The lung is the most frequent metastatic site in soft tissue and bone sarcoma, yet CT imaging predictors of survival remain underexplored. Hence, the aim of this study was to evaluate baseline CT imaging predictors for overall survival (OS) and progression-free survival (PFS) in patients with pulmonary metastases from soft tissue and bone sarcoma. Consecutive patients treated from 2016 to 2021 were screened; those without lung metastases, systemic therapy, baseline CT imaging, or with prior lung surgery were excluded. Tumor burden (long axis, volume) and number of pulmonary lesions were assessed at baseline CT imaging and tested for OS and PFS. Significant univariate predictors were entered into multivariate models and reported as hazard ratios (HR). In the 100 included patients, median OS was 22.1 months, and median PFS was 5.8 months. Tumor burden parameters were not predictive of OS nor PFS (HR 0.724–1.354, p = 0.265–0.975). The number of pulmonary lesions was prognostic, with ≥ 5 lesions predicting shorter OS in univariate (HR 1.709, 95

Trabectedin is standard for r/r soft tissue sarcomas. tTF-NGR accumulates in tumor vasculature leading to tumor vascular occlusion and tumor infarction. Both compounds in sequence could trap trabectedin inside tumors and increase its efficacy, which then optimizes the pro-coagulatory activity of tTF-NGR. This report summarizes translational data and results of the safety run-in patient cohort of the TRABTRAP trial combining trabectedin plus tTF-NGR. A dose of trabectedin of 1.5 mg/m2 (24 h, day 1) combined with 1.0 mg/m2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m2 tTF-NGR (days 2 and 3) the recommended starting dose for the randomized part of TRABTRAP. None of the 6 patients on 0.5 mg/m2 tTF-NGR had dose-limiting toxicity (DLT). Higher doses or additional days of application of tTF-NGR led to grade 3 DLT including early troponin T high sensitivity increase, a reversible non-ST-elevation myocardial infarction in one patient, and reversible thromboembolic events. Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.

BACKGROUND:In the EORTC 62961-ESHO 95 randomized trial (European Organization for Research and Treatment 62961-European Society of Hyperthermia Oncology 95; ClinicalTrials.gov identifier NCT00003052), neoadjuvant chemotherapy (NAC) combined with regional hyperthermia (RHT) improved survival in patients with soft tissue sarcoma (tumor size >5 cm, grade 2 or 3, deep location). This study investigated the survival benefit of NAC + RHT in a subgroup of patients who had extremity soft tissue sarcoma (ESTS) according to risk predictions using the Sarculator nomogram. METHODS:Overall survival (OS) was predicted with the Sarculator nomogram using baseline prognostic parameters. Kaplan-Meier analysis was used to estimate observed OS. A bivariable Cox model including the Sarculator score, treatment, and their interaction was fitted. Hazard ratios for OS were calculated for each decile of the Sarculator risk distribution. RESULTS:Of 143 patients with ESTS, 135 were analyzed (NAC, n = 70; NAC + RHT, n = 65) with a median follow-up of 136 months (interquartile range, 110-183 months). Survival in the NAC + RHT group exceeded Sarculator predictions and improved compared with the group that received NAC alone (hazard ratio, 0.67; 95% confidence interval, 0.39-1.17; p = .081), with an absolute 5-year OS difference of 15.6% (95% confidence interval, 0.0%-31.4%). Risk stratification suggested greater benefit of NAC + RHT as predicted OS decreased. However, the interaction between Sarculator score and treatment was not significant (p = .495). CONCLUSIONS:This analysis of ESTS from a randomized trial confirmed the previously reported OS benefit by adding RHT to NAC. Although patients with higher predicted risk seemed to benefit more from the combined treatment, these findings do not suggest that treatment decisions should be based on risk estimates alone, supporting the use of RHT combined with chemotherapy in patients who have primary ESTS.

