Soft tissue sarcomas are a rare group of mesenchymal malignancies, with greater than 100 histologic subtypes. Advancements in understanding these subtypes has enabled histology-tailored management. This primer describes the workup and management of generalized soft tissue sarcomas of the extremity, trunk, and retroperitoneum while also highlighting the unique attributes of many subtypes. The subtypes chosen for review include those that are most common as well as those demonstrating unique behaviors or targets for management. The focus is on initial management of localized disease; however, for situations in which novel systemic agents have been discovered, the treatment of metastatic disease is discussed. This report is a reference to be used in addition to other comprehensive reviews, such as guidelines from the National Comprehensive Cancer Network, the European Society for Medical Oncology, and the American Society for Radiation Oncology. It is not a substitute for referral to an expert sarcoma center for critical pathology review and management by an experienced team. Importantly, patients who are treated at expert sarcoma centers have better outcomes than those who are not.

Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.

Supplementary Data Methods, Figures S1-S7, and Table S1

Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most common types of adult sarcoma and holds valuable insights into dysfunctional differentiation given its well- and de-differentiated histologic subtypes (WDLPS and DDLPS, respectively). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood, limiting the therapeutic options for DDLPS to empiric cytotoxic chemotherapies. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human normal adipose, WDLPS, and DDLPS tissue samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) signaling and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 signaling loss was exclusive to the DDLPS component within mixed histology tumors and IGF1 loss was associated with worse overall survival in LPS patients. In normal adipocytes, IGF1 signals upstream of peroxisome proliferator-activated receptor gamma (PPARG) to induce lineage-specific terminal differentiation. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS cells led to a block in differentiation that could not be overcome with the addition of either exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease. Erica Maria Pimenta, Amanda E. Garza, Sabrina Y. Camp, Jihye Park, Samantha E. Hoffman, Laura Valderrabano, Jingxin Fu, Kevin Bi, Julie Karam, Breanna M. Titchen, Melin K. Khandekar, Erin Shannon, Yun Jee Kang, Anwesha Nag, Aaron R. Thorner, Chandrajit R. Raut, Jason L. Hornick, Priscilla Merriam, Nicole L. Solimini, Suzanne George, George D. Demetri, Eliezer M. Van Allen. Epigenetic dysregulation of IGF1 and PPARG2 in dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1180.

