Background. Epithelioid sarcoma (EpS) is an ultra-rare, aggressive soft tissue sarcoma (STS) driven by loss of the tumor suppressor INI1, encoded by SMARCB1 , which triggers hyperactivation of the chromatin-modifying enzyme EZH2. However, objective responses to the EZH2 inhibitor (EZH2i) tazemetostat (TZM) remain limited to approximately 15% of patients. Combination strategies incorporating EZH2i with doxorubicin (DOX), the first-line standard for advanced STSs, may enhance the activity of either agent alone, warranting investigation of determinants of response and resistance. Methods. Two INI1-deficient in-house generated proximal-type EpS (P-EpS) patient-derived xenograft (PDX) models, EpS-1 and EpS-2, and their matched cell lines were established. EpS-1 and EpS-2 models harbored a homozygous SMARCB1 deletion and underwent comprehensive genomic, epigenomic, transcriptomic, protein-level, and histological characterization. Both models were used to evaluate TZM and DOX, alone and in combination, and to investigate determinants of response and resistance. Results. TZM + DOX greatly inhibited tumor growth in EpS-1 in vivo, though regrowth occurred approximately three weeks after treatment cessation. EpS-2 displayed intrinsic resistance to all treatments. RNA sequencing of post-treatment PDXs revealed divergent transcriptional responses: in EpS-1 but not in EpS-2 TZM + DOX downregulated gene sets linked to chromatin organization and histone deacetylases (HDACs). Consistently, H3K27 acetylation (H3K27ac) accumulated exclusively in EpS-1, suggesting HDAC activity limits EZH2i-induced chromatin remodeling in resistant EpS. In EpS-2, co-treatment with TZM, DOX, and the pan-HDAC inhibitor vorinostat (SAHA) restored H3K27ac, induced apoptosis, and showed tendency toward synergism. Conclusions. This study identifies distinct resistance profiles to EZH2i-based therapy in P-EpS PDXs. HDAC activity limits chromatin remodeling induced by EZH2i (± DOX), and its inhibition with SAHA restores sensitivity, supporting HDAC inhibition as a rational strategy to overcome EZH2i resistance.

Medical decision analysis is a method to make rational clinical decisions under uncertainty, enabling a mathematical combination of probabilities and utilities (i.e. values assigned to outcomes under risk). Decision analysis is commonly used in health economics, but it is underexploited in the clinic. With a view to fostering the use of medical decision analysis at the cancer patient bedside, this paper provides basic templates for some typical clinical decisions in cancer treatment, namely affecting: the quantity/quality of life trade-offs in curable cancer; adjuvant/neoadjuvant treatments; cytoreductive treatments; active surveillance / watchful waiting choices; treatment of advanced cancer; cancer follow-up. The clinical use of medical decision analysis is challenged by several difficulties, which are briefly recalled. Contrary to clinical research, medical decision analysis does not build new evidence: it simply provides physicians with a method to personalize clinical decisions on the basis of available evidence. Its added value in clinical practice correlates with the complexity of a decision. However, it also has a great potential in medical education, in order to empower clinicians with skills improving their ability to rationally shape medical decisions and share them properly with their patients.

Background Atypical cartilaginous tumors (ACT) are low-grade cartilaginous lesions of the appendicular skeleton with debated diagnostic and therapeutic management. Methods The Italian Sarcoma Group (ISG) conducted a multidisciplinary consensus process involving 61 experts from six specialties across 22 institutions. A narrative literature review informed key questions discussed during an in-person consensus meeting, and agreement was assessed through structured voting. Results Six consensus statements were developed: three on diagnosis, two on treatment, and one on active surveillance and follow-up. Biopsy was recommended selectively in the presence of aggressive or equivocal radiological features. Active surveillance was endorsed for selected patients, while intralesional curettage remains the preferred surgical option when treatment is indicated. Structured follow-up protocols were proposed. Conclusions This consensus provides practical recommendations for the management of ACT, supporting imaging-driven decision-making and active surveillance in appropriate cases.

