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The improved outcome of extremity soft tissue sarcoma patients surgically treated until 2007 at the authors' institution was previously reported. This study updates the analysis at a later follow-up and extends the patients' cohort to assess changes in outcomes over time for extremity and superficial trunk soft tissue sarcoma (ESTSTS) treated at a single referral center.All consecutive patients with primary localized adult-type ESTSTS surgically treated at the authors' institution between 1987 and 2017 were included and divided into group 1 (1987-2002) and group 2 (2003-2017) according to primary surgery year. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DM) were calculated in a competing-risks framework. DM-free survival (DMFS) and post-DM survival were also assessed.The study identified 2382 patients. The median follow-up was 104 months (range, 63-127 months), and the post-DM follow-up was 76 months (range, 37-126 months). Since 2003, an increased adoption of preoperative treatments was observed: the use of chemotherapy, radiotherapy and combined chemoradiotherapy went from 10.5% to 23.7%, from 1.7% to 17.8%, and from 1% to 11.8% respectively. This change in treatment strategies was associated to an improvement in CCI-SSM (27.8% vs 19.5%; P0.001), CCI-LR (14.1 vs 7.5%; P0.001), DMFS (57.9% vs 65.8%; P = 0.004), and post-DM (12.2% vs 20.1%; P = 0.012), but not in CCI-DM.Increased adoption of preoperative treatments and greater availability of medical agents in the recent years were associated to better outcomes. New treatments are eagerly awaited for further improvement of outcome for ESTSTS patients because no major changes have been observed since 2003.

Heatmap of key genes in adipogenesis process.

Supplementary Table from A Prospective Observational Study of Active Surveillance in Primary Desmoid Fibromatosis

Purpose:This study was aimed at investigating whether the PPARγ agonist pioglitazone—given in combination with trabectedin—is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin.Experimental Design:The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting.Results:We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation.Conclusions:The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.

Purpose:To prospectively assess the behavior of primary sporadic (not familial adenomatous polyposis–associated) desmoid fibromatosis (DF) managed by active surveillance (AS).ExperimentalDesign:This is an Italian prospective, multicenter, observational study (NCT 02547831) including patients ≥16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Primary endpoint was progression-free survival (PFS) at 3 years. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated by Kaplan–Meier plots and compared by log-rank test. Cox proportional hazard multivariable regression analyses were performed.Results:From 2013 to 2018, 108 consecutive patients were included (82% female); median age was 39 years; median size was 51 mm. CTNNB1 mutations were T41A (50%), S45F (12%), other (19%), wild-type (19%). At 32.3-month median follow-up, 42 of 108 (39%) showed RECIST progression. Spontaneous regression was initially observed in 27 of 108 (25%), while it followed dimensional progression in another 33 of 108 (31%). PFS at 36 months was 54.5% [95% confidence interval (CI), 44.9%–66.1%]. Thirty-five of 108 (32%) patients received active treatment, 18 of 108 (17%) after RECIST progression and 17 of 108 (15%) after symptomatic progression. TFS at 36 months was 65.9% (95% CI, 57.3%–75.9%). Larger tumor size and extremity location were associated to shorter TFS and a trend for S45F mutation was also observed (P = 0.06), while none of the mentioned variables was significantly associated with PFS.Conclusions:In primary DF, AS can be proposed, because disease stabilization and spontaneous regression frequently occur. However, extra care should be taken for patients with tumors of larger size, extremity location, and S45F mutation.See related commentary by Greene and Van Tine, p. 3911