INTRODUCTION:Retroperitoneal sarcomas (RPS) require multidisciplinary decision-making. Following centre certification and the publication of national guidelines in German-speaking countries, the consistency and reliability of multidisciplinary team (MDT) recommendations for RPS remain unclear. MATERIALS AND METHODS:In this multi-centre study, 24 German-speaking sarcoma MDTs independently reviewed pre-treatment imaging and clinical information from 20 anonymised primary RPS cases. Centres provided standardised assessments of resectability, surgical strategy, and treatment allocation. Inter-centre agreement was quantified using percentage agreement with the per-case consensus and Krippendorff's alpha statistic (α), interpreted using established reference values. RESULTS:Review of the 20 cases resulted in up to 480 MDT assessments for each item. Across 468 assessments, 411 (88%) rated the tumour as resectable and 57 (12%) as non-resectable. Centre-level agreement with the per-case consensus was 90.2%, with fair inter-centre reliability (α = 0.21). Agreement was lower in large tumours (>20 cm: 79.6%, α = 0.27) compared with smaller tumours. Agreement on surgical strategy was 65.9% (284/431; α = 0.21), with marked variability in the extent of resection and the use of compartmental versus organ-sparing approaches. Agreement on treatment allocation was 75.6% (350/463; α = 0.24) with centres pursuing different subtype-specific treatment concepts. In 8 of 20 cases, at least one centre recommended palliative treatment while others proposed a potentially curative approach. CONCLUSION:The majority of patients were offered curative treatment options in almost all centres. Substantial variability was observed in histology-specific surgical strategies and treatment allocation. These findings indicate that centre-level interpretive frameworks substantially influence MDT recommendations. Strengthening cross-centre collaboration and refining histology-specific guidance may improve consistency in RPS care without undermining expert judgment.

Response assessment in the treatment of metastatic sarcoma primarily depends on imaging, as no established clinical or serological biomarkers reliably predict survival outcomes. This study evaluates the utility of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in predicting overall survival (OS) in sarcoma patients with pulmonary metastases. We selected consecutive study subjects from a prospective registry based on the following criteria: (1) available CT imaging at first diagnosis of pulmonary metastases from sarcoma, (2) available follow-up CT imaging within 16 weeks of systemic therapy initiation, (3) documentation of OS. Volumetric segmentation of up to 5 lung metastases was performed over time. Progressive disease (PD) was defined as increase of the unidimensional sum of lesions ≥ 20

High-dose ifosfamide (HD-IFO) remains an effective regimen for advanced bone and soft tissue sarcomas, but predictors of long-term benefit are poorly defined. This study evaluated clinical outcomes and prognostic factors using machine learning-assisted modeling in sarcoma patients treated with HD-IFO at a high-volume academic center. We retrospectively analyzed 26 patients with histologically confirmed bone or soft tissue sarcoma who received HD-IFO (≥ 12 g/m2 per cycle) between 2015 and 2025. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method and compared across RECIST response categories using log-rank testing. Prognostic factors were identified using Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with leave-one-out cross-validation. The top three variables were entered into multivariable logistic regression to estimate odds ratios (ORs) for OS > 24 months. Median PFS and OS from start of HD-IFO was 6.6 months (95

Sarcomas are malignant tumors of connective and supporting tissues characterized by substantial biological and clinical heterogeneity. Their optimal treatment requires specialized expertise, particularly in radiological diagnostics. The correct interpretation of imaging procedures represents the first crucial step in treatment planning. Radiologists play a key role by recognizing suspicious findings and initiating early referral to specialized sarcoma centers. Depending on the histological subtype, sarcomas require tailored imaging strategies. A notable example is whole-body magnetic resonance imaging (MRI) for the detection of osseous metastases in myxoid liposarcoma. The assessment of treatment response in the neoadjuvant setting also poses a particular challenge as it is not uncommon for treatment-related imaging changes to mimic tumor progression (pseudoprogression) and must be reliably distinguished from true progression. During follow-up an appropriate balance between oncologic safety, such as early detection of local recurrence or metastases, and minimizing cumulative radiation exposure must be achieved.

Gleich mehrere praxisverändernde Phase-III-Studien zu seltenen Weichgewebe- und Knochensarkomen sowie gastrointestinalen Stromatumoren (GIST) wurden im Rahmen der Jahrestagung der American Society of Clinical Oncology (ASCO) 2026 vorgestellt. Im Mittelpunkt stand der zunehmende Erfolg zielgerichteter Therapien, die bei mehreren Entitäten erstmals einen signifikanten Vorteil im progressionsfreien Überleben (PFS) und damit das Potenzial für neue Behandlungsstandards belegten – von der Inhibition der zyklin­abhängigen Kinase 4 (CDK4) beim dedifferenzierten Liposarkom (DDLPS) über die kombinierte KIT-Inhibition beim GIST bis hin zur Gamma-Sekretase-Hemmung beim Desmoidtumor und einem Death-Receptor-Agonisten beim konventionellen Chondrosarkom. Ergänzend etabliert sich beim Synovialsarkom die zelluläre Immuntherapie mit T-Zell-Rezeptor-modifizierten Zellen als neue Therapieklasse.