PURPOSE:The Complexity INdex in SARComas (CINSARC) predicts the metastatic risk in patients with soft-tissue sarcoma. The aims of this study were to provide the first independent validation of CINSARC in patients with retroperitoneal sarcoma (RPS) and evaluate whether CINSARC could enhance the performance of Sarculator. EXPERIMENTAL DESIGN:A retrospective cohort included patients with primary localized RPS resected with curative intent (2011-2015) at a single institution. The STRASS cohort comprised patients from the surgery-only arm of the EORTC-STBSG-62092 (STRASS) trial who had undergone CINSARC categorization. Patients were classified as CINSARC low-risk (C1) versus high-risk (C2). Primary study endpoints were overall survival (OS) and disease-free survival (DFS). Sarculator performance was assessed in terms of discrimination (the Harrell C-index) and calibration (calibration plots and the Brier score) before and after adding CINSARC. RESULTS:The study cohorts included 104 and 69 patients, respectively, with similar OS. In a pooled cohort, in multivariable analysis for OS considering Sarculator and CINSARC, only Sarculator was significantly associated with OS [HR, 1.93; 95% confidence interval (CI), 1.35-2.74; P < 0.001]. In multivariable analysis for DFS, both Sarculator (HR, 1.51; 95% CI, 1.09-2.09; P = 0.013) and CINSARC (HR, 2.01; 95% CI, 1.26-3.23; P = 0.004) were significantly associated with DFS. However, the addition of CINSARC did not improve Sarculator's discrimination or calibration for either OS or DFS. CONCLUSIONS:This study validates CINSARC as a prognostic predictor for OS and DFS in patients with primary RPS. CINSARC did not improve the performance of Sarculator, suggesting that its addition to the Sarculator may not provide added clinical benefit.

Extended molecular profiling using massive parallel sequencing (MPS) technologies, commonly referred to as next-generation sequencing (NGS), has revolutionized cancer diagnosis and treatment, including in bone and soft tissue sarcomas (BSTS). This heterogeneous group of mesenchymal tumors presents a complex spectrum of genetic alterations, such as chromosomal rearrangements, point mutations, and copy number variations. Unlike carcinomas, where driver mutations are often well defined, the role of specific genomic signatures in dictating BSTS prognosis and therapy response remains to be fully elucidated. Despite its promise, the adoption of MPS/NGS in BSTS is limited by variability in testing access, turnaround times, specimen quality, costs, and data interpretation. Although identified alterations are often not yet directly targetable, they provide critical insights that can refine diagnosis, enable better patient stratification, and guide treatment strategies. To optimize the use of MPS/NGS in BSTS, harmonization and multidisciplinary collaboration within molecular tumor boards (MTBs) are essential. With this aim, the Italian Sarcoma Group ETS (ISG) convened a consensus meeting to establish best practices for integrating MPS/NGS into everyday clinical care. ISG experts developed ten consensus statements: the first five address the role of extended molecular profiling in BSTS diagnostics, while the others offer guidance on MPS/NGS use and interpretation when searching for potentially actionable targets in the treatment of advanced disease. Furthermore, collaboration with the National Rare Cancer Network to offer expert consultation and systematically correlate MPS/NGS findings with clinical outcomes for BSTS cases undergoing extended molecular profiling will be critical to advancing precision medicine in this field.

