BACKGROUND/OBJECTIVES:Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, most commonly arising in the choroid. Its development is associated with phenotypic characteristics, ultraviolet radiation, and germline or somatic genetic alterations. Despite progress in diagnostics and local therapies, UM remains characterized by high metastatic risk and poor overall prognosis. This review aimed to summarize current knowledge on epidemiology, clinical features, genetic background, prognostic factors, and therapeutic approaches in metastatic UM. METHODS:A structured literature review was conducted to evaluate epidemiological trends, genetic alterations, prognostic markers, clinical presentation, and therapeutic strategies. The results of different systemic treatments were analyzed, with special attention to liver-directed interventions and emerging systemic therapies. RESULTS:The incidence of UM in Europe increases with latitude, ranging from two per million in the southern regions to more than eight per million in the North. The median age at diagnosis is 62 years, and most cases are detected incidentally during ophthalmological examinations due to nonspecific symptoms. Some genetic alterations serve as important prognostic indicators. Local treatment consists of globe-preserving procedures, including radiation therapy, surgery, laser therapy, or enucleation, with failure rates between 6.15% and 20.8%. Up to 70% of patients develop distant metastases, predominantly in the liver. Metastatic UM (mUM) carries a poor prognosis, with overall survival ranging from 3 to 30 months. Liver-directed therapies, particularly surgical resection, provide the most favorable outcomes. Systemic therapies demonstrate limited efficacy; however, tebentafusp has shown an overall survival benefit in HLA-A*02:01 (human leukocyte antigen A*02:01)-positive patients. CONCLUSIONS:UM is a rare but aggressive malignancy with limited treatment options once metastatic. Liver-directed strategies remain the mainstay of management, while novel systemic approaches, including tebentafusp, represent promising advances. Further research is required to improve survival and expand therapeutic opportunities.

Background Clear cell sarcoma (CCS) is a rare subtype of soft tissue sarcoma (STS). The objective of this analysis was to evaluate the effectiveness of multidisciplinary treatment of CCS and to identify potential factors that influence the outcome. Methods A retrospective analysis of curative-intent treatment of CCS patients between 1998 and 2024 in the sarcoma reference centre. Results The median Relapse-free Survival (RFS) and Overall Survival (OS) times were 33.1 (95% CI: 11.1-Not Reached, NR) and 55.5 (95% CI: 37.4-NR) months, respectively. One year after the surgery, the RFS was 63.5% (95% CI: 49.5-81.5), and at three and five years it was 41.8% (95% CI: 28-62.4) and 38.3% (95% CI: 24.8-59.2), respectively. Three years after the surgery 64.7% (95% CI: 50.3-83.2) of patients were alive, and at five years - 49.3% (95% CI: 34.1-71.2). Among 19 patients referred for sentinel lymph node biopsy (SLNB), it was positive in 8 (42.1%) patients, at the same time lymph node dissection (LND) was performed in 4 patients. Excluding patients undergoing electrochemotherapy and wide excision of scar, the R0 resection margins were achieved in 14 (48.3%) patients. Those patients had superior RFS compared to patients with R1/2 resection margins: 83 (95% CI: 14.8-NR) months and 11.1 (95% CI: 5.9-NR) months, respectively (p=0.0095). We observed a similar trend for OS, where patients with R0 margins had NR (95% CI: 30-NR) compared to 37.4 (95% CI: 10.6-NR) in the case of R1/2 margins, p=0.051. Conclusions Consequently, SLNB and LND procedures should be offered more often to patients with this diagnosis.

