Libtayo® (Cemiplimab-rwlc) Injection for Intravenous Use.

Libtayo® (cemiplimab-rwlc) injection for intravenous use was recently approved by the US Food and Drug Administration (FDA) for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC), both being the advanced stages of BCC. In the past, it was approved by the FDA for the treatment of metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC), both being the advanced stages of CSCC. Cemiplimab is a monoclonal antibody that works by blocking the programmed death-1 pathway. In two open-label, single-arm, phase 2 studies, cemiplimab was investigated for the treatment of advanced stages of BCC (study 1620, NCT03132636) and advanced stages of CSCC (study 1540, NCT02760498). The primary endpoint was objec-tive response rate (ORR) per independent central review. In the study 1620, both mBCC and laBCC received cemiplimab 350 mg every 3 weeks. ORR was 21% (6/28) and 31% (26/84) in the mBCC and laBCC groups, respectively. In the study 1520, mCSCC was divided into two groups: one receiving cemiplimab 350 mg every 3 weeks (Q3W) and another receiving 3-mg/kg cemiplimab every 2 weeks (Q2W); the third group, laCSCC, received cemiplimab 3 mg/kg every 2 weeks. ORR was 41% (23/56) in the Q3W group, 49% (29/59) in the Q2W group, and 44% (34/78) in the laCSCC group. An acceptable safety profile and antitumor activity was discovered in patients treated with cemiplimab. The recommended dosage for cemiplimab to treat advanced stages of BCC and CSCC is 350 mg every 3 weeks administered intravenously over 30 min.

The Efficacy of Curcumin Application to Melanoma in Mice: A Systematic Review and Meta-analysis.

OBJECTIVE: Melanoma is a skin tumor that poses a serious threat to human health. Our study explores the effectiveness and safety of curcumin in the treatment of melanoma based on animal models, and providing evidence-based medical evidence for curcumin in the treatment of malignant melanoma. METHODS: The study collected all randomized controlled trial data from the establishment of the database to October 2023 of curcumin for the treatment of melanoma in mice by searching PubMed, Embase, and the Cochrane Library. According to inclusion and exclusion criteria, data were extracted and quality assessment of included studies was performed by using the SYRCLE (Systematic Review Center for Laboratory animal Experimentation) animal experiment bias risk assessment tool. RevMan 5.4 and Stata 15.1 software were used for meta-analysis. RESULTS: Eighteen randomized controlled trials were included in this study with a total of 185 mouse models, including 93 mice in the experimental group and 92 in the control group. The results of meta-analysis showed that the IC50 (inhibitory concentrations of 50%) in the experimental group is lower than that of the control group [standardized mean difference (SMD) = -4.68, 95% confidence interval (CI) (-7.30, -2.06), P < 0.01]; the tumor volume is significantly smaller than the control group [SMD = -3.10, 95% CI (-4.45, -1.75), P < 0.01]; the tumor weight is smaller than the control group [SMD = -3.01, 95% CI (-4.81, -1.21), P < 0.01]. However, there was no significant statistical difference in the apoptosis rate between the experimental group and the control group [SMD = 2.27, 95% CI (-1.39, 5.92), P < 0.01]. CONCLUSION: Based on animal models for meta-analysis, curcumin can inhibit the growth and proliferation of melanoma in mice. Melanoma may be an effective method for treating melanoma. However, this result still requires further in-depth research.

Ceramide metabolism alterations contribute to Tumor Necrosis Factor-induced melanoma dedifferentiation and predict resistance to immune checkpoint inhibitors in advanced melanoma patients.

Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation. Methods: We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy. Results: Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Discussion: Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.

Long-Term Survival in Patients With Advanced Melanoma.

IMPORTANCE: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. OBJECTIVE: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. EXPOSURES: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). RESULTS: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). CONCLUSIONS AND RELEVANCE: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

In Vitro Superparamagnetic Hyperthermia Employing Magnetite Gamma-Cyclodextrin Nanobioconjugates for Human Squamous Skin Carcinoma Therapy.