Bone metastases (BMs) were reported in <15% of cases of neuroendocrine neoplasms (NENs). Their clinical behavior is various and clinical management is still undefined. This study aimed to describe the clinical practical management and survival outcome of neuroendocrine neoplasm patients with BMs. This is a retrospective, observational, multicenter, nationwide study, in which clinical‐pathological characteristics, diagnostic tools, skeletal‐related events (SREs), bone targeted agents (BTAs) and their correlation with clinical outcome were collected. Data from 320 patients from 18 Italian centers diagnosed with bone metastases during 2000–2013 were captured. Most patients had a well/moderately differentiated NEN, with synchronous distant metastases, mostly hepatic, the majority of which originated from a gastroenteropancreatic primary site. Bone was the first metastatic site in 41% of patients. After a median follow‐up of 27 months 122 patients died. The median overall survival (OS) was 62 months. In 22% of patients ( n = 72), SREs were observed, and 31% of patients received a BTA. At multivariable analysis of factors associated with OS after the development of BMs, primary lung site, Ki‐67 ≥55% versus ≤20%, >10 BMs, mixed pattern (osteoblastic/osteolytic) versus osteoblastic, prior lung metastases and SREs were found to be significant poor prognosis factors. At multivariable analysis Ki‐67 ≥55% versus ≤20% remains significantly associated with the development of SREs. Our study represents a real‐life nationwide scenario of a large series of NEN patients with BMs handled at dedicated centers. Several hypotheses generated by this study are warranted to be tested in future homogeneous studies, including objective criteria for the use of BTAs.

Supplementary Table 2: univariate and multivariable analyses for OS in specific subgroups

Ultra-rare sarcomas (URS) and ultra-rare cancers (URC) represent a unique challenge in oncology due to their rarity, heterogeneity, and the severe unmet clinical needs of affected patients. In 2024, the European Medicines Agency (EMA) and the European Organisation for Research and Treatment of Cancer (EORTC) convened two multi-stakeholder workshops, bringing together regulators, clinicians, researchers, and patient advocates. These workshops aimed to explore innovative strategies for treatment development and establish a framework for future collaboration. Key issues were discussed, including the scarcity of biological and clinical data, major barriers in conducting randomized trials, and limited pharmaceutical investment. A key outcome was the unanimous commitment of all stakeholders, including regulatory agencies such as EMA and the U.S. FDA, to work together towards pragmatic solutions. Participants recognized the necessity of flexible regulatory approaches, alternative trial designs, and meaningful endpoints tailored to ultra-rare conditions. The workshops also highlighted the importance of global collaboration, early regulatory engagement, and leveraging existing mechanisms like orphan drug designation and conditional approvals. The discussions emphasized that while scientific rigor must be upheld, regulatory frameworks must adapt to the specific challenges posed by URS. Stakeholders pledged to maintain open dialogue, share expertise, and develop innovative infrastructures to accelerate progress. This collaborative commitment marks a critical step forward in addressing the high unmet needs of URS. By fostering a unified effort among diverse stakeholders, the workshops established a model for advancing treatments in other URC, prioritizing patient outcomes while navigating the complexities of drug development for these challenging diseases.

Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory. To elucidate the molecular underpinnings of ES, and to identify diagnostic biomarkers and potential therapeutic vulnerabilities, we performed an integrated omics profiling (RNA sequencing and methylation array) of 24 primary, untreated ESs. Transcriptome and methylome analysis identified 2 distinct molecular clusters that essentially corresponded to the morphologic variants of ES, classic ES (C-ES) and the more aggressive proximal ES (P-ES). The P-ES group was characterized by hyperactivation of GATA3 and MYC pathways, with extensive epigenetic rewiring associated with EZH2 overexpression. Both DNA methylation and gene expression analysis indicated a striking similarity with the "MYC subgroup" of atypical teratoid/ rhabdoid tumor, another SMARCB1-deficient tumor, implying a shared molecular background and potential therapeutic vulnerabilities. Conversely, the C-ES group exhibited an endothelial-like molecular profile, with expression of vascular genes and elevated proangiogenic SOX17 signaling. Immunohistochemistry validated the overexpression of the chromatin regulators GATA3 (9/12 vs 0/ 16) and EZH2 (7/7 vs 2/6) in P-ESs, and of the vascular factors SOX17 (8/8 vs 1/10) and N-cadherin (5/9 vs 0/10) in C-ESs. Therefore, these molecules emerge as potential diagnostic tools to fill the gap represented by the lack of ES subtype-specific biomarkers. In summary, our study shows that P-ES and C-ES represent distinct molecular entities defined by MYC/GATA3 and SOX17/endothelial molecular traits, respectively. Besides providing insights into the biology of ES, our study pinpoints subtype-specific biomarkers and potential therapeutic vulnerabilities. (c) 2024 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Supplementary Figure 4. Transcriptomic profiles of EHE clinical tumor and PDX.