e23561 Background: Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare soft tissue sarcoma characterised by recurrent NR4A3 gene rearrangements. Real-world data on survival and prognostic biomarkers is limited. Therefore, we evaluated long-term oncological outcomes and inflammatory prognostic factors in a cohort of patients (pts) treated with curative intent at a national reference centre. Methods: We retrospectively analysed institutional records to identify consecutive pts with histologically confirmed EMC who underwent a curative-intent surgery over the last 25 years. Kaplan–Meier analysis was used to calculate the survival outcomes including overall survival (OS), relapse-free survival (RFS) and distant metastasis-free survival (DMFS). Log-rank test was used to determine the prognostic impact of pre-treatment peripheral blood biomarkers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], systemic immune-inflammation index [SII]). Results: 37 pts were included (median age 57.6 years; range 24.9–80.3; 51.4% female). Low-grade tumours accounted for 67.6%, while 24.3% were high-grade. Surgical resection margins were R0 in 24 (64.9%) pts, and R1/R2 in 11 (29.7%) pts. Metastasis were present at diagnosis in 5 (13.5%). Pre-operative radiotherapy was used in 24 cases, mostly 5 x 5 Gy. For the entire cohort median OS, RFS, and DMFS were 162.76, 46.88, and 58.87 months, respectively. Low values (below median) of PLR, LMR, MLR and SII were reported in pts with prolonged OS (216–276 months), whereas high values were associated with shorter survival curves. Also, high (above median or median) NLR tended to be associated with shorter OS than low NLR. However, statistical significance was not reached. Conclusions: In EMC pts treated with radical intent, long-term survival is favourable, although characterised by substantial recurrence and metastatic risk. Systemic inflammatory indices, derived from routine blood tests, identify prognostically distinct subgroups and may complement established clinicopathological factors. However, further research on a larger group is needed.

e21525 Background: Currently, three distinct combinations of BRAF and MEK inhibitors (BRAFi/MEKi) are approved for treatment of advanced melanoma patients. However, they have not been compared in a head-to-head trial. Objective of this study was to investigate if selection of BRAF/MEK inhibitors combination impacted progression-free survival (PFS) in real-world setting. Methods: This was a multi-centre, retrospective study, conducted in major melanoma centres in Poland. Only patients treated in routine clinical practice (not clinical trials) were included. Multivariable Cox proportional hazards (PH) regression model was created to assess prognostic impact of the selected variables. Results: A total number of 790 BRAF -mutant melanoma patients received BRAFi/MEKi as first-line systemic therapy in advanced metastatic/unresectable setting. Dabrafenib + trametinib (D+T) was used in 497 (62.9%) patients, encorafenib + binimetinib (E+B) in 146 patients (18.5%) and vemurafenib + cobimetinib (V+C) in 147 patients (18.6%). Table 1 provides baseline clinical characteristics and overall response rates (ORR). Median PFS was 8.11 (95% CI: 7.33 – 9.33) months in patients treated with D+T, 10.35 (7.95 – 12.42) months in patients treated with E+B and 8.71 (7.13 – 11.14) in patients treated with V+C. Median overall survival since the start of treatment was 14.1 (12.6 – 15.6) months, 14.7 (12.6 – 21.7) and 12.2 (10.7 – 16) months respectively. Multivariate Cox model included BRAFi/MEKi, baseline melanoma stage, age and gender as covariates, while lactate dehydrogenase level and ECOG score were used as stratification variables due to failure to meet PH assumption. Melanoma stage and age were the only significant prognostic factors with hazard ratio (HR) of 4.48 (2.34– 8.57; p < 0.001) in M1d patients, 2.41 (1.34 – 4.33; p = 0.003) in M1c patients, 2.08 (1.03 – 4.18; p = 0.04) in M1b patients and 0.74 (0.3 – 1.83; 0.511) in unresectable stage III patients compared to M1a patients as reference and HR 1.01 (1-1.03; p = 0.044) for age (continuous). Importantly, combination of BRAFi/MEKi was not a significant prognostic factor, with HR of 0.86 (0.52 – 1.42; p = 0.552) in E+B patients and 0.90 (0.53 – 1.50; p = 0.676) in V+C patients compared to D+T patients. Conclusions: In this retrospective analysis of real-world patients, type of used BRAFi/MEKi combination was not a significant prognostic factor, suggesting similar clinical activity of these combinations. These results require validation in randomized, prospective studies. Combination D+T E+B V+C Number of patients 497 146 147 TNM: M1c 189 (38%) 52 (35.6%) 50 (34%) TNM: M1d 135 (27.2%) 40 (27.4%) 48 (32.7%) TNM: M1a 65 (13.1%) 23 (15.8%) 21 (14.3%) TNM: M1b 70 (14.1%) 21 (14.4%) 21 (14.3%) TNM: stage III unresectable 33 (6.6%) 9 (6.2%) 7 (4.8%) ECOG: 1+ 359 (72.2%) 112 (76.7%) 98 (66.7%) ECOG: 0 122 (24.5%) 34 (23.3%) 49 (33.3%) ORR 245 (49.3%) 91 (62.3%) 85 (57.8%)

