A 25-year-old woman presented with a four-year history of widespread erythema, blisters, and erosions, accompanied by pain that had worsened over the past week. Four years ago, she was diagnosed with pemphigus vulgaris (PV)based on multiple oral ulcers, widespread erythema, and thin-walled blisters. Despite treatment with corticosteroids, immunosuppressants, and biologics such as rituximab, her condition remained poorly controlled with recurrent flares. A general examination revealed cushingoid features, a buffalo hump, and a Body Mass Index of 28.08. The dermatological examination showed extensive erythema, flaccid bullae, erosions, and crusting on the scalp, trunk, and extremities, with profuse serous exudate. Erythematous bullous, verrucous plaques were also noted in the axillary and genital areas. The Pemphigus Disease Area Index score was 49. Laboratory tests revealed anti-Dsg1 antibodies at 237.8 U/mL and anti-Dsg3 antibodies at 174.5 U/mL. Skin secretion cultures grew multiple pathogenic organisms. The final diagnoses were pemphigus vulgaris, cutaneous infection, and drug-induced Cushing's syndrome, and others. Following multidisciplinary consultation and informed consent, the patient received corticosteroids, methotrexate, and protein A immunoadsorption (PA-IA)therapy for a total of 10 sessions. After discharge, her autoantibody titers decreased, and skin lesions improved significantly. During a 6-month follow-up period, the patient remained lesion-free, with a sustained decline in pemphigus-related autoantibody titers.

3017 Background: Neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs) is associated with significant morbidity, including pain, disfigurement and functional impairment. Surgical treatment for PNs may be limited due to tumor size, location and extent. A randomized, double-blind, placebo-controlled, phase 3 trial (NCT05913037) was conducted to evaluate the efficacy and safety of Luvometinib in adults with inoperable NF1 PN causing significant morbidities. Methods: Adults (≥18 yrs) with NF1 and symptomatic, inoperable PNs were randomized in a 2:1 to receive oral Luvometinib (8 mg daily) or placebo in 28-day cycles, stratified by baseline (BL) NRS-11 tumor pain score (≥2 or＜2). An interim analysis was performed at 16 months after the last patient randomization. The primary endpoint was confirmed objective response rate (ORR) by Blinded Independent Review Committe (BIRC) per REiNS criteria. Key secondary endpoints included ORR by the investigator (INV), duration of response (DOR), time to response (TTR) by BIRC and INV, pain severity and safety. Results: 167 adults were randomized to receive luvometinib (n = 112) or placebo (n = 55). As of the data cutoff on Aug 19, 2025, the median follow-up was 19.7 months(range: 1.4-25.5). The confirmed ORR assessed by BIRC was 43.8%（95% CI, 34.4-53.4）with luvometinib, compared with 10.9%（95% CI, 4.1-22.3）with placebo (p＜0.0001). Luvometinib led to a rapid response (median 3.9 months). The median DOR was 15.1 months (95% CI, 14.8-NE), with a 85.2% rate of DOR ≥12 months with luvometinib. A greater proportion of patients with BL overall tumor pain scores ≥2 experienced a reduction in pain score of at least 2 points with luvometinib compared to placebo (81.0% vs. 53.6%). The most common treatment-emergent adverse events (TEAEs) were folliculitis, increased CPK, mouth ulcer, diarrhea. Serious AEs occurred in 14.3% (luvometinib) versus 7.3% (placebo) of pts. TEAEs led to discontinuation was 1.8% in both groups. Conclusions: Our study demonstrated that luvometinib achieved a statistically significant ORR per BIRC compared with placebo, with rapid and durable response, significant reductions in pain severity, and an overall manageable safety profile. These findings suggest that luvometinib may emerge as a new standard treatment for patients with NF1 and symptomatic, inoperable PNs. Clinical trial information: NCT05913037 .