and Purpose: Osteosarcoma (OS) and Leiomyosarcoma (LMS) are sarcomas with complex genomes for which there has been limited progress in identifying new treatments and improving outcomes. While slow progress is partially due to insufficient genomic characterization, generating large genomic datasets has been challenging because these are rare cancers. The OS and LMS Projects use various approaches to directly engage pediatric and adult participants with OS and LMS in genomics research. Working with patients and advocates at the design stage, we created websites (OSProject.org and LMSProject.org) where patients register and consent to participation. Any patient with OS or LMS living in the United States or Canada is eligible. Participant outreach approaches include partnership with advocacy organizations, webinars, social media posts, meeting presentations, stakeholder and physician engagement committees, and direct mailings. Blood and saliva are collected directly from consented participants by mail, archival FFPE tumor samples are obtained from pathology departments and medical records are requested from treating institutions. WES, WGS, DNA panel sequencing and RNASeq of tumor and germline (T/N) is performed. Results are shared with patient, advocacy, physician, and research communities in several ways. Individual participants receive a shared learning report describing the somatic variants identified in their tumor from T/N clinical WES and are offered clinical germline genetic testing and genetic counseling. The study outreach team has participated in or led a total of 33 online and in person events not including social media posts or stakeholder meetings. So far, in 26 months 515 LMS patients (ages 16-83y; median 55) and 145 OS patients (ages 7-74y; median 20) have consented. Thus far, 274 and 76 tumor samples and 555 and 127 germline samples have been obtained from LMS and OS consented participants, respectively. Analysis of the first 20 LMS participants with T/N WGS showed widespread alteration of TP53 (11 pts), RB1 (8 pts), and PTEN (16 pts), concordant with findings in past studies. Likewise, the first 7 OS pts with T/N WGS demonstrated inactivation of TP53 (4 pts) and RB1 (2 pts), as expected from past OS cohorts. Using community partnerships and direct outreach to connect and engage with participants and a virtual consenting process for genomics research in rare cancers is feasible. It is possible to obtain germline samples directly from about half of participants and archival tumor samples from treating pathology departments for about one third of participants consented in direct-to-patient online genomics studies. We have been able to utilize archival tumor samples to identify, with T/N WES/WGS, expected genomic events in complex genome cancers. Recruitment and sequencing are ongoing. Julia M. Wong, David Merrell, Eirian Siegal-Botti, Noorshifa Arssath, Carrie Cibulskis, Evelina Ceca, Alanna Church, Alex Wilson, Lorena Lazo De La Vega, Jill Stopfer, Ellen Sukharevsky, Nia Daley, Anusha Sharma, Sidney Benich, Zachary Kahn, Lauren Fisher, Parker Chastain, Brendan Reardon, Taisha Hendrickson, Colleen Nguyen, Melissa Chiumiento, Melissa Mirick, Noriela Elia, Priscilla Merriam, Eliezer Van Allen, Judy Garber, Riaz Gillani, Chandrajit Raut, Stacey Gabriel, Timothy Rebbeck, Jason L. Hornick, Jennifer Mack, Suzanne George, Diane Diehl, Gad Getz, Katherine A. Janeway. Directly engaging participants in rare cancer research is feasible: the osteosarcoma and leiomyosarcoma projects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 630.

Background:Comprehensive resection represents the standard of care for patients affected by retroperitoneal well- or dedifferentiated liposarcoma (WDLPS/DDLPS). However, reference values to indicate the best achievable results are currently lacking. As such, the study aimed to define clinically relevant benchmark values for intra- and postoperative outcomes of patients undergoing comprehensive resection for primary retroperitoneal WDLPS/DDLPS. Methods:The international, prospectively maintained Retroperitoneal Sarcoma Registry (RESAR; NCT03838718) was used to calculate benchmark values for 22 outcomes, including intraoperative factors, and rates of complications, recurrence and survival. Only low-risk patients undergoing comprehensive resection for WDLPS/DDLPS at high-volume centers between 1st January 2017 and 31st December 2021 were used to calculate the benchmark values. Specifically, "low risk" was defined as age <75 years, with minimal comorbidities, and undergoing a "standard" comprehensive resection including at least colon and kidney with or without other organs-excluding those associated with significant morbidity (e.g., pancreas). Benchmark values were defined based on the 25th or 75th percentiles of the center-level data. To validate the benchmark values, these were applied to two cohorts expected to have inferior outcomes, which were defined by changing one of the exclusion criteria; namely those treated in low-volume centers, and those with American Society of Anesthesiologists (ASA) score ≥3 ("ASA ≥ 3"). Findings:Of the 1510 patients undergoing surgery, 147 met the inclusion criteria and were included in the benchmarking analysis. This identified benchmark values including: median duration of surgery ≤278 min, intraoperative packed red cell transfusion rate ≤30%, R0/R1 resection rate ≥89%, median length of hospital stay ≤15 days, reoperation rate ≤13%, major postoperative complication rate ≤21%, and 90-day postoperative mortality/failure-to-rescue rates of 0%. The "low-volume centers" cohort failed to meet 10 of these benchmarks, including duration of surgery (median: 293 vs. ≤278 min), R0/R1 resection rate (82% vs. ≥ 89%), major postoperative complication rate (35% vs. ≤21%), and reoperation rate (35% vs. ≤13%), whilst the "ASA ≥ 3" cohort failed to meet seven benchmarks. Interpretation:These novel benchmark values can act as reference values to which sarcoma centers or individual surgeons can compare, which may help to identify performance gaps and improve the quality of care. Funding:"5 x mille" fund for healthcare research (Italian Ministry of Health).