Introduction Myocardial infiltration by primary cardiac neoplasm is a rare condition and the pathological spectrum includes more widespread benign cell types, providing exceptional diagnostic and therapeutic challenges. Refractory heart failure, pericardial effusion and arrhythmias due to infiltrative mass are the most common clinical manifestations. Multimodality imaging, with echocardiography, computed tomography and magnetic resonance imaging, is essential to determine the characteristics of a cardiac tumor. Clinical case: A 35-year-old man without cardiovascular risk factors presented with two months of shortness of breath and weight loss. A previous history of acute myeloid leukemia undergoing allogenic bone marrow transplant was reported. Transthoracic echocardiography revealed an apical thrombus in left ventricle with inferior and septal hypokinesia conditioning mildly reduced ejection fraction, circumferential pericardial effusion without cardiac tamponade and abnormal right ventricular thickening (Figure 1). The cardiac magnetic resonance imaging confirmed diffuse thickening of the right ventricular free wall (maximum diameter 30 mm), suspected for myocardial infiltration, extending to the right atrium and left ventricle with an ischemic pattern of the inferior wall (Figure 2). No coronary artery disease was found by coronary angiography, but the right coronary artery was incorporated by the pathological tissue in chest computed tomography scan. Cardiac positron emission tomography demonstrated the presence of neoplastic tissue with increased metabolic activity, whose similar characteristics were also evident in the ascending aorta and aortic arch. Being the percutaneous endomyocardial biopsy inconclusive, a pericardiectomy was performed through a median sternotomy incision, showing widespread cardiac neoplastic infiltration. Histopathological analysis, done on samples taken by surgical myocardial biopsy, revealed tissue involvement by a rare and aggressive cardiac anaplastic large T-cell non-Hodgkin lymphoma (ALK -, Ki-67 90%). Few days after surgery, the patient developed a refractory cardiogenic shock and unluckily died before establishing an adequate therapy. Conclusion Primary cardiac lymphoma is very infrequent and the non-specificity of the symptoms makes the diagnosis extremely challenging and often limited to autopsy findings. Our case highlights the importance of an appropriate diagnostic algorithm that can allow an early diagnosis and an adequate therapy of this otherwise fatal pathology. In this condition surgical removal of the tumor in not indicated, being chemotherapy the only effective treatment. However, because of rarity, data are lacking to produce definitive regarding guidelines.

[Background] The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS., [Methods] This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%)., [Results] The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105)., [Conclusions] High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS., This was a nonfunded analysis. In the ISG-STS 1001 trial, PharmaMar provided trabectedin for the HG-MRLPS cohort. That trial was partially funded through a European Union grant (EUROSARC FP7 278472).

Background The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high-risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG-STS 1001). Patients and Methods Patients with available pre-treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype-tailored (HT) chemotherapy, were scored according to CINSARC (low-risk, C1; high-risk, C2). The 10-year overall survival probability (pr-OS) according to SARCULATOR was calculated, and patients were classified accordingly (low-risk, Sarc-LR, 10-year pr-OS>60%; high-risk, Sarc-HR, 10-year pr-OS

Purpose: To prospectively assess the behavior of primary sporadic (not familial adenomatous polyposis–associated) desmoid fibromatosis (DF) managed by active surveillance (AS). Experimental Design: This is an Italian prospective, multicenter, observational study (NCT 02547831) including patients ≥16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Primary endpoint was progression-free survival (PFS) at 3 years. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated by Kaplan–Meier plots and compared by log-rank test. Cox proportional hazard multivariable regression analyses were performed. Results: From 2013 to 2018, 108 consecutive patients were included (82% female); median age was 39 years; median size was 51 mm. CTNNB1 mutations were T41A (50%), S45F (12%), other (19%), wild-type (19%). At 32.3-month median follow-up, 42 of 108 (39%) showed RECIST progression. Spontaneous regression was initially observed in 27 of 108 (25%), while it followed dimensional progression in another 33 of 108 (31%). PFS at 36 months was 54.5% [95% confidence interval (CI), 44.9%–66.1%]. Thirty-five of 108 (32%) patients received active treatment, 18 of 108 (17%) after RECIST progression and 17 of 108 (15%) after symptomatic progression. TFS at 36 months was 65.9% (95% CI, 57.3%–75.9%). Larger tumor size and extremity location were associated to shorter TFS and a trend for S45F mutation was also observed (P = 0.06), while none of the mentioned variables was significantly associated with PFS. Conclusions: In primary DF, AS can be proposed, because disease stabilization and spontaneous regression frequently occur. However, extra care should be taken for patients with tumors of larger size, extremity location, and S45F mutation. See related commentary by Greene and Van Tine, p. 3911