Background:Cutaneous squamous cell carcinoma (CSCC) accounts for 20% of all cutaneous cancers. Systemic treatment options for advanced CSCC (aCSCC) include immunotherapy, chemotherapy, and epidermal growth factor receptor (EGFR)-targeted therapy, although their efficacy is limited. HLX07 is a novel anti-EGFR antibody that showed preliminary anti-cancer activity and tolerability in phase I studies. Objectives:To evaluate the efficacy and safety of HLX07 in patients with aCSCC. Design:This is a multicenter, open-label, two-part phase II study. In Part 1, patients with metastatic or locally aCSCC not amenable to surgery or curative radiotherapy received 1500 mg (group A) or 1000 mg (group B) HLX07 intravenously every 3 weeks. In Part 2, patients received HLX07 at dose level determined with Part 1 results. Methods:The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee (IRRC). Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, immunogenicity, and quality of life. Results:Here we focus on Part 1 data. As of April 30, 2024, 31 patients were enrolled (group A, 21; group B, 10). Most patients had metastatic disease (85.7%; 90.0%). Per IRRC assessments, ORR was 19.0% (95% confidence interval (CI), 5.5-41.9) for group A and 60.0% (26.2-87.8) for group B; median progression-free survival was 4.9 (95% CI, 1.4-6.5) and 7.9 (95% CI, 2.2-11.1) months, and median duration of response was 5.0 (95% CI, 2.9-not evaluable (NE)) and 7.4 (95% CI, 2.8-NE) months, respectively. Median overall survival was 11.8 months (95% CI, 5.9-NE) and not reached (95% CI, 2.2-NE). Grade ⩾3 treatment-related adverse events (TRAEs) occurred in 8 (38.1%) and 3 (30.0%) patients, respectively. No TRAE leading to death or treatment discontinuation was reported. Conclusion:HLX07 monotherapy has demonstrated promising efficacy and a favorable safety profile in treating aCSCC, warranting further investigation in large-scale clinical studies. Trial registration:ClinicalTrials.gov NCT05238363.

As an effective therapeutic strategy for malignant neoplasms, boron neutron capture therapy(BNCT)has demonstrated promising clinical outcomes across various cutaneous malignancies. Multicenter studies in melanoma have reported complete response rates of 73% -78%, an overall disease control rate of 88%, and a 5-year disease-specific survival of 58%, with manageable toxicities including cutaneous radiation injury. For genital melanoma and extramammary Paget disease, BNCT has shown promising efficacy. In the first-in-human phase Ⅰ trial for cutaneous angiosarcoma, BNCT achieved a best overall response rate of 70% and a 2-year overall survival rate of 90.0%. Additionally, BNCT has exhibited therapeutic potential in cutaneous metastases and soft tissue sarcomas with cutaneous or subcutaneous involvement. This review systematically summarizes clinical advances in BNCT for cutaneous malignancies and discusses its clinical feasibility, current limitations, and future prospects.

BACKGROUND:Hemoporfin-mediated photodynamic therapy (HMME-PDT) is an established treatment for port-wine stains (PWS), but hypertrophic or nodular lesions often respond poorly, and the molecular mechanisms that govern treatment sensitivity remain unclear. The Ataxia Telangiectasia Mutated (ATM)-Seryl-tRNA synthetase (SerRS)-Vascular endothelial growth factor A (VEGFA) pathway has recently been implicated in hypoxia- and DNA damage-driven angiogenesis. METHODS:Human umbilical vein endothelial cells (HUVECs) were treated with HMME-PDT and/or all-trans retinoic acid (tRA). Cell viability was assessed by CCK-8 assay, angiogenic activity by tube formation assay, and mRNA expression of ATM, SerRS and VEGFA by quantitative real-time PCR. Protein levels of ATM, phosphorylated ATM (p-ATM), SerRS and VEGFA were evaluated by Western blotting. RESULTS:HMME-PDT significantly inhibited HUVEC viability and tube formation in a concentration- and light dose-dependent manner. HMME-PDT decreased total ATM and, more prominently, p-ATM, while upregulating SerRS and downregulating VEGFA at both mRNA and protein levels. tRA alone dose- and time-dependently reduced HUVEC proliferation, increased SerRS expression and suppressed VEGFA expression. Combined treatment with tRA and HMME-PDT produced the greatest inhibition of tube formation and the strongest induction of SerRS together with the most pronounced reduction in VEGFA, whereas changes in ATM and p-ATM were mainly driven by HMME-PDT. CONCLUSIONS:HMME-PDT exerts anti-angiogenic effects at least in part by modulating the ATM-SerRS-VEGFA axis in endothelial cells. Pharmacologic upregulation of SerRS by tRA further enhances VEGFA suppression and inhibition of angiogenesis, indicating a synergistic interaction between tRA and HMME-PDT. These findings provide a mechanistic rationale for tRA-augmented HMME-PDT as a potential strategy to improve outcomes in refractory PWS.

