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Vascular sarcomas encompass 3 well-defined sarcoma types: hemangioendothelioma, Kaposi sarcoma, and angiosarcoma. These distinct types are exceedingly rare and very different in terms of clinical behavior, biological features, and treatment approach. Because of this rarity and heterogeneity, it is crucial that vascular sarcomas are treated in sarcoma reference centers or networks, in order to ensure optimal management. The diversity of vascular sarcomas also needs to be taken into account in the design of clinical trials, in order to produce meaningful results that can be consistently translated into everyday clinical practice.

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.

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Epithelioid sarcoma (ES) is an aggressive ultra-rare soft-tissue sarcoma marked by SMARCB1/INI1 deficiency. SMARCB1/INI1 deficiency leads to elevated expression of EZH2, a component of polycomb repressive complex 2, which mediates gene silencing by catalyzing H3K27me3. Tazemetostat is an oral, SAM-competitive inhibitor of EZH2, whose blockade prevents the methylation of histone H3K27, thus decreasing the growth of EZH2 mutated or over-expressing cancer cells. Tazemetostat has been approved for the treatment of patients aged 16 years and older with metastatic or advanced ES not eligible for complete resection, based on the positive results of a single-arm Phase II basket study. Tazemetostat though represents a new treatment option for ES patients, although clinical/molecular predictors of response are still to be identified. The combination of tazemetostat with other drugs like doxorubicin and immunotherapeutic agents is currently under investigation in ES patients.

Desmoplastic small round cell tumor (DSRCT) is a ultra-rare pediatric scarcoma with poor overall survival. This tumor is dependent on the continued expression and activity of its pathognomonic molecular lesion, the EWS-WT1 transcription factor. DSRCT is often treated with multimodal approach of chemotherapy, surgery, and radiotherapy. Given the rarity of the disease, there have not been clinical studies to establish an effective therapeutic regimen. Indeed, the development of fully characterized preclinical models, able to reproduce the molecular characteristics of clinical tumors, appears instrumental for testing novel therapeutic strategies and accelerating the translation of preclinical findings to the clinical practice. In this study we exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological, genomic (CNV) and transcriptomic characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%], trabectedin had a higher effect (max TVI: 82%) while irinotecan and eribulin almost complete inhibited tumor growth (max TVI: 96% and 98%, respectively). Interestingly, combination of irinotecan with either eribulin or trabectedin resulted in complete responses which were maintained until the end of the experiment for irinotecan + trabectedin. The trabectedin + irinotecan combination markedly reduced the expression of anti-apoptotic proteins and caused caspase-3 cleavage, consistent with an apoptotic response, and also induced the accumulation of phospho-RIP1 (Ser166) and phospho-RIP3 (Ser227), indicating the occurrence of necroptosis, a type of programmed cell death with necrotic morphology. In line with these findings, transcriptomic profile analysis of ex-vivo tumor samples obtained from mice exposed to trabectedin ± irinotecan revealed a reduced expression of the biological pathways related to apoptosis and cell proliferation in tumor exposed to the drug combination. Mechanistically, we found that these effects were mediated, at least in part, by the down-regulation of EWS-WT1 chimeric protein and its downstream targets, as assessed by PCR and western blotting. Overall, this study emphasizes the importance of patient-derived pre-clinical models to explore new treatments in DSRCT and fosters clinical investigation in the activity of irinotecan plus trabectedin, providing a step forward for developing more effective trabectedin-based combinations for DSRCT to be tested in clinical trials. Citation Format: Valentina Zuco, Sandro Pasquali, Monica Tortoreto, Stefano Percio, Valentina Doldi, Marta Barisella, Paola Collini, Gianpaolo Dagrada, Silvia Brich, Patrizia Gasparini, Marco Fiore, Michela Casanova, Anna Maria Frezza, Alessandro Gronchi, Silvia Stacchiotti, Andrea Ferrari, Nadia Zaffaroni. Effectiveness of irinotecan plus trabectedin in a desmoplastic small round cell tumor patient-derived xenograft. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6726.

Background The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. Methods From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. Results All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. Conclusions The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.

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.

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain origin, marked by specific chromosomal translocations involving the NR4A3 gene, and usually characterized by an indolent course. Surgery (with or without radiotherapy) is the treatment of choice in localized disease. The treatment for advanced disease remains uncertain. In order to better evaluate prognostic factors and outcome, a retrospective pooled analysis of patients with EMC treated at three Italian Sarcoma Group (ISG) referral centers was carried out. Methods: All patients with localized EMC surgically treated from 1989 to 2016 were identified. Diagnosis was centrally reviewed according to WHO 2013. Only patients with NR4A3 rearrangement were included. Results: Sixty-seven patients were identified: 13 (20%) female, 54 (80%) male. Median age was 56years (range 18–84). Numbers and type of translocation were: 50 (80%) NR4A3-EWS, 10 (16%) NR4A3-TAF15, 1 (2%) NR4A3-TCF12, and 1 (2%) NR4A3-TFG. Median follow-up was 55months (range 2–312). Five- and ten-year overall survival rates were 94% (86–100 95%CI) and 84% (69–98 95%CI). Thirty-five (52%) patients relapsed: 9 had local recurrence (LR) and 26 had distant metastasis (5 with concomitant LR). The 5- and 10-year disease-free survival rates (DFS) were 51% (38–65 95%CI) and 20% (7–33 95%CI). Size of the primary tumor was significantly related to distant metastasis-free survival (DMFS) (p = 0.004). Patients carrying the NR4A3-EWS translocation had a trend in favor of better DFS (p = 0.08) and DMFS (p = 0.09) compared with the patients with NR4A3-TAF15. Conclusions: Prolonged survival can be expected in patients with EMC, in spite of a high rate of recurrence. Size is significantly associated with distant relapse. The type of NR4A3 translocation could influence outcome.