Desmoid tumors (DTs) are rare fibroblastic neoplasms driven by altered Wnt signaling pathways, through activating mutations in β-catenin (CTNNB1) or loss of repressive APC. DTs are considered as intermediate neoplasms that can be locally aggressive, with potential for significant medical complications that can threaten life and limb, as well as impact on patient function, quality of life, and emotional well-being. Historically, DTs were treated with similar paradigms as soft tissue sarcomas, with complete surgical resection the priority despite frequent postoperative recurrences, or use of radiation or cytotoxic chemotherapies for refractory/recurrent cases. Today, improved understanding of DT biology and natural history, along with the development of molecularly targeted therapies, has greatly changed the recommended approach to DT management. In this review, we highlight the role of active surveillance for initial management of most DTs, recognizing the potential for tumor stability or spontaneous regression. In the case of highly symptomatic or progressive tumors, we review the spectrum of treatment options, including surgery for select cases, systemic therapies such as novel gamma secretase inhibitors and tyrosine kinase inhibitors, and emerging local treatment options including cryoablation and high-intensity focused ultrasound. Through a multidisciplinary approach and careful assessment of the individual patient's DT biology and symptomatic impacts, the optimal treatment strategy can be selected to minimize unnecessary morbidity and toxicity and to improve outcomes and quality of life for this unique patient population.

Background Locally advanced, marginally resectable soft tissue sarcomas (STS) are frequently treated with multimodal neoadjuvant strategies to enable limb-sparing, R0 resection. However, pathological response (PR) to neoadjuvant chemoradiation is heterogeneous, and robust molecular predictors of response are lacking. We performed comprehensive DNA/RNA profiling to identify genomic correlates of PR and clinical outcomes in a real-world cohort treated with a uniform neoadjuvant chemoradiation regimen. Methods We retrospectively analyzed pre-treatment biopsies from 27 patients with high-grade, marginally resectable STS treated at a single sarcoma center (median age 55 years; range 28–74; 62.96% male). Histological subtypes included undifferentiated pleomorphic sarcoma (44.44%), myxofibrosarcoma (29.63%), malignant peripheral nerve sheath tumor (14.82%), myxoid liposarcoma (7.41%), and pleomorphic liposarcoma (3.70%). Targeted DNA/RNA sequencing was performed using the TruSight Oncology 500 assay to identify single-nucleotide variants (SNV), copy number variation (CNV), and gene fusions. Pathological response was assessed in resection specimens based on the proportion of viable tumor. Overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Results The cohort displayed a complex genomic landscape with recurrent SNV/CNV events and frequent fusion calls across STS subtypes. Presence of gene fusions was associated with improved OS ( p = 0.043), whereas PR itself was not significantly associated with survival ( p = 0.427). Exploratory analyses identified molecular features related to PR: ROS1 -associated gene fusions were observed exclusively in tumors with favorable PR, while MDM2 gene amplification and PTEN deletion were linked to poor PR. Additionally, likely pathogenic variants of TP53, PLCG2, PIK3C2B, GABRA6 , and KMT2C genes were clustered in poor-response cases. Molecular profiling also flagged potential diagnostic reclassification in selected tumors via highly specific fusion events, underscoring its value beyond prognostication. Conclusions Comprehensive DNA/RNA profiling in locally advanced STS treated with neoadjuvant chemoradiation suggests that fusion status and specific actionable alterations may stratify response biology and survival. These hypothesis-generating biomarkers, particularly ROS1 -associated gene fusions, MDM2 gene amplification, and PTEN loss — require validation in larger, histology-controlled cohorts and may inform future molecularly guided neoadjuvant strategies. Trial registration NCT03651375.