BACKGROUND:Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and non-invasive treatment for HPV-related diseases, but its underlying mechanisms still need further investigation. cGAS-STING signaling pathway takes part in antiviral innate immune defense, but its changes and regulatory mechanisms in ALA-PDT treatment remain unknown. METHODS:Under ALA-PDT treatment in HPV-transformed cells, the relative expression of mitochondrial DNA (mtDNA) was measured by qPCR. Cellular morphology and the spatial relationship between mitochondria and DNA were observed using confocal microscopy. Protein expression related to the cGAS-STING pathway was assessed by western blot, and apoptosis was detected via flow cytometry. Corresponding statistical analyses were performed. RESULTS:ALA-PDT treatment induced mitochondrial DNA (mtDNA) release into the HeLa cells cytosol and activated the cGAS-STING pathway, evidenced by upregulated cGAS and STING expression, and promoted cell apoptosis (P < 0.05). In addition, pharmacological inhibition of STING attenuated this effect. Notably, in mtDNA-depleted (ρ0) cells, the cGAS-STING response to ALA-PDT was markedly diminished, suggesting that the immunostimulatory effect of ALA-PDT may be mediated through mtDNA release. CONCLUSION:We identified that ALA-PDT could induce mtDNA release from mitochondria into cytoplasm and then activate cGAS-STING signaling pathway in HPV infected HeLa cells. These results might help expand our knowledge of ALA-PDT intervention mechanisms and is possibly instrumental to further exploration of novel photodynamic, photo-immuno and photo-immune-gene therapies.

Objective:Symmetrical acral keratoderma (SAK) is a rare dermatosis that primarily affects young males and manifests as symmetric, brownish, well-demarcated hyperkeratotic plaques on acral sites, particularly the wrists, dorsal hands, and fingers. Ichthyosis vulgaris (IV), the most common subtype of ichthyosis, is characterized by dry, rough skin with fine, adherent, diamond-shaped or polygonal scales on the extensor surfaces of the limbs and trunk. Clinical evidence frequently links the onset of SAK with the presence of IV. However, systematic analyses of this association remain limited. Materials and Methods:We searched PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) for English- and Chinese-language literature. Results:The comparative analysis revealed key parallels and distinctions. SAK predominantly affects young males and is exacerbated in hot and humid climates. IV typically manifests in infancy or early childhood, persists lifelong, and worsens during cold, dry winters. Both disorders involve FLG mutations at distinct loci. Clinically, SAK presents as symmetrically distributed, well-demarcated tan-to-dark brown macules or papules on acral sites, excluding the palms and soles. IV is characterized by light-to-dark brown diamond-shaped or polygonal scales with central adhesion and peripheral detachment, primarily on the extensor surfaces of the lower limbs. Histopathologically, SAK shows marked hyperkeratosis, thinning of the granular layer, and increased basal melanocytes. IV demonstrates mild-to-moderate hyperkeratosis with attenuation or absence of the granular layer and follicular keratin plugs. Both conditions are managed symptomatically with topical emollients and salicylic acid. Systemic approaches differ: retinoids are frequently used for IV but are seldom indicated for SAK. Conclusion:This systematic comparative analysis delineates the salient features of SAK and IV, suggesting that they may be classified as distinct disease entities.