Background: Large Language Models (LLMs) have demonstrated expert-level performance across many medical domains, suggesting potential utility in clinical practice. However, their reliability in the highly specialized domain of moderate hyperthermia (HT) remains unknown. We therefore evaluated the performance of three modern LLMs in answering HT-related questions. Methods: We conducted an evaluation study by posing 40 open-ended questions-22 clinical and 18 physics-related-to three modern LLMs (DeepSeek-V3, Llama-3.3-70B-Instruct, and GPT-4o). Responses were blinded, randomized, and evaluated by 19 international experts with either a clinical or physics background for quality (5-point Likert scale: 1=very bad, 2=bad, 3=acceptable, 4=good to 5=very good) and for potential harmfulness in clinical decision-making. Results: A total of 1144 quality evaluation responses were collected. Overall reported mean quality scores were similar across models, with DeepSeek scoring 3.26, Llama 3.18, and GPT-4o 3.07, corresponding to an "acceptable" rating. Across expert evaluations, responses were considered potentially harmful in 17.8% of cases for DeepSeek, 19.3% for Llama, and 15.3% for GPT-4o. Notably, despite "acceptable" mean scores, approximately 25% of responses were rated "bad" to "very bad," and potentially harmful answers occurred in ~15-19% of evaluations, indicating a non-trivial risk if used without domain expertise. Conclusion: Our findings indicate that the performance of LLMs in HT in versions available at the time of investigation is only partially satisfactory. The proportion of poor-quality responses is too high and may lead non-domain experts to misinterpret the available clinical evidence and draw inappropriate clinical conclusions. ### Competing Interest Statement Nikola Cihoric serves as Technical Lead for the SmartOncology project - the open-source online platform used to collect the evaluations of the domain experts in this study - and as a medical advisor for Wemedoo AG (Steinhausen, Switzerland). The other co-authors declare no disclosures directly related to the content of this study. ### Funding Statement No funding was received for this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study did not involve any patient- or person-related healthcare data. Therefore, approval from an ethics committee was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All the question-answer pairs with the results from the evaluation are provided in the Supplementary Material (Supplementary Table S1 and S2). The source code used to answer the questions by the three LLMs is publicly available on GitHub.

Evidence guiding the optimal sequencing of later-line systemic therapy in advanced soft tissue sarcoma (STS) remains limited. The aim of this study was to identify prognostic factors for overall survival (OS) beyond second-line treatment and to explore therapy sequencing in routine clinical practice. A total of 90 patients with advanced STS receiving third-line or later systemic therapy were retrospectively analyzed. Extreme gradient boosting (XGBoost) was used to identify clinical predictors of 1-year OS. The most influential variables were subsequently evaluated in multivariable Cox models for OS from the start of third- and fourth-line therapy. Sequencing analyses compared OS according to the line of administration of commonly used later-line agents. In the third-line cohort (n = 88), inferior OS was independently associated with progression on second-line therapy (hazard ratio [HR] 2.31, p = 0.005). In contrast, lipo-/leiomyosarcoma histology was associated with improved survival (HR 0.37, p = 0.002), as was a time to progression ≥ 12 months on first-line therapy (HR 0.43, p = 0.007). Findings were largely consistent in the fourth-line cohort (n = 57). Sequencing analyses suggested sustained activity of trabectedin in later lines (p = 0.023), greater benefit of earlier pazopanib use (p = 0.022), and no significant impact of treatment line for gemcitabine + docetaxel combination therapy (p = 0.12). Machine learning-guided variable selection identified clinically relevant predictors of survival in later-line STS. Prior treatment response and histology strongly influence outcomes, and exploratory sequencing analyses suggest differential timing effects across systemic therapy agents.

This series of case studies provides the first clinical experience with the fibroblast activation protein-α (FAP)-targeting radiopharmaceutical [177Lu]Lu-RTX-2358 in patients with advanced solid tumors. Methods: Six patients with advanced FAP-expressing solid tumor malignancies and no standard treatment options remaining, underwent radiopharmaceutical therapy (RPT) with [177Lu]Lu-RTX-2358. Biodistribution was monitored using whole-body planar and SPECT/CT imaging, and dosimetric parameters were calculated for critical organs, red marrow, and tumors. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Preliminary antitumor effects were evaluated after 2 RPT cycles. Results: RPT with [177Lu]Lu-RTX-2358 was tolerable with no dose-limiting toxicity. The mean red marrow absorbed dose was 0.131 ± 0.044 Gy/GBq (range, 0.057-0.227 Gy/GBq). The mean kidney absorbed dose was 0.509 ± 0.169 Gy/GBq (range, 0.272-0.893 Gy/GBq). The mean tumor absorbed dose varied across patients, ranging from 0.346 to 2.70 Gy/GBq. Tumor effective half-times ranged from 95.9 to 159.5 h. Disease stabilization was achieved in 4 patients; progressive disease occurred in 2 patients. Conclusion: [177Lu]Lu-RTX-2358 demonstrated a manageable safety profile in a series of patients who were heavily pretreated for their disease. Given a promising therapeutic index as a result of prolonged retention in tumors and clearance from normal organs, further clinical evaluation is warranted.