Nectins and nectin-like molecules (Necls) are calcium-independent immunoglobulin-like cell adhesion molecules with emerging roles in cancer biology, immune regulation, and targeted therapy. Their growing importance as therapeutic targets, immune checkpoint ligands, and predictive biomarkers across many tumour types has been described. NECTIN-1 functions as a major metastasis-suppressor gene in melanoma. NECTIN-1 is deleted in approximately 55% of melanomas, and its loss promotes IGF1-driven melanoma dissemination. Nectin-1 also serves as the entry receptor for oncolytic herpes simplex virus therapy (T-VEC, talimogene laherparepvec). Nectin-2/CD112 and Necl-5/CD155 are key T cell immunoreceptors with Ig and ITIM domains (TIGIT) and are CD226 immune checkpoint ligands. CD155 overexpression predicts resistance to anti-PD-1 therapy and poor prognosis in melanoma, non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC). Nectin-4 is an oncogenic driver (via PI3K/AKT and SOX-2) in lung cancer and BRAF-inhibitor-resistant melanoma, as well as a validated target of enfortumab vedotin in urothelial carcinoma. Necl-2/CADM1 acts as a tumor suppressor in melanoma and NSCLC, as it suppresses the epithelial-mesenchymal transition (EMT). Data on renal cell carci­noma remain limited. Nectins and Necls constitute a clinically significant protein family in oncology. Currently, Nectin-4 and CD155/TIGIT represent the most therapeutically actionable targets. Combination strategies targeting TIGIT (tiragolumab, ociperlimab, or vibostolimab) with PD-1/PD-L1 blockade are under investigation. Moreover, enfortumab vedotin, an antibody-drug conjugate (ADC) targeting Nectin-4-high tumors, is under investigation in many solid tumors.

INTRODUCTION: Malignant melanoma is the tumor most frequently associated with cardiac metastases. Melanocytes originate from the neural crest, which may underlie the tumor’s propensity for widespread hematogenous dissemi-nation, including to the heart. Cardiac involvement is found in up to 64% of patients with melanoma at autopsy; however, antemortem diagnosis remains rare because patients are frequently asymptomatic. CASE PRESENTATION: We report the case of a 42-year-old woman with malignant melanoma of the lumbar region and right atrial metastasis. Initial BRAF mutation testing of archival primary tumor tissue was nondiagnostic because of DNA degradation. Subsequent pyrosequencing of a subcutaneous metastasis detected the BRAF V600E mutation, which enabled targeted therapy. The patient received multiple lines of systemic therapy, includ-ing pembrolizumab, ipilimumab, and BRAF/MEK inhibitors (dabrafenib and trametinib). Serial echocardiographic monitoring demonstrated complete regression of the right atrial metastasis during BRAF/MEK inhibitor therapy, followed by recurrence upon disease progression. Electrocardiographic abnormalities, including sinus tachy-cardia, low QRS voltage, and nonspecific ST-T wave changes, were observed despite the absence of cardiac symptoms. The patient survived for approximately 3.5 years after the diagnosis of cardiac metastasis. CONCLUSIONS: This case demonstrates that BRAF/MEK inhibitor therapy can achieve complete resolution of cardiac metastases on transthoracic echocardiography. When initial BRAF testing is nondiagnostic, retesting of metastatic tissue using sensitive molecular methods may identify actionable mutations. An integrated mul-timodal imaging approach and routine electrocardiographic surveillance are recommended for patients with metastatic melanoma.