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

[Background] This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions., [Methods] Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method., [Results] Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported., [Conclusion] Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

Background Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. Methods The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. Results It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. Conclusions Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

e23520 Background: Retroperitoneal DDLPS is an aggressive tumor characterized by a WD component, morphologically similar to a WDLPS, and a DD component that drives patient prognosis. We aimed at unraveling whether WDLPS and DDLPS are distinct entities or entail a progressive evolution from WDLPS to DDLPS through a transcriptomic analysis. Methods: A transcriptomic analysis was performed in a retrospective series of 107 patients with primary retroperitoneal WDLPS (N = 68, 63.5%) or DDLPS (N = 39, 36.5%) who underwent surgery (2011-15). Paired DD, WD, and normal fat (NF) components were sampled in DDLPS, while paired WD and NF components were sampled in WDLPS. RNA-Seq data were normalized according to the trimmed mean of M-value (TMM) algorithm and differential expression was evaluated with the voom method implemented into the edgeR package. Enrichment in hallmark gene sets from Molecular Signatures Database (MSigDB) was evaluated with gene sets enrichment analysis (GSEA), by using t-statistic as measure of ranking. A false discovery rate (FDR) adjusted p-value < 0.05 was considered for statistical significance. Results: Differential expression analysis revealed marked transcriptional changes within paired components of DDLPS (DD, WD, NF) and WDLPS (WD, NF). Changes of WD and NF components between WDLPS and DDLPS were not statistically significant. Gene sets were analyzed to evaluate the ensemble and overcome the FDR correction applied to single genes. Hallmarks deregulated in WD component of DDLPS compared to WDLPS were detected also in their paired DD component. Among them, G2M checkpoint and mitotic spindle were up-regulated, while adipogenesis, fatty acid metabolism, cholesterol homeostasis, oxidative phosphorylation, and peroxisome were down-regulated. These differences persisted also when NF components were compared with their paired WD component of DDLPS and WDLPS. G2M checkpoint and mitotic spindle gene sets did not differ between NF of DDLPS and NF of WDLPS, suggesting these two hallmarks as tumor-specific. Conversely, expression of adipogenesis, fatty acid metabolism, and oxidative phosphorylation was up-regulated together with other gene sets related to metabolism in NF of DDLPS. Tumor inflammation and interferon response were up-regulated in WD components compared to their paired NF components. Also, interferon response was down-regulated in WD component of DDLPS compared to WDLPS, and inflammation was down-regulated in DD component compared to both WD components. Conclusions: Transcriptomic changes that distinguished WDLPS and WD component of DDLPS increased progressively also in the paired DD component of DDLPS, supporting the hypothesis of a progression from WDLPS to DDLPS in some liposarcomas. Changes observed in NF may suggest a paracrine effect sustaining tumor dedifferentiation.

11566 Background: EHE is an ultra-rare sarcoma marked by two specific fusions, WWTR1-CAMTA1 (̃90%) and YAP1-TFE3 (̃10%). The clinical course of EHE ranges from indolent to highly aggressive, often associated with systemic paraneoplastic symptoms. Molecular predictors of clinical outcome are unknown. While surgery is the mainstay of treatment in the localized setting, management of advanced disease is challenging due to the rarity and poor sensitivity to conventional chemotherapy. This hampers the conduct of large prospective clinical trials. We report herein the first available EHE PDX (developed at the Istituto Nazionale Tumori, Milan, Italy) (INT), to assess the activity of old and new anticancer agents in EHE and inform future clinical studies. We also report on the preliminary results of a prospective observational study, ongoing in collaboration with The EHE Rare Cancer Charity (UK) and The EHE Foundation (US) aimed at identifying prognostic factors. Methods: A PDX of EHE in SCID mice was generated at INT from a patient (pt) suffering with the aggressive clinical variant, presenting with systemic symptoms. The PDX fully reproduces the originating clinical tumor in terms of morphology, biology ( WWTR1- CAMTA1 positive), overall transcriptomic profile. 2D (monolayer) and 3D (sferoids) cell cultures were established following PDX disaggregation. We have started assessing the comparative activity of currently available drugs (doxorubicin, sirolimus), while the efficacy of novel agents is undergoing. In parallel, we analyzed the presence of a selection of inflammatory cytokines in prospectively collected blood samples from EHE pts who entered an international observational study and we looked at their presence and modulation in the PDX model. Results: PDX experiments showed almost negligible activity of doxorubicin while sirolimus induced an 80% tumor volume inhibition. Biochemical analysis in tumors explanted from sirolimus-treated mice confirmed the down-regulation of mTOR downstream signaling. Among all cytokines, Growth and Differentiation Factor-15 (GDF-15) was found significantly over-expressed in serum of EHE pts (n = 23), particularly those with the most aggressive clinical variant, compared to healthy subjects (n = 23; p< 0.01). Consistently, EHE PDX and cell culture were found to release in the blood/culture medium GDF-15. Sirolimus was found to down-regulate GDF-15 release in both in vivo and in vitro EHE models. Conclusions: Our preliminary results indicate that this EHE PDX model is suitable i) for comparatively assessing the activity of anticancer drugs, and ii) for identifying and pre-clinically validating novel biomarkers. The role of GDF-15 in EHE progression deserves further investigation.