Thermosensitive Liposomes (TSL) represent a promising tool for targeted drug delivery in combination with local hyperthermia (HT). Irinotecan (CPT-11) is approved for the treatment of various solid tumors but is rapidly metabolized after i.v. injection impairing intratumoral uptake. CPT-11 was therefore encapsulated in phosphatidyldiglycerol-based TSL (DPPG2-TSL-CPT-11) to extend its blood stability and to intravascularly release CPT-11 in the tumor. In vitro, DPPG2-TSL-CPT-11 demonstrated efficient drug retention at ≤ 39 °C and fast CPT-11 release at > 40 °C in presence of serum. DPPG2-TSL-CPT-11 showed a CPT-11 plasma half-life of 1.57 h in rats compared to 0.71 h for non-liposomal CPT-11 and 18.70 h for PEGylated non-thermosensitive CPT-11 (Onivyde®), respectively. Systemic exposure of the active metabolite SN-38 was reduced by DPPG2-TSL-CPT-11 compared to Onivyde®. One hour of HT treatment in combination with DPPG2-TSL-DOX delivered 24-fold and 36-fold more CPT-11 into tumors than Onivyde® and non-liposomal CPT-11, respectively. DPPG2-TSL-DOX and Onivyde® showed a comparable overall survival, superior (p < 0.005) to non-liposomal CPT-11. DPPG2-TSL-DOX was the only formulation that led to a tumor size reduction. In vivo data indicated an advantage of the intravascular CPT-11 release over systemic drug application or passive tumor accumulation of liposomes.

Background: The prognosis of patients with advanced soft tissue sarcoma (STS) remains dismal. Trofosfamide (TRO) has been proposed as a well-tolerated oral maintenance therapy. This retrospective analysis aims to determine the value of this therapy. Methods: Fifty-nine patients with advanced STS who received TRO maintenance therapy between 2016 and 2022 were reviewed and analysed regarding clinical parameters and outcomes. Results: The median age was 48 years; the most common histological subtype was synovial sarcoma (n = 22, 37%), and 71% of patients (n = 42) presented with metastatic disease. No radiological evidence of disease (NED) before the start of maintenance was reported in 36% of patients (n = 21). The median follow-up was 38.2 months with a median maintenance duration of 9.0 months. The median event-free survival (EFS) and overall survival (OS) were 9.5 and 33.2 months, respectively. In metastatic patients achieving NED before the initiation of TRO, the median EFS was 29.4 months, while the median OS was not reached. In metastatic patients with anthracycline + ifosfamide (AI) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of AI were 13.9 and 26.8 months, respectively. Multivariate analysis of the overall cohort demonstrated that NED before the start of maintenance was significantly associated with a prolonged EFS (p = 0.024, hazard ratio [HR] = 0.26), and G2 histology correlated with longer OS (p = 0.030, HR = 0.16, reference: G3). Interpretation: Oral maintenance therapy with TRO appears to improve outcomes in patients with advanced STS. Metastatic patients who achieve NED through prior metastasectomy may particularly benefit from TRO maintenance.

Kaplan-Meier estimates of recurrence-free survival (A, C) and overall survival (B, D) of patients with KIT exon 11 deletion mutation (A, B) and patients with KIT exon 11 indel mutation (C, D)

We report a long-lasting response to the immune checkpoint inhibitor nivolumab in combination with regional hyperthermia (RHT) in a patient with recurrent metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) and negative programmed death ligand 1 (PD-L1) expression. Treatment was well tolerated with no local side effects. Tumor-related symptoms in the orbital and masticator area gradually decreased under treatment with nivolumab and RHT. Over the course of treatment, magnetic resonance imaging (MRI) showed a local tumor control in the heated tumor areas, while metastatic lesions developed in areas outside of the RHT field. This is the first case report demonstrating the feasibility and clinical potential of the addition of RHT in this patient collective with poor outcomes and low response rates to immune checkpoint inhibitors. RHT might be an additional tool to activate an immunogenic milieu responsive to immune checkpoint inhibitors.