Background Soft tissue sarcomas are rare and heterogeneous malignancies lacking validated circulating genomic biomarkers for disease monitoring and prognostication. Advances in genomics and liquid biopsy technologies provide new opportunities to longitudinally assess tumor dynamics using minimally invasive approaches. The primary objective of this study was to identify predictive and prognostic biomarkers in sarcoma by evaluating whether copy number variations (CNV) of cancer-related genes ( MDM2 , TP53 , MET , RB1 , BRAF , and HSP90 ) correlate with clinical outcomes, with the aim of enabling early risk stratification and treatment monitoring in patients with soft tissue sarcomas. Methods We performed longitudinal analysis of CNVs of genes in plasma-derived cfDNA from 19 patients with STS using droplet digital PCR (ddPCR). CNVs were measured at six consecutive time points (B1-B6), spanning qualification, neoadjuvant chemotherapy ChTh and radiotherapy RTh, surgery, and post-treatment follow-up. Associations between CNVs and clinical parameters, including tumor size, necrosis, treatment response, disease progression, and progression-free survival (PFS), were evaluated. Results Strong correlations were observed between CNV profiles and clinical outcomes. Early time points (B1-B4) were characterized by highly interconnected CNV networks involving TP53, RB1, MDM2, BRAF, MET , and HSP90. Disease progression was associated with elevated CNVs of MDM2 and MET during ChTh (B2) and of TP53, RB1, MDM2 , and HSP90 following RTh (B3). MDM2 CNVs were significantly higher in non-responders at baseline and increased during therapy in patients who later progressed, indicating resistance to ChTh and RTh. A p-value minimization framework exploiting PFS curve differences enabled the identification of robust, gene-specific CNV thresholds at B2 and B3, with higher CNV levels consistently associated with significantly shorter PFS. Conclusions Longitudinal CNV profiling using LB reveals dynamic, biologically meaningful genomic alterations in STS. Coordinated deregulation of the TP53-MDM2-RB1 axis and stress-response pathways emerges as a central feature of therapy resistance and disease progression. In particular, MDM2 CNV represents a promising prognostic and potentially therapeutic biomarker. These findings provide foundational evidence supporting CNV-based liquid biopsy strategies for risk stratification, treatment monitoring, and personalized management in soft tissue sarcomas.

The growing popularity of immunotherapy shows a promising future for cancer treatment. However, a significant need to develop new therapeutics that could be successfully used in therapy still remains, especially in "immune-cold" tumors that are not responsive to classic anti-PD-1 treatment. Therefore, the discovery of lymphocyte activation gene-3 (LAG-3) as a new immune checkpoint (IC) molecule that physiologically participates in auto-tolerance mechanisms preventing auto-aggression was a significant milestone in immuno-oncology. Two main approaches aim to introduce LAG-3-directed therapies into clinical practice: anti-LAG-3 antibodies that are meant to inhibit LAG-3 function and recombinant soluble LAG-3 form that aim to activate immune response, especially by interacting with the antigen-presenting cells (APCs). So far, studies show that both approaches may be safe and effective anti-cancer treatment options. This review summarises the role of LAG-3 in immune response and emphasises the role of this IC molecule and its soluble form on APCs function, while also noting the primary physiological function of LAG-3 in autoimmunity and providing a dual perspective of the pros and cons of this novel anti-cancer therapy.

INTRODUCTION:Soft tissue sarcomas (STS) exhibit profound molecular heterogeneity. While recurrent gene fusions hold significant diagnostic and therapeutic value-guiding treatment selection and identifying novel molecular targets-our understanding of their broader clinical implications remains limited. MATERIALS AND METHODS:We performed next-generation sequencing (NGS; FusionPlex Sarcoma v2, Archer™) and bioinformatic analysis (STAR v.2.7, Arriba) on formalin-fixed paraffin-embedded (FFPE) core needle biopsy specimens. The cohort consisted of patients enrolled in a phase II clinical trial (NCT03651375) who received preoperative chemoradiotherapy according to the UNRESARC protocol. RESULTS:The analysed cohort comprised nine adult patients (median age 66 years; range 44-73) diagnosed with undifferentiated pleomorphic sarcoma (UPS; n = 3), malignant peripheral nerve sheath tumour (MPNST; n = 3), myxofibrosarcoma (MFS; n = 2), and leiomyosarcoma (LMS; n = 1), predominantly high-grade (G3; 5/9) and extremity-localised (6/9). Gene fusions were detected in one-third of patients (3/9), exclusively in G3 tumours. Specifically, we identified an SGSH-PRKCA fusion in MFS (thigh), a LINC01133-OGA fusion in MPNST (thorax), and a concurrent JAZF1-MYH7B (chr7:27995037 intronic-chr20:33563203 exon/splice-site, out-of-frame but preserving myosin domains) with a PRKCA-associated intergenic rearrangement (chr1, retaining C1/kinase domains) in UPS (upper back). Notably, the SGSH-PRKCA and JAZF1-MYH7B pairs have not been previously described in the literature for these STS subtypes. Fusion-positive (F1) cases showed stable radiological disease (RECIST 1.1 SD) and EORTC C/D pathological responses with 5-20% residual viable tumour, whereas fusion-negative (F0) cases showed a wider range of radiological and pathological outcomes, including partial response, progression, and stable disease. CONCLUSIONS:Our analysis suggests that broad genomic profiling may provide complementary molecular information in diagnostically challenging cases managed at specialised sarcoma centres, particularly when morphology and immunohistochemistry are insufficient. In the present series, however, the detected rearrangements did not alter systemic treatment, and the data do not support claims of prognostic, predictive, or therapeutic actionability.