Condyloma acuminatum (CA) is a recurrent HPV-associated lesion characterized by a locally immunosuppressive microenvironment. Although 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is widely used for CA, the mechanisms underlying its immunomodulatory effects remain incompletely understood. In this study, we investigated whether ALA-PDT-induced ferroptosis is associated with macrophage polarization and immune microenvironment remodeling in CA. HPV16-positive SiHa cells were used as an HPV-positive epithelial model to examine the cellular response to ALA-PDT, and the findings were further validated in an ex vivo CA tissue culture model. ALA-PDT suppressed the GPX4/SLC7A11 antioxidant system and promoted the accumulation of reactive oxygen species, malondialdehyde, and lipid peroxides in SiHa cells, consistent with ferroptosis-associated changes. In a Transwell co-culture system, ALA-PDT-treated SiHa cells promoted macrophage polarization toward an M1-like phenotype, as indicated by increased expression of CD86, iNOS, and IL-1β and decreased expression of CD206 and CD163. These effects were partially attenuated by ferrostatin-1. In ex vivo CA tissues, ALA-PDT similarly reduced GPX4 and SLC7A11 expression and was accompanied by an increase in CD86-positive macrophages and a decrease in CD206-positive macrophages. Collectively, these findings suggest that ALA-PDT may exert therapeutic effects in CA not only through direct cell death but also through ferroptosis-associated macrophage reprogramming, thereby contributing to modulation of the local immune microenvironment.

The human papillomavirus (HPV) E6/E7 proteins are thought to be critical in its pathogenesis, and the extracellular matrix (ECM) is a class of complex spatial network structures whose function involves a variety of biological processes. Differentially expressed genes were detected by transcriptome sequencing in HPV type 11 E6/E7-transfected HaCaT cells, and their expression and changes in ECM components were verified at the cellular and condyloma acuminatum tissue levels by qPCR. A total of 16 common differential genes were identified, which were mainly involved in regulating the structure and function of ECM. The transfected cells showed decreased adhesion, increased migration, and proliferation. qPCR showed that 11 genes were down-regulated. Tissue level showed that the expression of seven genes and components of the ECM was reduced in wart tissues of patients with warts infected with various HPV types. These differential genes may be critical for the regulation of ECM components by HPV viruses.

Pemphigus vulgaris (PV), a severe autoimmune disease with high morbidity and mortality, necessitates innovative therapies to improve outcomes while minimising the adverse effects of conventional immunosuppressants. Immunohistochemical analysis revealed elevated phosphorylated Janus kinase (p-JAK)1 and p-JAK2 expression in PV lesions, complemented by transcriptome data showing JAK/STAT pathway dysregulation. Using a PV acantholysis model, we demonstrated that Ruxolitinib, a JAK1/2 inhibitor, significantly reduced keratinocyte apoptosis, enhanced cell adhesion, and alleviated endoplasmic reticulum (ER) stress. Additionally, Ruxolitinib mitigated tunicamycin-induced ER stress and apoptosis in HaCaT cells. These findings establish a crucial role for JAK1/2 in PV pathogenesis, demonstrating that their inhibition alleviates ER stress, reduces apoptosis, and improves cell adhesion. Our results provide a theoretical foundation for the clinical application of JAK inhibitors in PV treatment.

Significance This subject explore the molecular biological mechanism of photodynamic therapy for port wine stain and provide new research directions and strategies for the treatment of port wine stain. Results 1. HMME-PDT down-regulated the expression of VEGFA in HUVEC cells and inhibited the tube formation of HUVEC cells.2. HMME-PDT up-regulated the expression of SerRS in HUVEC cells, downregulated the expression levels of ATM, p-ATM and VEGFA, and the downregulation of p-ATM was more obvious than that of ATM.3. Compared with HMME-PDT group and tRA group, the inhibition of tube formation experiment of HUVEC cells in the combined group was more obvious, and the expression of VEGFA was down-regulated more obviously after combined treatment. Conclusion HMME-PDT can inhibit ATM phosphorylation, so that SerRS can exert its transcriptional inhibitory effect on VEGFA.