Author(s): Gelderblom, Hans; Wagner, Andrew J; Tap, William D; Palmerini, Emanuela; Wainberg, Zev A; Desai, Jayesh; Healey, John H; van de Sande, Michiel AJ; Bernthal, Nicholas M; Staals, Eric L; Peterfy, Charles G; Frezza, Anna Maria; Hsu, Henry H; Wang, Qiang; Shuster, Dale E; Stacchiotti, Silvia | Abstract: BackgroundThe objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).MethodsThis was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019.ResultsOne hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).ConclusionsThis study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Contains fulltext : 220839.pdf (Publisher’s version ) (Closed access) BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Five-year relative survival (RS) of adults with bone and soft-tissue cancers in Europe was still60% by 1995-1999. There was large geographical survival variability, mainly for bone tumours, and survival decreased with increasing age at diagnosis.Data from 87 population-based cancer registries in 29 countries, extracted from the EUROCARE-5 database, were used to provide updated estimates of survival and describe trends in survival of adults with cancers of these sites across Europe. We calculated 5-year RS for patients diagnosed in 2000-2007. We estimated 5-year RS by the period approach to assess changes in survival between 1999-2001, 2002-2004 and 2005-2007, and provide reliable predictions for recently diagnosed patients.Five-year RS was 60% for adults diagnosed with soft-tissue cancer in 2000-2007 and 53% for those with bone cancer. RS declined with increasing age at diagnosis, especially for bone cancer. Survival from bone cancer varied widely between European regions, from 63 to 62% in Northern and Central Europe to 39% in Eastern Europe. Inter-regional variation was much less for soft-tissue cancer. For both site groupings, there was little evidence of change in five-year RS up to 2002-2004, followed by increases of 3-4% during 2005-2007.Outcomes for adults with bone and soft-tissue cancer in Europe began to improve around 2005; new therapeutic developments are expected to result in further progress. Survival improvements already achieved must be brought more fully to elderly patients and those in Eastern Europe. European Reference Networks on rare cancers will have a vital role in future progress.

Rare cancers represent approximately one fourth of all cancers. Despite being a heterogeneous group of diseases, they share similar problems including lack of expertise, issues in quality of care, discrepancies in outcome and limitations in research. Traditionally, centralization of rare cancer patients to dedicated reference centres has been recommended to ensure expertise, multidisciplinarity and access to innovation. However, centralization entails health migration, rationing of resources and a potential failure in routine care. By ensuring appropriate care to all patients regardless the point of access, networking seems the most appropriate answer to the problem of rare cancers. The launch of the Joint Action on Rare Cancers as well as the recent establishment of the European Reference Networks represent for the first time a concrete opportunity to make networking a reality and ultimately reduce disparities and improve outcome in these diseases.

[Background] Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma., [Methods] In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285., [Findings] Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18–30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1–36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%])., [Interpretation] Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients., Funding: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin&ndash, ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin&ndash, ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

11558 Background: R showed antitumor activity in a PDX model of dedifferentiated SFT (D-SFT), inducing a superior tumour growth inhibition than with other antiangiogenic agents (A), such as pazopanib (P) and axitinib (A). The efficacy of P and A in patients (pts) with advanced typical- (T-)/ malignant- (M-)SFT has been already confirmed in phase 2 clinical trials, but not in D-SFT. An exploratory phase 2 study was designed to investigate the activity of R in advanced SFT. Methods: An investigator-initiated exploratory phase 2 trial was started in December 2015 at the Istituto Nazionale Tumori, Milan, Italy, to evaluate the activity of R, 160 mg OD, 3 weeks on/1 week off, until progression or limiting toxicity. in > 18 years old pts with advanced SFT. The target sample size was 16 evaluable pts; at least 3 responses were requested to reject the null hypothesis of 5% in favour of an alternative hypothesis of 30% (with type-I and type-II error rates fixed at the 10% level). Eligible pts had to have evidence of progression. Prior treatment with A was allowed. Centralized pathologic review was performed, distinguishing T-SFT, M-SFT and D-SFT subtypes. The primary end-point was the overall response rate (ORR) by Choi. Secondary end-points were ORR by RECIST, progression-free survival (PFS), overall survival (OS). Results: Enrolment was completed in February 2021. Eighteen pts were enrolled (D-SFT = 4; M-SFT = 13; T-SFT = 1). Four pts were naïve, 14 were pre-treated [12 with antiangiogenics (4 with > 1 prior antiangiogenic line); 11 with cytotoxic agents]. Three pts are ongoing, 13 completed their treatment (11 = progression, 1 = toxicity, 1 = other). Fourteen pts are evaluable for response by Choi and RECIST (1 = screening failure; 1 = early discontinuation for toxicity before radiologic assessment; 2 = too early). A definitive dose reduction was required in 5 of 14 evaluable (35.7%) pts. The ORR by Choi was 42.9% (exact binomial 95% Confidence Interval [CI]: 17.7%-71.1%), with 6/14 (42.9%) partial responses (PR), 5/14 (35.7%) stable disease (SD) and 3/14 (21.4%) progressions (PD). Best responses by RECIST were: 1/14 (7.1%) PR, 10/14 (71.4%) SD, 3/14 (21.4%) PD. 5/6 pts responsive by Choi were pre-treated with another antiangiogenic. No responses were seen in the 3 D-SFT pts. At a m-FU of 23 months, m-PFS by Choi was 3.68 (IQR: 2.73-8.54) months, with 23.4% pts progression free at 1 year. m-PFS by Choi in responsive pts was 5.62 (IQR: 2.89 – 8.54) mos. Median OS was 15.7 (IQR: 7.35-not reached) months. Conclusions: R did not show a higher activity in D-SFT compared to P and A. The response rate was in the range observed with other A, but m-PFS was shorter. This may be due to discrepancies in pt populations and a high-rate of dose reductions with R. However, responses to R were seen also in pts previously treated with other A and almost one fourth of pts benefited from R for more than a year. Clinical trial information: 2015-002629-21.