Introduction. Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma (<= 1/1,000,000 inhabitants/year), characterized by an indolent but metastasizing course; distant metastases (M1) occur in 30-50% of cases, predominantly to the lungs. However, there is limited research on the management of metastatic disease, particularly when metastasectomy and chemotherapy (CHT) are employed. Material and methods. Two patients with a histopathologically confirmed diagnosis of EMC are described and were treated between 2013 and 2024 at a reference center, who underwent metastasectomy in the course of metastatic disease. Results. Both patients underwent radical resection of the primary tumor (R0) and perioperative radiotherapy. Pulmonary M1 were indentified 17 months and 1 month after surgery, respectively. A total of 5 metastasectomies were performed. M1 recurrences were typical - the first after approximately 3 months in patient A and between 6 and 34 months after subsequent resections in patient B, with widespread progression diagnosed 24 months after the last extrapulmonary M1 resection. In the treatment of metastatic disease, first-line CHT (ADIC regimen; agents and dosing varied by case) was used in patient B with radiological progression after 3 months, while in patient Athe ADIC regimen was limited due to a high risk of cardiotoxicity - LVEF 35-40%. In the second line, GEM/DTX brought short-term stabilization in patient B; in the case of A, second-line treatment was not implemented for cardiological reasons. No lasting systemic responses were achieved. Conclusions. Metastasectomy in patients diagnosed with EMC allows for temporary control of the disease, however, does not prevent subsequent M1 recurrences - repeat surgical procedures are necessary. The implementation of CHT is of limited benefit and cardiac risk has to be considered.

e21575 Background: The treatment of early-stage melanoma is rapidly changing. Recent advancements include neoadjuvant treatment in stage III clinically detected disease and adjuvant treatment in stage IIB/C melanoma. In particular, adjuvant immunotherapy for IIB/C disease has become recently available. We took this opportunity to evaluate changes in outcomes in patients diagnosed with stage II and III melanoma. Methods: We have analyzed the accessible, retrospective data on patients diagnosed with melanoma between 2015 and 2022 who underwent sentinel lymph node biopsy or therapeutic lymph node dissection in high-throughput centers in Poland. The data on primary staging, patients’ demographics, and information on follow-up and overall survival (OS) were collected. A prespecified OS Cox model with non-linear terms for age, sex, stage (II vs. III), and availability of adjuvant treatment in stage III (i.e., since 2021) was fitted. Results: There were 1970 patients (45.2% female) included in this analysis. The mean age was 62 (range:14-97). The exact stage distribution and 3-year OS rates are presented in Table 1. Patients diagnosed with stage III melanoma before 2021 had worse prognoses than stage II patients (HR: 1.33, 95%CI: 1.11-1.60, p=0.002). Since then the prognosis for stage II patients did not improve (HR: 1.13, 95%CI: 0.89-1.45, p=0.325) while the prognosis in stage III melanoma became similar to stage II after the introduction of adjuvant therapy (HR: 1.09, 95% CI: 0.78-1.53, p = 0.607). Conclusions: The introduction of adjuvant treatment improved the OS of stage III melanoma patients in this nationwide study. The modern prognosis is similar to patients with stage II melanoma without adjuvant treatment, with excellent results in stage IIIA/IIIB cases. The practitioners should be cautious when discussing historical prognosis with their patients and it implies the necessity of changes in AJCC staging. Stage distribution and 3-year survival rates. Stage Number of patients Percentage of group 3 year survial rate (%) 95% Confidence Interval (%) IIA 352 17.9 86.5 82.9 - 90.3 IIB 378 19.2 76.5 72.2 - 81.2 IIC 443 22.5 59.9 55.3 - 64.8 IIIA 84 4.3 94.3 89.1 - 99.9 IIIB 132 6.7 94.6 90.5 - 98.9 IIIC 518 26.3 68.5 64.3 - 73.1 IIID 63 3.2 53.3 42.2 - 67.4

