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Background: After a huge efficacy of imatinib in treating patients with gastrointestinal stromal tumors (GISTs) was proven, a maximum effort was made to make a differential diagnosis between GISTs and gastrointestinal leiomyosarcomas (GI‐LMS), showing the latter to be an extremely rare tumor entity. Limited data on GI‐LMS biology, clinical behavior and drug‐sensibility are available, and the clinical decision‐making in this subgroup of patients is usually challenging. Methods: We conducted a multicenter, retrospective observational study on patients with diagnosed GI‐LMS from 2004 to 2020 within six high‐volume referral centers in Italy. Results: Thirty‐three patients had diagnosis of KIT‐negative GI‐LMS confirmed by sarcoma‐expert pathologist. The most common site of origin was the intestine. Twenty‐two patients had localized disease and underwent surgery: with a median follow‐up of 72 months, median disease‐free survival was 42 months. Overall survival (OS)‐rate at 5 years was 73% and median OS was 193 months. Five out of 10 patients with local relapse received a salvage surgery, and 2/5 remained with no evidence of disease. Thirteen patients received neoadjuvant (6) or adjuvant (7) chemotherapy, and 2/13 patients remained free from relapse. The median OS for patients with metastatic LMS was 16.4 months. Conclusion: GI‐LMS is very rare and extremely aggressive subgroup of sarcomas with a high tendency to systemic spread. Localized GI‐LMS at diagnosis may be cured if treated with adequate surgery with or without (neo) adjuvant chemotherapy, while de‐novo metastatic disease appeared to have a poor prognosis. Clinical effort to understand GI‐LMS biology and clinical behavior and to develop active treatment strategy, especially for metastatic‐disease, is warranted. [ABSTRACT FROM AUTHOR]

Background: Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile.Methods: The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics.Results: Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively.Conclusion: Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data. [ABSTRACT FROM AUTHOR]

To investigate the activity of regorafenib in advanced solitary fibrous tumour (SFT). An Italian monocentric investigator-initiated exploratory single-arm Phase II trial was conducted of regorafenib in adult patients with advanced and progressive SFT, until progression or limiting toxicity. Prior treatment with antiangiogenics was allowed. Primary and secondary end-points were: overall response rate (ORR) by Choi criteria, and ORR by RECIST, progression-free survival (PFS), overall survival (OS). From January 2016 to February 2021, 18 patients were enroled [malignant-SFT = 13; dedifferentiated-SFT (D -SFT) = 4; typical-SFT (T-SFT) = 1]. Fourteen patients were pre-treated, in 12 cases with antiangiogenics (median [m-] lines of treatment = 3). Sixteen patients were evaluable for response (one screening failure; one early discontinuation). Six/16 (35.2%) required a definitive dose reduction. ORR by Choi was 37.5% (95% CI: 15.2–64.6), with 6/16 (37.5%) partial responses (PR), 6/16 (37.5%) stable disease (SD) and 4/16 (25%) progressions; 5/6 responses occurred in patients pre-treated with antiangiogenics. No responses were detected in D -SFT. Best RECIST responses were: 1/16 (6.2%) PR, 12/16 (75%) SD, 3/16 (18.8%) progressions. At 48.4 month m-FU, m-PFS by Choi was 4.7 (inter-quartile range: 2.4–13.1) months, with 31.2% patients progression-free at 1 year. Regorafenib showed activity in SFT, with 30% patients free-from-progression at one year. Responses were observed also in patients pretreated and refractory to another antiangiogenic agents. However, ORR and m-PFS were lower than reported with other antiangiogenics, and this was possibly due to discrepancies in the patient population and the high-rate of dose reductions. • Regorafenib (R) is active in advanced, progressive solitary fibrous tumour (SFT). • R activity was seen in typical-/malignant-SFT but not in dedifferentiated-SFT. • R was effective also in cases refractory to previous antiangiogenic agents. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None of the authors has any interests to report directly related to this manuscript. Outside the scope of this manuscript: Elena Palassini, Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Giacomo Giulio Baldi, consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, Istituto Gentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai. Sara Sulfaro, Marta Barisella, Giuseppe Bianchi, Domenico Campanacci, Marco Fiore, Marco Gambarotti, Massimiliano Gennaro, Carlo Morosi, no conflict of interests to declare. Federico Navarria, travel grants from Pharmamar, Boehringer Ingelheim. Claudia Sangalli, advisory board from Boehringer Ingelheim, Astra Zeneca. Rossella Bertulli, travel grants from PharmaMar. Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Alexia Bertuzzi, Roberto Biagini, Angela Bonadonna, Antonella Brunello, Dario Callegaro, no conflict of interests to declare. Ferdinando Cananzi, speaking fee from Istituto Gentili. Marco Cianchetti, Paola Collini(,) Danila Comandini, Annalisa Curcio, no conflict of interests to declare. Lorenzo D’Ambrosio, advisory board: PSI CRO Italy, GSK, AstraZeneca, Boehringer Ingelheim, Eisai. Meeting participation: GSK, AstraZeneca, PharmaMar. Martino De Pas, participation on advisory board from Glaxo Smith Kline, Boehringer Ingelheim. Trial support from: Pfizer, BluPrint Medicine, Gilead, Amgen, Merck. Angelo Paolo Dei Tos, no conflict of interests to declare. Virginia Ferraresi, Travel grants from PharmaMar, Gentili, Boehringer Ingelheim. Advisory Board: SERB Pharmaceuticals. Andrea Ferrari, Alessandro Franchi, no conflict of interests to declare. Anna Maria Frezza, Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Elena Fumagalli, Advisory Board from Deciphera Pharmaceuticals. Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Matteo Ghilli, Daniela Greto, no conflict of interests to declare. Giovanni Grignani, advisory board from Pharmamar, Incyte, Merck, Novartis, Deciphera,Bayer. Michele Guida, advisory board from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre. Toni ibrahim, advisory board and consultation fees from Amgen, Glaxosmithkline, PharMamar and Istituto Gentili. Travel grants from Istitaka Gentili and Pharmamar. Marco Krengli, Roberto Luksch, Andrea Marrari, Marinella Mastore, Alessandra Merlini, no conflict of interests to declare. Giuseppe Maria Milano, Advisory board from Bayer, GSK, SERBS Pharmaceuticals. Piera Navarria, Maria Abbondanza Pantaleo, Antonina Parafioriti, no conflict of interests to declare. Ilaria Pellegrini, Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Elisabetta Pennacchioli, Marco Rastrelli, Elisabetta Setola, Salvatore Tafuto, Salvatore Turano, Sergio Valeri, Bruno Vincenzi, Viviana Vitolo, Andrei Ivanescu, Fiammetta Paloschi, no conflict of interests to declare. Paolo Giovanni Casali, Institutional Research Funding: Deciphera Pharmaceuticals, Blueprint Medicines, Cogent Biosciences, Amgen/Dompè, Bayer, GlaxoSmith Kline, Novartis, Pfizer, PharmaMar, Eisai, Eli Lilly, Advenchen Laboratories , Arog, Epizyme, Karyopharm Therapeutics, SpringWorks Ther,Daiichi Sankyo, Boehringer Ingelheim, Rain Therapeutics, Foghorn Ther Inc, Hutchinson MediPharam Lt, INBRX, PTC Ther. Alessandro Gronchi, no conflict of interests to declare. Silvia Stacchiotti, personal financial interests (honoraria, consultancy or advisory role): Aadi, Astex Pharmaceuticals, Bavarian Nordic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, Epizyme, Gentili, GSK, Agenus, Ikena, MaxiVAX, Novartis, PharmaMar, Pharma Essentia, Rain Therapeutics, Servier. Support for attending meetings and/or travel Pharmamar; Institutional financial interests: Advenchen, Bayer, Blueprint, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, GSK, Hutchinson, Inhibrx, Karyopharm, Novartis, PharmaMar, Rain Therapeutics, SpringWorks; unpaid Member of the Scientifc Advisory Board of the Chordoma Foundation, Member of the Scientifc Advisory Board of the Desmoid Foundation, Member of the Scientifc Advisory Board of the Epithelioid Hemangioendothelioma Group, Member of the Scientifc Advisory Board of the Leiomyosarcoma Foundation., (Copyright © 2024. Published by Elsevier Ltd.)