Supplementary Figure 6. Time-course analysis of siRNA-mediated down regulation of GDF-15 in EHE cell line.

Angiosarcoma (AS) represents a rare and aggressive vascular sarcoma, posing distinct challenges in clinical management compared to other sarcomas. While the current European Society of Medical Oncology (ESMO) clinical practice guidelines for sarcoma treatment are applicable to AS, its unique aggressiveness and diverse tumor presentations necessitate dedicated and detailed clinical recommendations, which are currently lacking. Notably, considerations regarding surgical extent, radiation therapy (RT), and neoadjuvant/adjuvant chemotherapy vary significantly in localized disease, depending on each different site of onset. Indeed, AS are one of the sarcoma types most sensitive to cytotoxic chemotherapy. Despite this, uncertainties persist regarding optimal management across different clinical presentations, highlighting the need for further investigation through clinical trials. The Italian Sarcoma Group (ISG) organized a consensus meeting on April 1st, 2023, in Castel San Pietro, Italy, bringing together Italian sarcoma experts from several disciplines and patient representatives from "Sofia nel Cuore Onlus" and the ISG patient advocacy working group. The objective was to develop specific clinical recommendations for managing localized AS within the existing framework of sarcoma clinical practice guidelines, accounting for potential practice variations among ISG institutions. The aim was to try to standardize and harmonize clinical practices, or at least highlight the open questions in the local management of the disease, to define the best evidence-based practice for the optimal approach of localized AS and generate the recommendations presented herein.

Supplementary Figure 1. Representative growth curves of the EHE PDX at different passages in mice.

Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ∼50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene, SMARCB1—a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.

11517 Background: EGFR and Her2 overexpression in chordoma is well known, and chordoma cell-lines and mouse models were proven to be sensitive to EGFR inhibitor afatinib. This phase 2, single arm, European multi-center trial was designed to evaluate the efficacy of afatinib as first- or later-line tyrosine kinase inhibitor (TKI) treatment in advanced chordoma. Here we report efficacy and safety data. Methods: Eligible patients (pts) had locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies, with confirmed measurable and progressive lesions according to RECIST1.1. Pts were treated with afatinib 40mg/day in a 4 week cycle until disease progression (PD), unacceptable toxicity or withdrawal. Radiological tumor response assessment was performed every 3 cycles. The primary endpoint was response defined as progression free survival (PFS) rate ≥12 months (mos) for first-line cohort 1 and ≥ 9 mos for further-line treatment cohort 2, and change from baseline in EORTC QLQ- C30 and Brief pain inventory (BPI) questionnaires. Pts were enrolled using a Simon’s two-stage design, enrolling 13 patients in stage one, ≥3 patients with a PFS ≥ 12 or 9 mos were needed to enter stage two, where 43 pts total were to be enrolled, and ≥13 free from progression at 9 or 12 mos were required to meet the primary endpoint for success. Results: From Jun 2018 to Oct 2022, 47 pts were included. Four were ineligible for efficacy analysis (1 withdrawal, 3 stopped due to toxicity before first radiological evaluation). 34 entered cohort 1, 13 cohort 2. 31 (66.0%) were men, median age was 53 (range 28-85) years. 16 (34.0%) pts received prior systemic therapy (3 chemotherapy, 13 TKI, 2 immunotherapy, 2 other). The PFS rate at 12 mos was 40.0% in cohort 1 (12/30 pts), and 38.5% in cohort 2 (5/13 pts). Overall median PFS was 8.6 mos (95% CI 5.6-13.6); 9.1 mos (95% CI 5.8-16.6) in cohort 1 and 7.1 mos (95% CI 2.8-16.5) in cohort 2. Two pts remained on treatment at time of analysis. Best objective response by RECIST 1.1 was partial response in 4 pts (9.3%), stable disease in 33 (76.7%), PD in 5 pts (11.6%) and 1 (2.3%) unknown due to clinical progression. Median follow-up time was 23.7 mos (interquartile range 11.0-21.2). 16/47 pts (30.4%) experienced grade ≥3 adverse events (AEs). No grade 5 AEs related to afatinib were reported. Most common grade 3-4 afatinib-related AEs were skin toxicity (10.6% of pts), diarrhea (10.6%), mucositis (6.4%), hypertension (4.3%). Dose reduction was needed in 20/47 (42.6%) pts, and at least one dose interruption was needed in 31/47 (66.0%) pts. Conclusions: With a PFS rate at 12 mos of 40.0% in the first-line cohort and 38.5% at 9 mos in the further-line cohort, this phase 2 study met the PFS endpoint. QoLQ data will be provided at the conference . Partial response by RECIST was seen in 4/43 pts. Toxicity and dose reductions were relevant but manageable in most pts. Clinical trial information: NCT03083678 .