Trabectedin is a chemotherapeutic agent that has shown activity in the treatment of patients with soft tissue sarcomas after failure of anthracycline-based therapy and the best results were recorded in the treatment of L-sarcomas. There is a need for prognostic and predictive factors that will help clinicians with therapy selection. In this study we aim to analyze treatment results, prognostic and predictive factors in patients treated with trabectedin in routine clinical practice. We retrospectively analyzed the medical records of patients who started treatment with trabectedin between 04/2008 and 09/2021. Demographic and clinical data were extracted, and markers of systemic inflammation, including neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation index (SII), were calculated. We identified 251 patients, including 174 with complete baseline laboratory data. Objective responses were noted in 10.8% of patients, and disease stabilization was noted in 49.0%. Median PFS and OS were 5.26 months and 17.98 months, respectively. In the overall population, liposarcoma and metastasis-free interval (MFI) > 10 months were predictive factors for PFS, while female sex and MFI > 10 prognostic factors for OS. Among patients with available laboratory data, the median NLR at baseline was 2.87, and SII was 1047.26. In multivariate analysis, SII ≤ 670 significantly correlated with longer PFS but not with OS. Long-term results of trabectedin treatment in Polish patients with L-sarcomas are comparable to the results of other real-world evidence studies. In conclusion, the systemic inflammation index correlates significantly with PFS, is a simple marker available for daily clinical practice to identify patients most likely to benefit from treatment.

Background/Objectives : Pleomorphic liposarcoma (PLS) is a rare and aggressive subtype that accounts for 5% of all liposarcomas, with a 5-year survival rate of only 55-65%. Although PLS can metastasize in 30-50% of cases, isolated liver metastasis is extremely rare (0.5%) phenomenon. Surgical resection with histologically negative margins is considered the gold standard treatment in solitary metastasis of PLS. We present the second case reported worldwide of solitary liver metastasis in extremity pleomorphic liposarcoma patient. Methods : A 39-year-old male presented with metastasis in liver segment IVa following surgical resection of a primary PLS in his right lower leg. On physical examination, the liver protruded 1.5 cm below the costal margin without tenderness on palpation. The patient underwent hepatic segment IV resection with cholecystectomy, achieving negative margins. Postoperative recovery was uneventful, but disease recurrence occurred rapidly, with new metastases detected in the vertebral column at three months, followed by progression to the bones, peritoneum, lungs, and eye. Results : Despite multiple chemotherapy regimens, the patient succumbed to the disease 14 months after hepatic resection. Conclusions : Complete surgical resection offers the lowest recurrence rate for PLS but is most effective when disease is diagnosed at an early stage. This case highlights the aggressive nature of PLS and its unpredictable metastatic pattern. Given the rarity and diverse clinical course of this malignancy, further research and standardized management guidelines are urgently needed to improve outcomes for patients with this challenging disease.