Textbook outcome (TO) has been utilized to assess the quality of surgical care. This study aimed to define TO rates for minimally invasive gastric gastrointestinal stromal tumor (GIST) resections in a bi-institutional cohort. Patients with gastric GIST (≤ 5 cm) who underwent laparoscopic or robotic resection (January 2014 to January 2024) were retrospectively identified from two GIST centers. We excluded patients with concurrent procedures, tumor involvement of adjacent organs, or metastatic disease. To balance perioperative and oncologic outcomes, we defined TO as: R0 resection, no conversion to open surgery, operative time ≤ 120 min, no perioperative transfusions, no intraoperative complications, no Clavien-Dindo ≥ II complications, hospital length of stay (LOS) ≤ 3 days, no 90-day readmission or death, no tumor rupture, and recurrence-free status at 2 years (5

Comsplete resection is the primary treatment for retroperitoneal sarcomas (RPS). The role of neoadjuvant chemotherapy (NACT) in improving oncologic outcomes is currently under investigation in the STRASS 2 trial. This study assessed the association between change in tumor size or pathologic response and oncologic outcomes. Data were retrieved from the international Retroperitoneal Sarcoma Registry and included patients who had RPS treated with NACT between January 2017 and October 2020. The correlation between radiologic response (RECIST1.1), change in tumor size, pathologic response, and oncologic outcomes was evaluated. Binary logistic, Cox, and polynomial spline regression and log-rank tests were performed as statistical analyses. The study enrolled 141 patients from 14 medical centers. The most common histologies were dedifferentiated liposarcoma (36.9

OBJECTIVE:To examine variations in patterns of care for retroperitoneal sarcoma (RPS) among sarcoma centres globally, including diagnostic work-up, surgical strategies and (neo)adjuvant therapies. METHODS:Retrospective analysis for primary RPS, from 19 RPS referral centres worldwide, prospectively collected within the RESAR repository (NCT03838718) between Feb 2017 - July 2022. Centres were categorised high volume (HVC) or low volume (LVC). Comprehensive resection (CR) was defined as en-bloc resection of ipsilateral kidney and colon. RESULTS:1718 primary RPS were included. Preoperative biopsy was utilised frequently (median rate 98%) for solid (non-liposarcoma) RPS. In liposarcoma, the median rate of CR was 64%, with wide variation (IQR 37% [43%-80%], range 0-100%). There was greater variation in CR in liposarcoma in LVC (IQR 39.5% [40.5%-80%]) versus HVC (IQR 9.5% [58.3%-67.8%]). Perioperative chemotherapy was seldom used for liposarcoma (median 0%), with higher rates for leiomyosarcoma (median 10%) with high variation (IQR 26% [2%-28%]). Radiotherapy was used consistently infrequently in leiomyosarcoma (IQR 13% [0%-13%]. There was higher use of radiotherapy in HVC than LVC (median HVC 18.5% vs. LVC 5%). There was a significant decrease in radiotherapy use after the STRASS trial (pre 19% vs. post 14%, P=0.045). CONCLUSIONS:Low variation was found in pre-operative biopsy of non-liposarcomas, use of chemotherapy in liposarcoma and radiotherapy in leiomyosarcoma, suggesting agreement between centres. There was high variation, suggesting equipoise, in the role of chemotherapy in leiomyosarcoma and the value of CR in liposarcoma. The STRASS study results seem to have been accepted, with a reduction in radiotherapy after its publication.

Retroperitoneal sarcomas (RPS) are a group of rare malignancies with many histologic types. Surgery is the hallmark of curative therapy for non-metastatic disease with the extent of resection depending on the histology. Neoadjuvant therapies have limited response and efficacy in RPS; however, the benefit, regimen, and timing depend on histology. Innovative therapeutics are emerging and may prove promising. This review discusses the work-up, management, and advances in the field of retroperitoneal sarcoma.