In vitro alternative therapy of human epidermoid squamous carcinoma (A431) by superparamagnetic hyperthermia (SPMHT) using Fe3O4 (magnetite) superparamagnetic nanoparticles (SPIONs) with an average diameter of 15.8 nm, bioconjugated with hydroxypropyl gamma-cyclodextrins (HP-γ-CDs) by means of polyacrylic acid (PAA) biopolymer, is presented in this paper. The therapy was carried out at a temperature of 43 °C for 30 min using the concentrations of Fe3O4 ferrimagnetic nanoparticles from nanobioconjugates of 1, 5, and 10 mg/mL nanoparticles in cell suspension, which were previously found by us to be non-toxic for healthy cells (cell viabilities close to 100%), according to ISO standards (cell viability must be greater than 70%). The temperature for the in vitro therapy was obtained by the safe application (without exceeding the biological limit and cellular damage) of an alternating magnetic field with a frequency of 312.4 kHz and amplitudes of 168, 208, and 370 G, depending on the concentration of the magnetic nanoparticles. The optimal concentration of magnetic nanoparticles in suspension was found experimentally. The results obtained after the treatment show its high effectiveness in destroying the A431 tumor cells, up to 83%, with the possibility of increasing even more, which demonstrates the viability of the SPMHT method with Fe3O4-PAA-(HP-γ-CDs) nanobioconjugates for human squamous cancer therapy.

Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics.

BACKGROUND: Advanced skin cutaneous melanoma (SKCM) is responsible for the majority of skin cancer-related deaths. Apart from the rare BRAF V600F mutation, which can be targeted with specific drugs, there are currently no other novel effective therapeutic targets. METHODS: We used SMR analysis with cis-expressed quantitative trait locus (cis-eQTL) as the exposure variable and SKCM as the outcome variable to identify potential therapeutic targets for SKCM. Colocalization assays and HEIDI tests are used to test whether SKCM risk and gene expression are driven by common SNPs. Replication analysis further validated the findings, and we also constructed protein-protein interaction networks to explore the relationship between the identified genes and known SKCM targets. Drug prediction and molecular docking further validated the medicinal value of drug targets. Transcriptome differential analysis further validated that there were differences between normal tissues and SKCM for the selected targets. RESULTS: We identified 13 genes significantly associated with the risk of SKCM, including five protective genes and eight harmful genes. The HEIDI test and co-localization analysis further indicates a causal association between genes (SOX4, MAFF) and SKCM, categorized as Class 1 evidence targets. The remaining 11 genes, except for HELZ2 show a moderately causal association with SKCM, categorized as Class 2 evidence targets. Target druggability predictions from DGIdb suggest that SOX4, MAFF, ACSF3, CDK10, SPG7, and TCF25 are likely to be future drug targets. CONCLUSION: The study provides genetic evidence for targeting available drug genes for the treatment of SKCM.

Recurrent squamous cell carcinoma of the upper eyelid treated with combination therapy of ALA photodynamic therapy and surgery with secondary healing.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) frequently occurs in photoexposed areas. Surgery remains the mainstay of treatment in attempts to reduce recurrence, but it must be combined with other therapy because of the limited excision possible in the region of the eyelid, lip, and nose. Photodynamic therapy (PDT) is a relatively new treatment modality that involves the administration of a photosensitizing drug and its subsequent activation by specific wavelengths of light to produce reactive oxygen species that specifically destroy target cells. CASE REPORT: An 87-year-old female presented 4 weeks after initial resection with recurrent medium-differentiated cSCC measuring 5.2 cm × 3 cm × 2 cm in the left upper eyelid. Subsequent treatment involved palliative resection with an additional 1 cm at 3 margins of the tumor (excluding the bottom edge of the double eyelid line) and 3 applications of PDT using 5-aminolevulinic acid as the photosynthesizing agent in the open wound over a 2-week period. The wound healed well within 6 weeks. During the following 4 years, the patient showed satisfactory progress in both aesthetics and function, with no sign of recurrence or metastasis. CONCLUSION: Refractory cSCC was successfully managed using a combination of PDT and secondary healing, and functions of the head and face were well protected. These results suggest that such management warrants consideration in clinical settings.

Merkel cell carcinoma associated with TNF inhibitor therapy: a systematic review of case reports.

A rare neuroendocrine skin cancer called Merkel cell carcinoma (MCC) primarily affects elderly people. The objective of this study is to comprehensively review the impact of immunosuppressive medications, particularly TNF inhibitors, on the emergence of MCC. METHODS: PubMed, Web of Science, Science Direct, and Cochrane Library were searched. Study articles were screened by title and abstract at Rayyan Qatar Computing Research Institute, then a full-text assessment was implemented. RESULTS: A total of eight case reports with 9 patients were included. Of the total population, seven were women and only two were men. Their age ranged from 31 to 73 years. More than half the population (5 cases) were being treated for rheumatoid arthritis. All received TNF inhibitors that were associated with the induction of MCC. CONCLUSION: We found that it is essential for physicians to explain potential cancer risks to patients before starting long-term immunosuppressive therapy and to conduct routine checks for MCC and other side effects. TNF inhibitors (infliximab, adalimumab, etanercept, and golimumab) were all associated with MCC development. Women constituted the majority of cases and most were elderly.