Immune checkpoint inhibitors (ICIs) have become a standard treatment for various cancers, but their use is often associated with immune-related adverse events (irAEs), including cutaneous irAEs (cirAEs). Here, we report a rare case of subacute cutaneous lupus erythematosus (SCLE) induced by sintilimab, a PD-1 inhibitor, in a 30-year-old woman undergoing neoadjuvant chemo-immunotherapy for gastric cancer. The patient presented with erythema, macules, papules, and vesicles, with positive ANA (108U/mL) and strongly positive anti-SSA/Ro. After discontinuation of sintilimab and treatment with corticosteroids, hydroxychloroquine, and intravenous immunoglobulin (IVIG), her symptoms improved. This case represents the first reported instance of drug-induced lupus caused by sintilimab and emphasizes the importance of distinguishing between paraneoplastic lupus and ICI-induced lupus.

10044 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by multiple progressive tumor and non-tumor manifestations, with abnormal activating MAPK pathway. Plexiform neurofibromas (PN) presents in 20-50% of NF1 patients (pts) and may cause serious complications. One MEK1/2 inhibitor was approved for pediatric pts with NF1-related PN in US, EU and China, but therapeutic options remain limited. Luvometinib is a highly potent selective anti-tumorigenic inhibitor of MEK1/2, potentially effective in NF1-related PN. Previous studies have confirmed that luvometinib is expected to be a targeted therapy for neurofibromatosis type 1 in pediatric patients (pts). Methods: This multi-center, open-label phase 2 clinical trial is to assess safety and efficacy of luvometinib in pediatric pts with NF1- related PN. The primary endpoint was objective response rate (ORR) evaluated by investigators (INV). The key secondary endpoint was ORR evaluated by Blinded independent review committee (BIRC), and other secondary endpoints include 1-year PFS and others. Preliminary findings from the phase 2 trial were previously disclosed at ASCO 2024. Here, we present the updated efficacy and safety results in pediatric participants. Results: As of data cut-off (September 23, 2024), 46 pediatric pts were enrolled and treated with a dose of 5 mg/m 2 (the recommended phase 2 dose according to phase 1 study). The median follow-up time was 25.1 months. ORR evaluated by INV was 60.5% (95%CI: 44.4, 75.0), and 26 pts had partial response. ORR evaluated by BIRC was 44.2% (95%CI: 29.1, 60.1), and 19 pts had partial response. 11 of 14 pts (78.6%) with tumor pain at baseline (overall tumor pain NRS≥2) decreased to 0 points. The median DOR and median PFS were still not reached. 1-year PFS rate evaluated by INV was 95.3%. 45 pts (97.8%) experienced treatment-related adverse events (TRAEs). Among these, grade ≥3 TRAEs occurred in 10 pts (21.7%), including folliculitis(4.3%), dermatitis acneiform (4.3%), blood creatine phosphokinase increased (4.3%), ejection fraction decreased (2.2%), upper respiratory tract infection (2.2%), pneumonia (2.2%), anemia (2.2%) and gastrointestinal disorders (2.2%). 2 pts (3.1%) reported treatment-related serious adverse events. 14 pts (30.4%) experienced TRAEs led dose interruption. No reported TEAE led to dose reduction, discontinuation or death. No new safety signal was observed. Conclusions: Overall, luvometinib was well-tolerated and demonstrated promising anti-tumor activity in pediatric participants with NF1-related PN. Long-term efficacy and safety follow-up are ongoing. Clinical trial information: NCT04954001 .