e23555 Background: Desmoplastic small round cell tumor (DSRCT) is an ultra rare sarcoma predominantly involving the abdomino-pelvic peritoneum and mostly occurring in male children and young adults. It is marked by the EWSR1-WT1 fusion gene. Prognosis is poor with reported 5-year overall of < 20%. Methods: Data of patients with primary intra-abdominal DSRCT, who had surgery at our institution between 2000 and 2020, were analyzed. Information regarding disease presentation, cytoreductive surgery (CRS) with or without hypertermic intraperitoneal chemotherapy (HIPEC) and perioperative treatments were reported. Kaplan-Meier survival analysis was performed for both the whole cohort (A) and separately for peritoneal (B) vs peritoneal + lymphnode involvement (C) at disease presentation. Also, patients who underwent CRS alone vs CRS + HIPEC were compared. Results: 43 patients (pts) were identified, only 18 (42%) underwent surgical resection with curative intent in addition to perioperative chemotherapy (CT) ± radiotherapy (RT). 6 pts had also synchronous abdominal nodal metastases and one resectable liver metastases. Median tumor size was 19cm (12-20). 9 pts received pre and postoperative chemotherapy (CT), 7 pts preoperative CT, 2 pts postoperative CT. Postoperative abdominal RT was administered in 3 pts. Partial response (PR) to preoperative CT was observed in more than 50% of pts. Complete cytoreduction was achieved in 14 pts (78%). HIPEC was performed in 5 patients (28%). Overall, 8 pts died (44%), 1 patient after developing liver and lung metastases while 7 had peritoneal and intra-abdominal lymphnode recurrence. Of 10 patients alive, 7 had a recurrence. Of them, 5 are alive with disease (1 presenting extra-abdominal recurrence, 3 lymph node involvement and 1 liver metastases) at 75, 38, 33, 15 and 31 months, respectively, from diagnosis. 2 are alive without disease (after having a further surgery for local recurrence) at 35 and 36 months, respectively, from diagnosis. 3 patients are alive without disease at 12, 64, and 213 months from diagnosis. As a result, 5-year OS was 39.6%, 35.6% and 40% for group A, B and C, respectively. Median survival time was 39.2, 39.2 and 57.7 months for group A, B and C, respectively. 5-year OS was 35.2% and 50% for CRS and CRS + HIPEC group respectively. Conclusions: Despite an intense multimodal approach, DSRCT prognosis remains poor. CRS may improve oncologic outcomes. Our data confirmed significant tumor shrinkage after administration of preoperative CT which may be helpful to achieve macroscopically complete resections. The value of HIPEC and radiation therapy is more controversial and needs to be further investigated in a larger series. Interestingly, the presence of synchronous nodal metastases was not a negative survival prognosticator showing comparable outcome to peritoneal disease.