Importance:Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effort to harmonize the strategy among clinicians has been made. To update the 2020 global evidence-based consensus guideline on the management of patients with DT, the Desmoid Tumor Working Group convened a 1-day consensus meeting in Milan, Italy, on June 30, 2023, under the auspices of the European Reference Network on Rare Adult Solid Cancers and Sarcoma Patient Advocacy Global Network, the Desmoid Foundation Italy, and the Desmoid Tumor Research Foundation. The meeting brought together over 90 adult and pediatric sarcoma experts from different disciplines as well as patients and patient advocates from around the world. Observations:The 2023 update of the global evidence-based consensus guideline focused on the positioning of local therapies alongside surgery and radiotherapy in the treatment algorithm as well as the positioning of the newest class of medical agents, such as γ-secretase inhibitors. Literature searches of MEDLINE and Embase databases were performed for English-language randomized clinical trials (RCTs) of systemic therapies to obtain data to support the consensus recommendations. Of the 18 full-text articles retrieved, only 4 articles met the inclusion criteria. The 2023 consensus guideline is informed by a number of new aspects, including data for local ablative therapies such as cryotherapy; other indications for surgery; and the γ-secretase inhibitor nirogacestat, the first representative of the newest class of medical agents and first approved drug for DT. Management of DT is complex and should be carried out exclusively in designated DT referral centers equipped with a multidisciplinary tumor board. Selection of the appropriate strategy should consider DT-related symptoms, associated risks, tumor location, disease morbidities, available treatment options, and preferences of individual patients. Conclusions and Relevance:The therapeutic armamentarium of DT therapy is continually expanding. It is imperative to carefully select the management strategy for each patient with DT to optimize tumor control and enhance quality of life.

The management of sarcomas in specialist centers delivers significant benefits. In much of the world, specialists are not available, and the development of expertise is identified as a major need. However, the terms ‘specialist’ or ‘expert’ center are rarely defined. Our objective is to offer a definition for patient advocates and a tool for healthcare providers to underpin improving the care of people with sarcoma. SPAGN developed a discussion paper for a workshop at the SPAGN 2023 Conference, attended by 75 delegates. A presentation to the Connective Tissue Oncology Society (CTOS) and further discussion led to this paper. Core Principles were identified that underlie specialist sarcoma care. The primary Principle is the multi-disciplinary team discussing every patient, at first diagnosis and during treatment. Principles for optimal sarcoma management include accurate diagnosis followed by safe, high-quality treatment, with curative intent. These Principles are supplemented by Features describing areas of healthcare, professional involvement, and service provision and identifying further research and development needs. These allow for variations because of national or local policies and budgets. We propose the term ‘Sarcoma Intelligent Specialist Network’ to recognize expertise wherever it is found in the world. This provides a base for further discussion and local refinement.

Improving surgical resection outcomes for locally aggressive tumors is key to inducing durable locoregional disease control and preventing progression to metastatic disease. Macroscopically complete resection of the tumor is the standard of care for many cancers, including breast, ovarian, lung, sarcoma, and mesothelioma. Advancements in cancer diagnostics are increasing the number of surgically eligible cases through early detection. Thus, a unique opportunity arises to improve patient outcomes with decreased recurrence rates via intraoperative delivery treatments using local drug delivery strategies after the tumor has been resected. Of the current systemic treatments (e.g., chemotherapy, targeted therapies, and immunotherapies), immunotherapies are the latest approach to offer significant benefits. Intraoperative strategies benefit from direct access to the tumor microenvironment which improves drug uptake to the tumor and simultaneously minimizes the risk of drug entering healthy tissues thereby resulting in fewer or less toxic adverse events. We review the current state of immunotherapy development and discuss the opportunities that intraoperative treatment provides. We conclude by summarizing progress in current research, identifying areas for exploration, and discussing future prospects in sustained remission.