AbstarctBackground: Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and non-invasive treatment for HPV-related diseases such as condyloma acuminatum. However, its underlying mechanisms remain to be fully elucidated. The cGAS-STING signaling pathway plays a critical role in antiviral innate immune defense, yet its changes and regulatory mechanisms in the context of ALA-PDT intervention warrant further investigation.Methods: Under ALA-PDT treatment in HPV-infected cells, the relative expression of mitochondrial DNA (mtDNA) was measured by qPCR. Cellular morphology and the spatial relationship between mitochondria and DNA were observed using confocal microscopy. Protein expression related to the cGAS-STING pathway was assessed by Western Blot, and apoptosis was detected via flow cytometry. Corresponding statistical analyses were performed.Results: In HeLa cells, ALA-PDT induced the release of mitochondrial DNA and activated the cGAS-STING signaling pathway, thereby promoting cell death. In contrast, in mtDNA-depleted HeLa cells, ALA-PDT failed to effectively activate the cGAS-STING pathway.Conclusion: ALA-PDT treatment in HeLa cells triggers the release of mtDNA from mitochondria into the cytoplasm. The released mtDNA activates the cGAS-STING signaling pathway, leading to HeLa cell death.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by plexiform neurofibromas (PNs), which are present in 20–60

Atopic dermatitis (AD) and psoriasis exhibit opposing T-cell polarization patterns and cytokine axes. Dupilumab, a monoclonal antibody targeting the interleukin-4/interleukin-13 (IL-4/IL-13) signaling pathway, has become a first-line biologic for moderate-to-severe AD. However, emerging clinical observations reveal that some patients with AD develop psoriasiform eruptions following biologic therapy, while certain patients with psoriasis may conversely develop eczematous lesions after corresponding biologic treatments. This paradoxical immune response has been termed the "immune drift phenomenon." This review synthesizes current evidence regarding the immunological mechanisms, clinical manifestations, histopathological characteristics, temporal patterns, and therapeutic strategies associated with this phenomenon, with particular emphasis on comprehensive management approaches, including topical therapies, systemic medication adjustments, biologic switching, and targeted small-molecule agents. In particular, it is important to acknowledge the potential limitations of small-molecule inhibitors, such as Janus kinase (JAK) inhibitors, or combination biologic therapies for managing immune drift, including the current lack of robust long-term safety and efficacy data in this specific context. We aim to provide clinicians with evidence-based management recommendations while outlining future research directions.

Patients with autoimmune diseases are susceptible to developing a second autoimmune disorder. Psoriasis, a common autoimmune disease, frequently occurs alongside other autoimmune conditions in some individuals. We report the case of a young female patient diagnosed with plaque psoriasis, initially treated with secukinumab, and achieved complete skin clearance at 12 weeks. However, she experienced a decline in the efficacy of secukinumab, with recurrence of symptoms and subsequent development of chronic spontaneous urticaria (CSU) and was switched to treatment with deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor. The use of deucravacitinib resulted in a favorable therapeutic outcome, effectively managing both psoriasis and CSU 12 weeks after treatment. This case highlights the potential of deucravacitinib as a novel monotherapy for patients with both psoriasis and CSU.

Janus kinase (JAK) inhibitors are increasingly being used in dermatology due to their broad potential in managing both local and systemic inflammation. More recently, abrocitinib, an oral JAK 1 inhibitor, has shown promising clinical efficacy in the treatment of various skin disorders beyond moderate to severe atopic dermatitis (AD). We firstly presented three cases, each with diagnosis of pyoderma gangrenosum (PG), livedoid vasculopathy (LV), or hidradenitis suppurativa (HS), and conducted a comprehensive scoping review of the available literature on the use of abrocitinib in the treatment of diverse skin disorders. We summarized a total of 16 skin disorders, including our cases. The results indicated that abrocitinib, whether used as monotherapy or in combination with other treatments, was effective and well-tolerated in these disorders. These findings expanded the range of diseases for which abrocitinib may serve as an alternative therapeutic choice.