Aims Left ventricular (LV) aneurysms and pseudoaneurysms are two complications of myocardial infarction, either symptomatic or silent, leading to death or serious morbidity in several cases and often precluding non-cardiac surgery. Here the differential diagnosis is challenging and multimodality imaging is often needed to assess the risk of heart rupture. Methods and results A 71 years-old woman was referred to our Cardiology Department for a preoperative evaluation before lung lobectomy. Her past medical history included multiple cardiovascular risk factors and abdominal aorta aneurysm. She also had severe peripheral arterial disease treated with femoral popliteal bypass surgery in June 2021. In August 2021 she suffered from vascular graft thrombosis requiring a redo surgery. During hospitalization, she was found to have a lung adenocarcinoma. The patient had an unremarkable cardiological history and was asymptomatic. EKG was unremarkable. Transthoracic echocardiography revealed a mildly impaired LV systolic function (EF = 40%), an inferolateral basal wall akinesia and a huge aneurysm with intracavitary thrombus and a wide neck arising right below the posterior mitral annulus. The annular distortion caused by the expanding aneurysm contributed to the development of mitral regurgitation (MR) by displacing the annulus and subvalvular apparatus, resulting in restriction of the posterior mitral valve leaflet, coaptation failure, and moderate MR. Coronary angiography demonstrated a severe 3-vessel coronary artery disease. To further characterize the aneurysm, a cardiac magnetic resonance was carried out. T1 weighted inversion recovery LGE 2-chamber and short axis views showed transmural LGE of the inferior wall and confirmed the presence of a saccular dilatation with thin wall, wide neck (5 × 6 cm) and large intracavitary thrombus at high risk of rupture. Since the presence of metastatic lesions was excluded, the patient underwent cardiac surgery followed by elective lobectomy. Intraoperative findings were consistent with LV aneurysm with a thin myocardial wall. Aneurysm and related thrombus were removed and the orifice was closed with a Dacron patch. In the same setting a myocardial revascularization with two coronary artery bypass grafts was also performed. Surgery was successfully performed without any complication. Intraoperative transesophageal echocardiography clearly revealed the aneurysm and witnessed the reduction of MR after the restoration of LV inferolateral wall geometry. Conclusions Our case highlights the importance of thorough evaluation prior to non-cardiac surgery using multimodality imaging, especially when incidental echocardiographic findings in asymptomatic patients occur. A careful pre-operative assessment of patients planned for non-cardiac surgery is the key to favourable postoperative outcome.

