer levels did not significantly correlate with response metrics. CONCLUSIONS:High pre-treatment D-dimer levels are an independent predictive biomarker for reduced DCR and ORR in advanced cSCC patients treated with cemiplimab. On-treatment D-dimer levels did not exhibit discriminatory value as a monitoring biomarker in this real-world cohort. Further studies are needed to confirm the role of D-dimer levels in response prediction in advanced cSCC.

Circulating tumor cells (CTCs) play an important role in metastasis formation. Aberrant signaling of oncogenic pathways (e.g., PI3K/AKT/mTOR pathway) drives tumor progression. In this work, the susceptibility of the colon cancer CTC-derived cell line CTC-MCC-41 to AKT and mammalian target of rapamycin (mTOR) inhibitors was evaluated. Additionally, the functional role of the expressed AKT isoforms was characterized in this cell line. The efficacy of the AKT inhibitor MK2206, the mTOR inhibitor RAD001, and the combination was examined in CTC-MCC-41 cells in a murine intracardiac xenotransplantation model. Furthermore, stable isoform-specific AKT1 or AKT2 knockdowns (KDs) as well as AKT1/AKT2 double-KD cells were generated. Differentially regulated proteins and phospho-peptides were identified using liquid chromatography coupled mass spectrometry (LC-MS). CTC-MCC-41 cells showed a high susceptibility for dual targeting of AKT and mTOR in vivo, indicating that selective eradication of CTCs by AKT/mTOR inhibitors may be considered a new treatment option in cancer. KD of AKT1 or AKT2 significantly reduced the proliferation of CTC-MCC-41 cells. AKT KDs share commonly regulated proteins and phospho-proteins, but also regulate a large number uniquely. AKT1/AKT2 double-KD cells show a strongly dysregulated replication machinery, as well as a decrease in cell cycle activity and stem-cell-associated processes, underlining the non-redundant role of AKT isoforms.