Mycosis Fungoides Palmaris et Plantaris Mimicking "Dyshidrotic Eczema": A Case Report.

Mycosis fungoides palmaris et plantaris (MFPP) is a rare variant of mycosis fungoides (MF), a type of cutaneous T-cell lymphoma. MFPP primarily affects the palms and soles of the feet and is often misdiagnosed as dyshidrotic eczema due to its similar clinical presentation. This case report presents a middle-aged woman with MFPP whose initial presentation was mistaken for dyshidrotic eczema. Despite treatment with topical corticosteroids, the patient's lesions persisted, prompting further investigations that led to the diagnosis of MFPP. The patient was initiated on betamethasone dipropionate ointment and hydroxyzine for pruritus management, with a pivotal referral to oncology for comprehensive evaluation. This case highlights the importance of considering MFPP in the differential diagnosis of persistent eczematous lesions on the palms and soles, especially when treatment with topical corticosteroids is ineffective. J Drugs Dermatol. 2024;23(7):569-570.     doi:10.36849/JDD.8474.

Antitumor activity of anlotinib in malignant melanoma: modulation of angiogenesis and vasculogenic mimicry.

Malignant melanoma presents a formidable challenge due to its aggressive metastatic behavior and limited response to current treatments. To address this, our study delves into the impact of anlotinib on angiogenesis and vasculogenic mimicry using malignant melanoma cells and human umbilical vein endothelial cells. Evaluating tubular structure formation, cell proliferation, migration, invasion, and key signaling molecules in angiogenesis, we demonstrated that anlotinib exerts a dose-dependent inhibition on tubular structures and effectively suppresses cell growth and invasion in both cell types. Furthermore, in a mouse xenograft model, anlotinib treatment resulted in reduced tumor growth and vascular density. Notably, the downregulation of VEGFR-2, FGFR-1, PDGFR-ß, and PI3K underscored the multitargeted antitumor activity of anlotinib. Our findings emphasize the therapeutic potential of anlotinib in targeting angiogenesis and vasculogenic mimicry, contributing to the development of novel strategies for combating malignant melanoma.

Genistein transfersome-embedded topical delivery system for skin melanoma treatment: in vitro and ex vivo evaluations.

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.

Review on radiomic analysis in 18F-fluorodeoxyglucose positron emission tomography for prediction of melanoma outcomes.

Over the past decade, several strategies have revolutionized the clinical management of patients with cutaneous melanoma (CM), including immunotherapy and targeted tyrosine kinase inhibitor (TKI)-based therapies. Indeed, immune checkpoint inhibitors (ICIs), alone or in combination, represent the standard of care for patients with advanced disease without an actionable mutation. Notably BRAF combined with MEK inhibitors represent the therapeutic standard for disease disclosing BRAF mutation. At the same time, FDG PET/CT has become part of the routine staging and evaluation of patients with cutaneous melanoma. There is growing interest in using FDG PET/CT measurements to predict response to ICI therapy and/or target therapy. While semiquantitative values such as standardized uptake value (SUV) are limited for predicting outcome, new measures including tumor metabolic volume, total lesion glycolysis and radiomics seem promising as potential imaging biomarkers for nuclear medicine. The aim of this review, prepared by an interdisciplinary group of experts, is to take stock of the current literature on radiomics approaches that could improve outcomes in CM.

Enhanced Skin Penetration and Efficacy: First and Second Generation Lipoidal Nanocarriers in Skin Cancer Therapy.

Skin carcinoma remains one of the most widespread forms of cancer, and its global impact continues to increase. Basal cell carcinoma, melanoma, and squamous cell carcinoma are three kinds of cutaneous carcinomas depending upon occurrence and severity. The invasive nature of skin cancer, the limited effectiveness of current therapy techniques, and constraints to efficient systems for drug delivery are difficulties linked with the treatment of skin carcinoma. In the present era, the delivery of drugs has found a new and exciting horizon in the realm of nanotechnology, which presents inventive solutions to the problems posed by traditional therapeutic procedures for skin cancer management. Lipid-based nanocarriers like solid lipid nanoparticles and nanostructured lipid carriers have attracted a substantial focus in recent years owing to their capability to improve the drug's site-specific delivery, enhancing systemic availability, and thus its effectiveness. Due to their distinct structural and functional characteristics, these nanocarriers can deliver a range of medications, such as peptides, nucleic acids, and chemotherapeutics, via different biological barriers, such as the skin. In this review, an effort was made to present the mechanism of lipid nanocarrier permeation via cancerous skin. In addition, recent research advances in lipid nanocarriers have also been discussed with the help of in vitro cell lines and preclinical studies. Being a nano size, their limitations and toxicity aspects in living systems have also been elaborated.