e23553 Background: DSRCT is an ultra-rare soft tissue sarcoma marked by the presence of the EWS-WT1 translocation and a dismal prognosis. Anecdotal activity of T in DSRCT pts was reported. We describe herein three advanced DSRCT pts treated with T and a comparative assessment of doxorubicin (D), pazopanib (P) and T in a patient-derived xenograft (PDX) model of DSRCT. Methods: Three pts (#1, #2 and #3) suffering from progressive, metastatic, unresectable relapsing disease from a primary peritoneal DSRCT previously treated with 8 cycles of anthracycline-based neoadjuvant chemo and complete surgical resection, were started on T (1.3 mcg/sqm every 3-4 weeks). A PDX model was generated by subcutaneously implanting small tumor fragments obtained at surgery from a treatment-naïve DSRCT patient into the right flank of SCID mice. Consistency of PDX and the originating tumor was confirmed in terms of histomorphology and presence of the EWS-WT1 gene fusion. Mice were randomized to receive D, P and T, administered as single agents at optimal doses and schedules. Drug activity was assessed in terms of tumor volume inhibition (TVI) percentage in treated versus control mice. An orthotopic xenograft model was also generated by injecting DSRCT cells into the peritoneal cavity of SCID mice. Results: At the time of this report, pt #1 and #2 are on therapy with T, with a partial response by RECIST maintained after 48 and 36 months from treatment start, respectively, while #3 progressed after 4 months. In the DSRCT PDX model, T was the most effective drug, with a maximum TVI of 82%, while D and P showed lower, comparable activity (maximum TVI: 59% and 66%, respectively). In the orthotopic DSRCT PDX, DSRCT cells spreading in the abdominal cavity generated different tumor masses, properly recapitulating the dissemination pattern in patients, confirming the reliability of this preclinical model. Conclusions: Both our preliminary model and our further clinical observations support the potential of T in DSRCT. A confirmatory prospective clinical study is now warranted.

11065 Background: To report on a multi-institution retrospective study on the activity of anthracycline-based (Ab) and gemcitabine-based (Gb) regimens as well as pazopanib (P) in patients with advanced epithelioid sarcoma (ES) treated within 16 sarcoma reference centres in Europe, US and Japan. Methods: Patients with a histologically confirmed diagnosis of locally advanced/metastatic ES were selected. Classic and distal subtypes were defined based on morphology (WHO 2014). INI1 expression is under evaluation.Response was evaluated by RECIST.Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results: Ninety ES patients were identified (Table 1). They were treated with Ab (72), Gb (30) and P (20); 25 pts received more than one treatment. The median follow-up for Ab, Gb and P groups was 32, 24 and 22 months, respectively. The response rate (RR) for Ab was 25% (95% CI 16%-37%), with a median PFS and OS of 6 and 17 months. The RR for Gb was 23% (95% CI 10% - 42%), with 1 complete response and a median PFS and OS of 5 and 20 months. In the P group, no objective responses were reported, and median PFS and OS were 3 and 9 months. A non-statistically significant trend towards a greater RR in proximal than classic subtype was seen in both Ab (27% vs 22%) and Gb (30% vs 13%) groups. Conclusions: This retrospective series, the largest currently available, confirms the activity of Ab and Gb in ES, with a similar RR and PFS in both groups. In this population, the value of P seems limited. These data may serve as a benchmark for trials of novel agents in ES. [Table: see text]

Background Despite the efficacy of prophylaxis with serotonin type 3 (5-HT3) receptor antagonists, nausea and vomiting are still among the most common chemotherapy-induced toxicities. The aim of this study was to evaluate the efficacy of adding aprepitant in patients with chemotherapy-induced nausea and vomiting (CINV) refractory to prophylaxis with 5-HT3 receptor antagonists and dexamethasone. Patients and Methods Between January 2008 and November 2010, 51 patients (median age 59 years) with a variety of malignancies (breast cancer: 23; lung cancer: 12; sarcoma: 6; ovarian cancer: 3; other: 7) were enrolled. All patients were refractory to antiemetic therapy according to ASCO guidelines and developed at least grade 2 nausea and/or vomiting after the first chemotherapy course. Aprepitant was given at 125 mg on day 1 and 80 mg on days 2–3. Patients also received a single dose of palonosetron 250 μg on day 1 plus dexamethasone 12–20 mg at a constant dose. Results After addition of aprepitant, the number of patients with grade 3/4 nausea decreased from 31 (61%) to 4 (8%), and those with grade 2 nausea from 20 (39%) to 6 (12%) [both p

Objectives Although one out of four persons affected by cancer in Europe has a rare cancer (RC), it is unknown to which extent they are addressed in National Cancer Control Plans (NCCPs) and National Rare Diseases Plans (NRDPs). The objective of this review was to analyse the content included in European NCCPs and NRDPs on RCs in adults. The working hypothesis is that RCs have a lower presence in NCCPs compared to more common cancers, and that NRDPs do not generally approach them. Methods A review based on a documentary analysis on the priorities and recommendations in the area of RCs was conducted in 15 European NCCPs and 18 NRDPs. After identifying the areas covered therein, we performed a thematic analysis to allow a narrative description of the status of RCs’ health policy. Results Rare cancers are hardly addressed in NCCPs and not addressed in NRDPs. Of the 15 NCCPs analysed, only 8 contained some elements on RCs, and only 3 of these described specific measures to address this disease group or took a comprehensive approach. The cross-cutting analysis of the 8 NCCPs allowed identifying 14 critical issues necessary to reach a comprehensive approach to RCs’ policy. Conclusions The scarce presence of RCs in most of NCCPs may indicate low visibility and limited political understanding of their specificities. The critical issues emerging from the analysis are intended to improving the national policy frameworks addressing RC challenges and to place the NCCPs as strategic documents that must play a key role in this process.