GDF-15 was released by tumor cells in patient-derived models of EHE. A, Assessment of released cytokines in the culture medium of EHE cells using the Human XL Cytokine Array. Detection of GDF-15 by ELISA in culture medium of EHE cell lines and cell lines of PLPS and DDLPS-1 and -2. B, Data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins. RT-qPCR and ELISA results are reported as mean ± SD of three independent experiments. C, Detection of GDF-15 by ELISA in the plasma of healthy mice and mice carrying EHE PDX or PLPS PDX. D, siRNA-mediated downregulation of GDF-15 in the EHE cell line as detected at the mRNA level by RT-qPCR (left), protein level by Western blotting (middle), and as cytokine released in cell culture medium by ELISA 3 days after transfection (right). ELISA data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins and reported as mean ± SD of three independent experiments. E, GSEA (RRID: SCR_003199) was employed on Hallmark (H) collection of the Molecular Signature Database, showing a limited number of modulated pathways following GDF-15 knockdown. DDLPS, dedifferentiated liposarcoma; PLPS, pleomorphic liposarcoma.

BackgroundWe report on a series of consecutive patients with localized radiation-associated angiosarcoma (RAAS) of the breast region (BR) treated at two Italian sarcoma reference centers.Materials and methodsWe retrospectively reviewed all cases of primary, localized, resectable RAAS of the BR, treated at one of the two participating institutions from 2000 to 2019. Relapse-free survival (RFS) and overall survival (OS) were calculated. The prognostic role of several variables was investigated. A propensity score matched (PSM) analysis was carried out.ResultsEighty-four patients were retrospectively identified. Nineteen out of 84 patients (22.6%) were pretreated with an anthracycline-based regimen for previous cancer. All patients but one underwent surgery, with 37/84 (44.1%) receiving surgery alone and 46/84 (54.8%) a multimodal approach: 18/84 (21.4%) received radiation therapy (RT) and 46/84 (54.9%) received chemotherapy. An anthracycline-based regimen was used in 10/84 patients (11.9%), while a gemcitabine-based regimen was used in 33/84 (39.3%). With a median follow-up of 51 months (interquartile range: 30-126 months), 36/84 patients (42.9%) relapsed and 35/84 patients (41.7%) died (8/84, 9.5% in the lack of metastatic disease). Five-year OS and 5-year RFS were 57% [95% confidence interval (CI) 43% to 68%] and 52% (95% CI 39% to 63%), respectively. Both (neo)adjuvant RT and chemotherapy were associated with better RFS [hazard ratio (HR) 0.25, 95% CI 0.08-0.83; HR 0.45, 95% CI 0.23-0.89] with a trend towards a better OS (HR 0.51, 95% CI 0.18-1.46; HR 0.60, 95% CI 0.29-1.24). Gemcitabine-based regimens seemed to perform better (HR 4.28, 95% CI 1.29-14.14). PSM analysis retained the above results.ConclusionsThis retrospective study supports the use of (neo)adjuvant RT and chemotherapy, in primary, localized resectable RAAS of the BR. An effort to prospectively validate the role of (neo)adjuvant RT and chemotherapy is warranted.