11508 Background: An ISG, GEIS, FSG and PSG randomized trial on 3 cycles of neoadjuvant epirubicine+ifosfamide (EI) versus a histology-tailored (HT) regimen in selected localized high-risk STS showed some superiority of EI in all histologies with the exception of Myxoid Liposarcoma (MLPS) where EI and HT regimens seemed equivalent (J Clin Oncol 2020; 38:2178-86). This MLPS cohort was expanded with the aim to assess the non-inferiority of the HT regimen compared to EI. Methods: This was a multicenter European randomized trial comparing EI versus a HT regimen. Patients (pts) had localized high-risk (grade = 3; size >5 cm; deeply seated) undifferentiated pleomorphic sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma or MLPS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). Secondary end-point was Overall Survival (OS). The MLPS cohort was expanded after the results of the 3rd interim analysis (Lancet Oncol 2017; 18:812-22) in order to reject the hypothesis that HT regimen trabectedin is associated with a HR of relapse = 1.25 with a non-inferiority design. To this aim, a Bayesian monitoring approach was used until the probability that the true HR is higher than 1.25 was greater than 80% or smaller than 5%. Results: From May 2011 to June 2020, 101 pts affected by high-risk MLPS were randomized, 56 to EI and 45 to HT regimen. The median follow-up was 66 months (IQ range 37-89). Median size was 107 mm (IQ range 84-143), 108 mm (IQ range 86-150) in the EI and 106 mm (IQ range75-135) in the HT arm. The DFS and OS probabilities at 60 months were 0.86 and 0.73 (HR:0.60; 95%CI: 0.24-1.46; log rank p = 0.26 for DFS) and 0.88 and 0.90 (HR:1.20; 95%CI:0.37-3.93; log rank p = 0.77 for OS), in the HT and EI arm, respectively. 5-yr observed and Sarculator-predicted OS were 0.89 (95% CI 0.82-0.97) and 0.80 in all patients (p = 0.020), 0.90 (95% CI 0.81-1.00) and 0.79 in the EI arm (p = 0.049) and 0.88 (95% CI 0.77-1.00) and 0.81 in the HT arm (p = 0.204) respectively. Conclusions: In the expanded cohort of MLPS, the HT neoadjuvant therapy trabectedin was not inferior to EI. While survival in both arms was better than predicted by Sarculator, it is left to understand whether this patient population, who had on average a lower Sarculator-predicted risk of death compared with the rest of the trial population, may benefit from a neoadjuvant therapy. Clinical trial information: NCT01710176.

11575 Background: To further explore the activity of T as second/further line treatment in retroperitoneal leiomyosarcoma (LMS) and well differentiated/dedifferentiated liposarcoma (LPS). The primary endpoint of the study was the growth modulation rate (GMR) defined as the ratio between the time to progression under T (TTP) and during previous chemotherapy treatment (TTP-1). The secondary end-points were objective response rate as per RECIST and PFS. Methods: This was a multicenter, single-arm Phase 2 study, conducted in 20 Italian centers. Patients with locally relapsed or metastatic disease, already treated with one or more previous systemic treatments with anthracyclines and/or ifosfamide, were enrolled. T was administered at a dose of 1.3-1.5 mg/mq with a top dose of 2.6 mg per cycle. T was administered as a 24h continuous infusion until progressive disease, major toxicity, patient’s intolerance or medical decision. As per protocol, patients were considered responders if the GMR was > 1.33, non-responders if < 0.75 and neither if 0.76-1.32. Eighty evaluable patients were needed to detect an odds of trabectedin response ≥ 2.5, corresponding to 71.4% of patients with a GMR > 1.33 (80% power, one-sided alpha 2.5%). Results: From August 2014 to February 2019, 104 patients were registered and 91 were evaluable for the primary endpoint (32 pts with LMS and 59 with LPS). Overall, the median number of cycles received was 6.0 (q1-q3 3.0-12.0), the main reason for treatment discontinuation was disease progression in 72% of patients, followed by medical decision (8%). The median TTP was 6.0 months (6.2 and 6.0 for LMS and LPS), while the median TTP-1 was 7.5 months (8.1 and 6.4 for LMS and LPS). Thirty three patients (52% 95%CI: 36-58, p = 0.674, odds of response = 1.1) had a GMR > 1.33 (LMS: 46%, 95%CI 26-67,odds = 0.85; LPS 56%, 95%CI 40-72, odds = 1.3).Overall, response rate (CR+PR) was 16% (24% for LMS and 12% for LPS). Overall, in LPS we observed 15/47 patients with GMR < 0.5 and 15/47 with GMR > 2. Among LMS patients, 9/26 had a GMR < 0.5 and 10/26 > 2. Between LPS six patients had a GMR > 5. Previous treatment had been based on anthracyclines and/or ifosfamide in 85% of patients (91% in LPS population). Conclusions: While the primary end point of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with T in comparison to previous therapy (GMR < 0.5 or > 2, the latter including some pts with a long TTP with T). Efforts are ongoing to assess the pathologic counterparts of such discrepancies. T seems to be selectively active in poorly understood subgroups, with a pattern of activity distinct from other available agents. Clinical trial information: 2012-005428-14.