e23552 Background: Epithelioid sarcoma (ES) is an ultra-rare sarcoma with distinctive pathologic and clinical features, marked by the loss of the expression of the SWI/SNF chromatin remodeling complex subunit SMARCB1. The current WHO classification recognizes two ES subtypes, different by morphology, clinical behavior and outcome: the “classic-type” and “proximal-type” ES. This study is aimed to better understand the molecular grounds sustaining this difference, and to identify new potential treatment targets to personalize therapy in this rare disease. Methods: RNA sequencing profiling was conducted on FFPE samples. Functional annotation enrichment was evaluated through over representation and gene set enrichment analyses (GSEA). Inference of immune contexture was obtained through deconvolution and single sample GSEA (ssGSEA) approaches. Results: Twelve samples from 5 proximal-type ES and 7 classic-type ES were profiled, 10 naïve and 2 pre-treated with chemotherapy. Proximal variant samples featured an overepresentation of MYC activity signatures and of other signatures impacting on cell cycle, protein synthesis and chromatin metabolism. Pathways enriched in the classic variant included NOTCH/HEDGEHOG and immune system regulation (e.g. inflammatory, interferon alpha and interferon gamma). Accordingly, deconvolution and ssGSEA approaches predicted an increased immune infiltration in classic subtype samples, essentially involving T cells, as well as increased expression of HLA class I molecules. Conclusions: Different regulatory networks seem to contribute to the different biologic and clinical behavior of proximal and classic ES. These preliminary data suggest a potential greater sensitivity of proximal type ES to drugs targeting the cell cycle, whilst immune checkpoint inhibitors might have some activity in classic variant ES. Further studies are ongoing to validate these preliminary observations.

Objectives Giant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution. Design and setting Retrospective, single-institutional study. Participants Adult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019. Main outcome measures Incidence, time of onset and clinical features of MR-ONJ. Results 29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1–125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable. Conclusion A clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated.

Item does not contain fulltext Importance: Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease. Objective: To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES. Design, Setting, and Participants: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria. Exposures: All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib. Main Outcome and Measures: Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines). Results: Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months. Conclusions and Relevance: This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

The 7th edition of the ‘ESMO Sarcoma and GIST Symposium’ was held in Milan in February 2018. For the first time, the Symposium brought together representatives from the European Reference Network on rare adult solid cancer (EURACAN) joined by sarcoma experts from the USA, Japan and patient advocacy groups, to share insights and discuss future directions in this rare condition. This commentary will summarise the highlights in soft tissue sarcomas.

Perivascular epithelioid cell tumor (PEComa) is a family of mesenchymal tumors. Conventional chemotherapy has little activity in this disease, but case reports are available on the activity of mammalian target of rapamycin inhibitors (e.g. sirolimus and temsirolimus). Pharmacokinetic assays of sirolimus are available as this drug has a precise therapeutic window and blood levels might be influenced by CYP3A4 polymorphisms and drug interactions. We report on a case of a patient with metastatic, progressive PEComa who started sirolimus at a dose of 5 mg/day with evidence of grade (G) 3 mucositis, G2 thrombocytopenia, and G1 leucopenia 10 days after the treatment started, in absence of concomitant medications or prohibited food assumption. Elevated sirolimus blood levels were detected (156.8 ng/ml). Sirolimus was stopped, and toxicity resolved in 5 weeks. Computed tomography scan 2 months after the treatment started showed a partial response (RECIST). After toxicity resolution, the patient restarted sirolimus at a dose of 1 mg/day, with blood levels in the range of 10-20 ng/ml. Tumor response was confirmed and maintained, and the patient is still under treatment 18 months later, with no additional adverse effects. Genetic analysis of five selected polymorphisms (rs2740574, rs776746, rs1128503, rs2032582, and rs1045642) in drug metabolism enzymes and transporters did not provide a clear explanation of the observed unusual pharmacokinetic. This case confirms the activity of mammalian target of rapamycin inhibitors in PEComa and strengthens the importance of pharmacokinetic drug blood levels monitoring in patients treated with sirolimus. In our patient, after dose adjustment, sirolimus could be restarted with a prolonged clinical benefit and no additional toxicity.

Background Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization. Procedure Retrospective study (1996–2012) on 56 patients. Results Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume

Herein, we summarise the results of the most relevant studies presented at the 2017 ASCO Annual Meeting in the field of soft tissue sarcomas (STSs) and gastrointestinal stromal tumours (GISTs). Innovations on the management of localised disease, highlights from the different experiences in the metastatic setting and large studies on rare histologies will be included. Special attention will be paid to results on immunotherapy, antiangiogenics use in histology with limited sensitivity to standard chemotherapy and new compounds. The preliminary results on the impact of the next generation sequencing in the everyday management of STS and GIST patients will be also discussed.

Background: Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. Patients and methods: We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. Results: Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). Conclusion: Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

For metastatic soft tissue sarcoma (STS) patients not eligible for surgery, systemic treatments, including standard chemotherapy and newer biological compounds, still play the most relevant role in the management of the disease. An anthracycline and alkylating agent combination has formed the cornerstone of chemotherapy in STS for more than 30 years, with its value over that of administration of anthracycline as a single agent still being debated. Efforts have been made to improve the activity and minimise the toxicity of the combination, as well as to explore the upfront efficacy of agents known to be active in sarcoma and to develop new biological compounds. Nevertheless, beyond the first line, evidence for medical treatment in STS is less robust and all the more driven by histology. Thus, the introduction of kinases and small molecule inhibitors in the treatment armamentarium for STS is a major achievement in this setting. Preliminary data on immunotherapy are also available and discussed in this review.