Melanoma and cannabinoids: A possible chance for cancer treatment.

The endocannabinoid system is composed by a complex and ubiquitous network of endogenous lipid ligands, enzymes for their synthesis and degradation, and receptors, which can also be stimulated by exogenous compounds, such as those derived from the Cannabis sativa. Cannabis and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied in different conditions. Recent data have shown that the endocannabinoid system is responsible for maintaining the homeostasis of various skin functions such as proliferation, differentiation and release of inflammatory mediators. Because of their role in regulating these key processes, cannabinoids have been studied for the treatment of skin cancers and melanoma; their anti-tumour effects regulate skin cancer progression and are mainly related to the inhibition of tumour growth, proliferation, invasion and angiogenesis, through apoptosis and autophagy induction. This review aims at summarising the current field of research on the potential uses of cannabinoids in the melanoma field.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

BACKGROUND: Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. METHODS: Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). RESULTS: Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. CONCLUSION: QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.

Real-world outcomes of patients with resected stage III melanoma treated with adjuvant therapies.

BACKGROUND: Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real-world outcomes are limited. In addition, a significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti-PD1 IO and TT in a real-world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies. METHODS: We retrospectively analyzed 130 patients who received adj therapy (100 anti-PD1 IO and 30 TT). RESULTS: At a median follow-up of 30 months, median relapse-free survival (RFS) was 24.6 (95% CI, 17-not reached [NR]) versus 64 (95% CI, 29.5-NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment-related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5-NR), respectively, p = 0.02. CONCLUSION: In summary, both TT and IO yielded prolonged RFS in a real-world setting, however, longer follow-up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real-life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re-treatment.

Health-related quality of life in patients with metastatic basal cell carcinoma treated with cemiplimab: Analysis of a phase 2 trial.

BACKGROUND: A phase 2 cemiplimab study (NCT03132636) demonstrated a 24.1% objective response rate in patients diagnosed with metastatic basal cell carcinoma (mBCC) who were not candidates for continued hedgehog inhibitor (HHI) therapy due to intolerance to previous HHI therapy, disease progression while receiving HHI therapy, or having not better than stable disease on HHI therapy after 9 months. Here, health-related quality of life (QoL) for this patient population is reported. METHODS: Adult patients with mBCC were treated with intravenous cemiplimab at a dose of 350 mg every 3 weeks for 5 treatment cycles of 9 weeks/cycle then 4 treatment cycles of 12 weeks/cycle. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and Day 1 of each cycle. Across Cycles 2 to 9, the overall change from baseline was analyzed using a mixed model with repeated measures. Responder analyses determined clinically meaningful improvement or deterioration (changes ≥10 points) or maintenance across all scales. RESULTS: Patients reported low symptom burden and moderate-to-high functioning at baseline. Maintenance for QLQ-C30 global health status (GHS)/QoL and across all functioning and symptom scales was indicated by overall mean changes from baseline. Clinically meaningful improvement or maintenance was reported at Cycle 2 for GHS/QoL (77%), functioning scales (77% to 86%), and symptom scales (70% to 93%), with similar proportions of improvement or maintenance at Cycles 6 and 9, excluding fatigue. On the Skindex-16, clinically meaningful improvement or maintenance was reported across the emotional, symptom, and functional subscales, in 76%-88% of patients at Cycle 2, which were generally maintained at Cycles 6 and 9. Overall mean changes from baseline showed maintenance across these subscales. CONCLUSIONS: The majority of patients treated with cemiplimab reported improvement or maintenance in GHS/QoL and functioning while maintaining a low symptom burden.

Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma.

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression across a variety of cancers. Recent evidence suggests MIF as a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas, however clinical evidence of MIF and particularly of DDT remain limited. This retrospective study analyzed 97 patients treated at Yale for melanoma between 2002-2020. Bulk-RNA sequencing of patient tumor samples from the Skin Cancer SPORE Biorepository was used to evaluate for differential gene expression of MIF, DDT, CD74, and selected inflammatory markers, and gene expression was correlated with patient survival outcomes. Our findings revealed a strong correlation between MIF and DDT levels, with no statistically significant difference across common melanoma mutations and subtypes. Improved survival was associated with lower MIF and DDT levels and higher CD74:MIF and CD74:DDT levels. High CD74:DDT and CD74:MIF levels were also associated with enrichment of infiltrating inflammatory cell markers. These data suggest DDT as a novel target in immune therapy. Dual MIF and DDT blockade may provide synergistic responses in patients with melanoma, irrespective of common mutations, and may overcome ICI resistance. These markers may also provide prognostic value for further biomarker development.