Importance: Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure., Objective: To evaluate the outcomes of guideline-based follow-up in low-risk GIST., Design, Setting, and Participants: This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up., Exposures: All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines., Main Outcomes and Measures: The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed., Results: A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients., Conclusions and Relevance: In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy.

Introduction: This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants ("classic-type" and "proximal-type"). The value of a subtype-adapted grading system based on pathological features is explored., Methods: Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995-2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into "high-grade" and "low-grade", according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated., Results: Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03)., Conclusions: Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the "high-grade" classic-type ES was associated with outcomes close to proximal-type ES., Competing Interests: Declaration of competing interest AMF received institutional clinical trials support from Amgen Dompé, AROG Bayer, Blueprint Medicines, Eli Lilly, Daiichi Sankyo Pharma, Epizyme, GlaxoSmithKline, Novartis, Pfizer, PharmaMar and travel grants from PharmaMar. GGB received travel grants and advisory honoraria from Pharmamar and Eli Lilly, advisory honoraria from Eisai. NS received institutional clinical trials support from Amgen Dompé, AROG Bayer, Blueprint Medicines, Eli Lilly, Daiichi Sankyo Pharma, Epizyme, GlaxoSmithKline, Novartis, Pfizer, PharmaMar. PGC has reported advisory roles for Deciphera Pharmaceuticals, Eisai, Eli Lilly, Nektar Therapeutics, speaker's honoraria from Eisai, Eli Lilly, Pfizer, PharmaMar, and conducted studies sponsored by Amgen Dompé, AROG Bayer, Blueprint Medicines, Eli Lilly, Daiichi Sankyo Pharma, Epizyme, GlaxoSmithKline, Novartis, Pfizer, PharmaMar. SSt has received honoraria from Eli Lilly, PharmaMar, Takeda; institutional research grants from Amgen Dompé, Advenchen, Bayer, Eli Lilly, Daiichi Sankyo Pharma, Epizyme Inc., Novartis, Pfizer and PharmaMar; travel grants from PharmaMar and has reported advisory/consultant roles for Bayer, Daiichi, Eli Lilly, Epizyme, Karyopharm, ImmuneDesign, Maxivax and PharmaMar. MS, SLV, FF, DC, DC, SP, AG, APDT, MG, MB, AP, LM have nothing to declare., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Sarcomas are rare malignant neoplasms that develop from mesenchymal cells and include a heterogeneous and large group of histological subtypes that may occur at any anatomical site. Soft tissue sarcomas (STS), the focus of this review, account for ≈70‒80% of sarcomas and represent <1% of all cancers. The heterogeneity of STS applies to both their topography and morphology, and 5-year survival can vary widely depending on disease stage and the complex interplay between anatomical site and histology for different STS subtypes. The rarity and heterogeneity of STS, together with other factors, such as the lack of clinical expertise often lead to difficulties and delays in making an accurate diagnosis and to the inappropriate management of each STS subtype. Therefore, this group of cancers requires special attention and approaches to diagnosis and treatment. Epidemiological data on STS are limited, and concerns have been raised regarding accurate registration of STS in cancer registries, including issues related to details of the histotypes. This review provides an overview of the epidemiology of STS in Italy, focusing on data from the Italian Association of Cancer Registries (AIRTUM), and compares findings with those from other European countries. Based on these data, and considering that STS is among the most common group of rare cancers, the relevance of multidisciplinary care for STS patients through reference centres, clinical networks and collaborative disease-specific groups is discussed., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)