SignificanceHemoporfin-mediated photodynamic therapy (HMME-PDT) has been recognized as a safe and effective treatment for port wine stain (PWS). However, some patients show limited improvement even after multiple treatments. Herein, we aim to explore the effect of autophagy on HMME-PDT in human umbilical vein endothelial cells (HUVECs), so as to provide theoretical basis and treatment strategies to enhance clinical effectiveness.MethodsEstablish the in vitro HMME-PDT system by HUVECs. Apoptosis and necrosis were identified by Annexin Ⅴ-FITC/PI flow cytometry, and autophagy flux was detected by monitoring RFP-GFP-LC3 under the fluorescence microscope. Hydroxychloroquine and rapamycin were employed in the mechanism study. Specifically, the certain genes and proteins were qualified by qPCR and Western Blot, respectively. The cytotoxicity was measured by CCK8, VEGF-A secretion was determined by ELISA, and the tube formation of HUVECs was observed by angiogenesis assay.ResultsIn vitro experiments revealed that autophagy and apoptosis coexisted in HUVECs treated by HMME-PDT. Apoptosis was dominant in early stage, while autophagy gradually increased in the middle and late stage. AMPK, AKT and mTOR participated in the regulation of autophagy induced by HMME-PDT, in which AMPK was positive regulation, while AKT and mTOR were negative regulation. Hydroxychloroquine could not inhibit HMME-PDT-induced autophagy, but capable of blocking the fusion of autophagosomes with lysosome. Rapamycin might cooperate with HMME-PDT to enhance autophagy in HUVECs, leading to increased cytotoxicity, reduced VEGF-A secretion, and weakened angiogenesis ability.ConclusionsBoth autophagy and apoptosis contribute to HMME-PDT-induced HUVECs death. Pretreatment of HUVECs with rapamycin to induce autophagy might enhance the photodynamic killing effect of HMME-PDT on HUVECs. The combination of Rapamycin and HMME-PDT is expected to further improve the clinical efficacy.

3096 Background: Neurofibromatosis type 1(NF1) is an autosomal dominant tumor predisposition syndrome characterized by NF1 gene variants, resulting in over-activation of the RAS pathway. Plexiform neurofibroma (PN) is benign tumors that arise from nerve tissue and are a hallmark feature of NF1. They typically grow along nerves and cause disfigurement, pain, and other complications depending on their location and size. FCN-159, a highly potent and selective inhibitor of MEK1/2 by targeting inhibition of the RAS pathway, holds promise as a therapeutic agent for treating NF1-related PN. Methods: A multi-center, open-label phase 1/2 clinical trial was conducted to assess the safety and efficacy in pediatric patients(pts) with NF1-related PN. Here, we reported the safety and efficacy outcomes observed during phase 2 in pediatric pts, who received FCN-159 at the 5 mg/m2 dose once daily on a continuous basis in a 28-day cycle. Preliminary findings from the phase 1/2 trial were previously disclosed at ASCO 2023. Results: As of November 24, 2023,46 pts enrolled. The median age is 8.0 years (range 2-17). The most frequent PN related complications were disfigurement (69.6%) and pain (63.0%). Median volume of target neurofibroma were 37.7 cm³ (range 2.2-1144.1). Efficacy outcomes are reported for 43 pts (modified intent-to-treat population). With the median follow-up of 15.1 months (range 14.1-16.4), the investigator and Blinded Independent Review Committee (BIRC) assessed ORR were 48.8% and 30.2%, respectively. The mDoR and median mPFS were not reached. Preliminary efficacy data are presented in the table. Among the 16 pediatric subjects with tumor pain at baseline (overall tumor pain NRS≥1) and at least one post-baseline assessment, pain scores decreased by at least 2 points in 81.3% (13/16) pts, and pain scores reduced to 0 points (indicating no pain sensation) in 81.3% (13/16) pts, signifying clinically meaningful improvement. 43 pts (93.5%) experienced TRAEs with grade ≥3 TRAEs occurred in 8 pts (17.4%), including dermatitis acneiform (4.3%), folliculitis (4.3%), pneumonia (2.2%), upper respiratory tract infection (2.2%), ejection fraction decreased (2.2%), and blood creatine phosphokinase increased (2.2%). 2 pts (4.3%) reported treatment-related serious adverse events (one case of dermatitis acneiform and pneumonia each). No TRAEs resulting in dose reduction, discontinuation or death. Conclusions: FCN-159 demonstrated good tolerability and exhibited notable anti-tumor activity in pediatric pts with NF1-related PN. Clinical trial information: NCT04954001 . [Table: see text]