Background: Tobacco smoke causes lung disfunction and inflammation. Methods: Twenty-two consecutive smokers with undetermined lung nodules were included. All underwent a baseline imaging, exhaled carbon monoxide level evaluation and spirometry, repeated at three months from smoking cessation therapy. Results: A significant reduction in size of the lung nodules was reported (p = .037) as a trend in number reduction (p = .11). A significant increase in blood arterial oxygen pressure (p < .0001), heart rate reduction (p < .01), and FEV1 increase (p < .0001) was recorded. Conclusions: Smoking cessation reduces number and size of lung nodules and improves in lung functionality.

e22540 Background: Epithelioid hemangioendothelioma (EHE) is an exceedingly rare soft tissue sarcoma subtype. EHE often presents as a multifocal/ multivisceral disease and its clinical behavior is highly unpredictable from indolent to very aggressive forms. A common choice in advanced patients is a close, active surveillance (AS), considering a treatment only in case of disease progression. Our retrospective study aimed to identify clinical features associated with a more aggressive behavior. Methods: Patients affected by advanced EHE treated in 6 centers of the Italian Rare Cancer Network were retrospectively reviewed. Diagnosis was confirmed by a sarcoma expert pathologist and molecular analysis was performed. Baseline clinical features were evaluated, including the presence of systemic symptoms (fever, weight loss, anorexia) and/or tumor related pain. Number of organs involved (1 vs > 1 and 1-2 vs > 2, mitotic index (< 2 vs ≥= 2 mitosis/10 high power fields - HPF). Results: 74 patients were identified (M:F = 42:32; mean age = 44 yrs - range = 16-81, median number of mitosis/10 HPF = 2 - range 0/8, systemic simptoms Y:N = 30:44; fever Y:N = 21:53; tumor related pain Y:N = 23:51; pleural effusion Y:N = 11:63). All patients had metastatic disease; 29 showed the involvement of one organ while 45 had multivisceral disease (18 of them > 2 viscera). At the time of diagnosis, all patients were naive from any systemic therapy and underwent exclusive AS. At a median FU of 32 months (range: 3-212), 48 (65%) patients progressed while 26 (35%) remained stable. No spontaneous regressions were observed. Median PFS was 30 months (range 2-115). Median OS was 54 months (range 3-151). Age, gender, mitotic index, number of involved organs, anorexia and weight loss did not correlate with median PFS (m-PFS). Fever correlated with shorter m-PFS (8 vs 45 months, P= 0.004), as well as pain (10 vs 42 months, P= 0.02) and the presence of pleural effusion (5 vs 46 months, P= 0.0001). In addition, fever and pleural effusion correlated with a shorter m-OS, respectively 29 vs 60 months (P = 0.03) and 11 vs 77 months (P < 0.001). The presence of pain corresponded to a not significant worse m-OS (39 vs 54 months, P= 0.16). Conclusions: Despite the small number of cases, this retrospective study suggests that in advanced EHE patients the presence of fever and/or tumor related pain and/or of pleural effusion can be associated with a more aggressive clinical behavior. Pleural effusion seems to be associated with the worse outcome, with a m-OS of 12 months. These data are worth confirming on a larger patient population.

11065 Background: EHE is an exceedingly rare soft tissue sarcoma (STS) with no active standard treatment available in advanced patients (pts). We already reported on the activity of sirolimus in a retrospective series of 18 EHE treated within the RTR. We herein update this series on a longer follow-up in a larger number of pts. Methods: Adult pts affected by an advanced, progressive and centrally confirmed EHE treated with sirolimus within the RTR from 2006 to 2018 were retrospectively reviewed. Sirolimus was administered at the starting dose of 5 mg/day, until toxicity or progression. Sirolimus dose was adjusted according to plasma levels (target: 15–20 ng/dL). Response was assessed by RECIST 1.1. Survival was estimated by Kaplan-Meier method. Results: 33 patients were retrospectively identified (median age = 47 years, female = 20 (60%), male = 13 (40%); pretreated = 8, naïve = 25; presence of pleural effusion at baseline = 6). All patients had metastatic disease and evidence of disease progression before starting sirolimus. Mean sirolimus daily dose was 5 mg (range 2-10). 9 pts are still on therapy, 24 stopped sirolimus (13 progression, 5 toxicity, 6 other). 31 pts were evaluable for response (2 pts too early). Best RECIST response was: 1 (3.2%), PR, 26 (83.8%) SD, 4 (12.9%) progression. At a 14-mo median FU, median PFS (m-PFS) was 12.3 mos (range 8–15) and median OS (m-OS) was 19 mos (range 1–40). Pleural effusion correlated with a short m-PFS (3.4 vs 14.3 mos in patients without pleural effusion, p = 0.006) and m-OS (10.6 vs 40 mos in patients without pleural effusion, p 24 mos was 23%, with 54 % being alive. Conclusions: We selected pts with advanced EHE with clear evidence of disease progression. This singles out a subgroup of EHE pts with a bad prognosis. Prognosis was shown to be exceedingly bad when there was evidence of serosal effusion, and sirolimus was not effective. Though in an uncontrolled setting, apparently sirolimus is able to slightly prolong PFS and, above all, to allow mid-term freedom of progression in roughly 25% of pts.

Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration.One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded.Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population.Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

11062 Background: Extraskeletal myxoid chondrosarcoma (EMC) is an exceedingly rare sarcoma, marked by a specific translocation involving the gene NR4A3 that can be rearranged with different partners. Preliminary retrospective data suggest that sunitinib is active, but no formal prospective studies are available. We report on a multicentric European prospective, investigator-driven, Phase 2 study on pazopanib (P) in NR4A3+ advanced EMC patients (pts), carried out by the Spanish, Italian and French Sarcoma groups. Methods: From June 2014 to November 2016, 24 advanced EMC pts entered this study (median age: 64 yrs - disease extent: metastatic 77%, locally advanced 23% - prior medical treatment: 18 (86%) naive; 2 (9%) 1 line, 1 (5%) > 1 line). Path diagnosis and NR4A3 rearrangement (FISH and/or real-time PCR analysis) were centrally confirmed. Pts received P 800 mg/day (relative dose intensity = 0,82%, 658 mg/day), until progression or toxicity. The primary study end-point was response rate as per RECIST 1.1. Secondary end-points were overall survival, progression-free survival (PFS), clinical benefit rate (CBR) (RECIST CR+PR+SD≥6mos). An exploratory evaluation of the correlation between the rearrangement subtype and the outcome is ongoing. Results: 20/24 pts were evaluable for response (1 early death; 3 too early). One patient (5%) had a partial response, 17 (75%) stable disease, 2 (10%) progression as their best RECIST responses. At the time of this analysis, 12 pts were still under treatment, while 12 interrupted P (10 progression, 1 toxicity, 1 other). At a 13-month median follow-up, the median PFS was 13 months (range 1.6-25.1), with 29% pts progression-free at 18 months and a 65% CBR. Median OS was not reached. Conclusions: This Phase 2 study is formally negative since the target of at least 3/21 RECIST responses was not reached. However, looking at PFS, P was associated with a prolonged disease stabilization in a significant proportion of pts. This suggests to further explore the use of P in EMC. Clinical trial information: NCT02066285.

We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient’s clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma.

Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant-a neurokinin receptor inhibitor-for management of severe pruritus induced by biological drugs.In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552.Median VAS in the refractory group was 8·00 (95% CI 7·93-8·57) at baseline and 1·00 (0·00-2·00) after 1 week of treatment with aprepitant (p0·0001). In the naive group, VAS score was 8·00 (7·43-8·37) at baseline and 0·00 (0·06-1·08) after 1 week of treatment (p0·0001). 41 (91%) patients responded to aprepitant (ie, had a50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred.Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials.None.

11578Background: ES is a rare soft tissue sarcoma with two variants, i.e., the proximal and the distal. Retrospective data on the activity of anthracycline- and G-based regimens are available. EZH2...

e23547Background: EMC is an extremely rare soft tissue sarcoma, marked by a translocation involving NR4A3 gene. EMC are usually indolent and generally are moderately sensitive to anthracycline-base...

11561Background: EMC is a rare sarcoma mostly originating from soft tissues. EMC carries a specific translocation, involving NR4A3, which is fused more often with EWSR1 and less frequently with oth...

Soft tissue sarcomas are rare mesenchymal tumors accounting for1% of all adult neoplasia. In the last decade, locally advanced and metastatic soft tissue sarcoma have been managed only through surgery, radiotherapy and standard chemotherapy (mainly based on anthracycline and ifosfamide). Despite the efforts, overall 5-year survival rate in patients with soft tissue sarcomas of all stages remains only 50 - 60%.In the present article, all the main new molecules under clinical evaluation for the treatment of soft tissue sarcoma are revised by describing the mechanism of action, the biological rationale of their use in sarcoma and by reporting the available data about safety and efficacy, up to 2009.A brief summary of the standard treatments available at the moment and a complete analysis of the state of art about the development of new target therapies in the management of soft tissue sarcoma.The identification of new biological therapies that target soft tissue sarcoma tumorigenesis key points seems to offer a real opportunity of improving the prognosis of this often aggressive disease. In this sense, the best management for soft tissue sarcoma patients is in a clinical trial and participation in clinical trials should be encouraged.

Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.

Background Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 , a key negative regulator of T-cell activation approved by the Food and Drug Administration as of March 2011 for the treatment of metastatic melanoma. As a result of the up-regulation of the immune system, several immune-mediated adverse effects have been reported including colitis, dermatitis, hepatitis and rarely hypophysitis. The most frequent immune-mediated adverse effects described in literature include gastrointestinal toxicity such as diarrhea, colitis and case of colitis and ileitis. Case presentation In this paper we report an interesting case of immune-mediate ileitis without colitis in a 54 years old woman with metastatic melanoma treated with ipilimumab. We also discuss about case management and the possible pathological mechanisms considering also previous reports. Conclusions The aim of this article is to support further investigations concerning epigenetic and genetic analysis in order to personalize biological therapy and to reduce immune related adverse events observed after ipilimumab administration.

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