Radiation-associated sarcomas (RAS) and in-volume recurrent sarcomas (IRS) are significant therapeutic challenges due to prior radiotherapy (RT) exposure and the risks associated with re-irradiation. The aim of this study was to evaluate the safety and efficacy of moderately hypofractionated RT combined with locoregional hyperthermia (HT) in patients with RAS/IRS. A prospective, proof-of-concept, single-arm, phase II clinical trial (NCT04398095) was conducted in which 20 patients with locally advanced RAS/IRS of the extremities and trunk wall were enrolled. Treatment consisted of RT at 36 Gy in 12 fractions over three weeks, combined with at least weekly HT sessions. Unresectable tumors received an integrated boost to 42 Gy. The primary endpoint was grade 3 or higher late toxicity according to the Common Terminology Criteria for Adverse Events version 5.0 at 18 months, while secondary endpoints included local control, progression-free survival (PFS), and cancer-specific survival (CSS). Median follow-up was 48.9 months. No patient developed grade ≥ 3 late toxicity. Seven patients (35

9524 Background: There is an urgent need for more robust methods to differentiate immunotherapy responders from non-responders. In this study, we present a novel multiplex imaging (MI)-based immunotherapy panel and a comprehensive analysis pipeline to characterize the spatial distribution and function of immune cells and its application for spatial biomarker detection in a cohort of immunotherapy-treated melanoma patients. Methods: We designed a 28-plex panel to perform sequential immunofluorescence (seqIF) on the COMET platform to target key biomarkers associated with tumor microenvironment (TME), immune cell infiltration, and immune checkpoint pathways. Pre-treatment biopsies were obtained from 12 patients with known long-term response or rapid progression to immunotherapy combination treatment from the SECOMBIT Trial (NCT02631447) and profiled utilizing Nucleai’s deep-learning-based MI analysis pipeline, aiming to identify spatial biomarkers that can differentiate between long-term responders and non-responders. We identified 15 cell types, including 10 immune cell populations, in addition to 10 cell state markers. Cells were assigned to the tumor area or TME, and spatial features were calculated based on cell type, marker positivity, and gross area assignment. Results: Our novel MI panel and analysis pipeline demonstrated highly balanced accuracy (> 0.8) and F1 scores (> 0.8) in cell typing and protein quantification for most cell types and markers. This analysis pipeline enabled the quantification of known biomarkers such as T cell activation states, T cell infiltration patterns, and tertiary-lymphoid structure maturation. A comparison of calculated spatial features between long-term responders and rapid progressors revealed distinct immune cell interactions and differences in activation status across the tumor areas associated with response. Within the tumor area, the reciprocal interactions of tumor cells, cytotoxic CD8 T-cells and antigen-presenting cells (APC) were associated with a better outcome. In contrast, a high percentage of proliferating regulatory T cells within the tumor invasive margin was associated with a worse outcome. In the adjacent TME, endothelial cell interactions with T-cells and macrophage proliferation were associated with immunotherapy resistance. In contrast, the interaction between HLA-DR-expressing macrophages and APC cells was associated with an improved clinical outcome. Conclusions: Integrating MI with AI analysis has the potential to enhance our understanding of treatment efficacy and resistance mechanisms. Our preliminary data demonstrate that area-specific immune niches contribute to the success or failure of immunotherapy response and highlight the importance of spatial biology in predicting immunotherapy outcomes. Clinical trial information: NCT02631447 .

Clinical research in oncology is essential for improving patient outcomes; however, cancer care provision and access to novel therapies remains highly heterogeneous across Europe, particularly between Western and Eastern EU27 regions. This has been further compounded by the Russian invasion of Ukraine, severely disrupting regional cancer treatment, research infrastructures and clinical trials activity. Challenges to clinical research in the Central and Eastern regions of the European Union (EU27-CEE) are multifactorial, relating to patient access, local implementation and conduct of trials, education, infrastructure and regulatory procedures. Nevertheless, EU27-CEE comprises a very active clinical trial landscape with its specialist workforce, high productivity and quality of data, empowering a growing regional pharmaceutical industry and establishing itself as an important clinical cancer research hub for conducting global trials. Consequently, patients recruited in EU27-CEE exercise an important impact on global cancer drug development. Poland has proven to be a model for biomedical innovation, serving as the region’s blueprint for a productive clinical trials ecosystem. Multi-stakeholder collaboration and patient-centric approaches are required to streamline procedures for quicker trial initiation, simpler trial conduct, and better cross-border access. Recognizing these challenges and opportunities, we have developed, through a consultative approach, a Call to Action that, if implemented, would enhance the cancer clinical trials landscape in EU27-CEE countries and empower patient access to the latest advances and therapies in cancer drug development.